JP5926616B2 - Aging inhibitor - Google Patents
Aging inhibitor Download PDFInfo
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- JP5926616B2 JP5926616B2 JP2012122773A JP2012122773A JP5926616B2 JP 5926616 B2 JP5926616 B2 JP 5926616B2 JP 2012122773 A JP2012122773 A JP 2012122773A JP 2012122773 A JP2012122773 A JP 2012122773A JP 5926616 B2 JP5926616 B2 JP 5926616B2
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- resorcinol
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- aging
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Description
本発明は、老化の抑制に関する。 The present invention relates to suppression of aging.
ヒトを含む動物においては、加齢とともに個体の機能低下、例えば、視力または聴力の低下、運動能力の低下、免疫機能の低下、記憶障害、生体内の各臓器の機能低下などが引き起こされる。このような個体の機能低下を老化と称する。老化は、個体の様々な組織や器官で徐々に進行する多面的な現象である。老化が進行すると、個体はその恒常性を維持することができなくなり、最終的には死に到る。 In animals including humans, the function of an individual decreases with age, for example, a decrease in visual acuity or hearing, a decrease in motor ability, a decrease in immune function, memory impairment, and a decrease in function of each organ in a living body. Such a decrease in function of the individual is called aging. Aging is a multifaceted phenomenon that gradually progresses in various tissues and organs of an individual. As aging progresses, the individual can no longer maintain its homeostasis and eventually die.
現在、先進諸国では、医療技術の発達によって人々の寿命そのものは顕著に延長しているが、しかしその一方で、高齢者らは、老化に伴う心身の機能低下により生活に支障が生じたり、様々な疾患に罹患したりするなどの問題を抱えている。高齢者らのための福祉や医療の費用の増加は、先進諸国における深刻な問題となっている。したがって、個体の恒常性を維持し、老化に伴う心身の機能低下や疾患を引き起こすことなく寿命を延長させることができれば、福祉や医療費の抑制および個人のQOL（Quality of life）の観点から有用である。 Currently, in developed countries, people's life expectancy has been significantly extended due to the development of medical technology, but on the other hand, elderly people suffer from various problems such as impaired life due to deterioration of mental and physical functions accompanying aging. Have problems such as suffering from various diseases. Increasing welfare and medical costs for the elderly are a serious problem in developed countries. Therefore, if the individual's homeostasis can be maintained and the lifespan can be extended without causing deterioration of mental and physical functions and diseases associated with aging, it is useful from the viewpoint of welfare and medical expenses control and individual quality of life (QOL). It is.
老化を抑制しまたは寿命を延長する効果を有する薬剤として、いくつかの化合物がこれまでに報告されている。例えば、ワインに含まれているポリフェノールの１種であるレスベラトロールが、高カロリー食を摂取したマウスの寿命を延長させることができることが報告されている（非特許文献１）。しかしながら、より効果の高い老化抑制剤の開発が所望されている。 Several compounds have been reported so far as agents that have the effect of inhibiting aging or extending lifespan. For example, it has been reported that resveratrol, which is a kind of polyphenol contained in wine, can extend the life of mice that have ingested a high-calorie diet (Non-patent Document 1). However, development of a more effective aging inhibitor is desired.
サーチュイン遺伝子は、その活性化により生物の寿命の延長に貢献することが報告されている遺伝子である。サーチュイン遺伝子は、長寿遺伝子または抗老化遺伝子とも呼ばれている。サーチュイン遺伝子は、酵母のＳｉｒ２や哺乳類のＳＩＲＴ１〜７等が知られているが、タンパク質サーチュイン（Ｓｉｒｔｕｉｎ）をコードしている。サーチュインは、ＮＡＤ依存的ヒストン脱アセチル化酵素として働き、ヒストンやｐ５３等の転写因子上のアセチル化タンパク質のアセチル基を脱離する。サーチュイン遺伝子が活性化されると、サーチュイン発現が上昇し、その結果様々な遺伝子の発現が調節されることで、寿命が延長すると考えられている（非特許文献２）。サーチュイン遺伝子の活性化による寿命延長効果は、酵母（非特許文献３、４）、線虫（非特許文献５）、ショウジョウバエ（非特許文献６）、マウス（非特許文献７）で報告されている。 A sirtuin gene is a gene that has been reported to contribute to the extension of the lifespan of an organism through its activation. Sirtuin genes are also called longevity genes or anti-aging genes. Sirtuin genes such as yeast Sir2 and mammalian SIRT1-7 are known, and encode a protein sirtuin. Sirtuins act as NAD-dependent histone deacetylases and remove acetyl groups of acetylated proteins on transcription factors such as histones and p53. When a sirtuin gene is activated, sirtuin expression increases, and as a result, the expression of various genes is regulated, and it is considered that the life span is extended (Non-patent Document 2). The life extension effect by sirtuin gene activation has been reported in yeast (Non-patent Documents 3 and 4), nematodes (Non-patent Document 5), Drosophila (Non-patent Document 6), and mice (Non-patent Document 7). .
サーチュインの寿命延長効果は、サーチュイン発現の増加またはサーチュイン蛋白の活性化によってもたらされる、種々の作用によるものと考えられている。そのような作用としては、加齢による生理学的な機能低下を抑制する作用、（非特許文献８）、自己免疫による障害を回復する作用（非特許文献９）、テロメア遺伝子の不具合に起因する細胞増殖の不具合を回復する作用、神経変性に起因する障害（例えば、パーキンソン病、アルツハイマー病、ハンチントン病、筋萎縮性側索硬化症）を回復する作用、脳における神経栄養因子遺伝子の機能低下を回復し、学習、記憶能力を改善する作用（非特許文献１０）等が考えられる。 It is believed that the sirtuin prolongation effect is due to various effects brought about by increased sirtuin expression or activation of sirtuin proteins. Such actions include an action that suppresses physiological functional decline due to aging (Non-patent Document 8), an action that recovers damage caused by autoimmunity (Non-Patent Document 9), and a cell that is caused by a malfunction of the telomere gene. Actions to restore proliferative defects, actions to recover from disorders caused by neurodegeneration (eg Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis), recovery of neurotrophic factor gene decline in the brain In addition, an effect of improving learning and memory ability (Non-Patent Document 10) can be considered.
サーチュインを活性化または老化を抑制する因子としては、カロリー制限やレスベラトロールが以前より知られている（非特許文献２、４等）。さらに最近、レスベラトロールよりも強いサーチュイン活性化作用を有する化合物として、グネツム科植物メリンジョの実もしくは種子の抽出物またはグネチンＣ（特許文献１）、およびε−ビニフェリン（特許文献２）が開示された。 As factors that activate sirtuins or suppress aging, caloric restriction and resveratrol have been known (Non-Patent Documents 2, 4, etc.). More recently, as a compound having a sirtuin activating action stronger than that of resveratrol, an extract of a fruit or seed of a gnetum plant, or gnetin C (Patent Document 1), and ε-viniferin (Patent Document 2) are disclosed. It was.
アルキルレゾシノールは、小麦やライ麦などの多くの植物や菌類に含まれている化合物である。アルキルレゾシノールは、腸内炭水化物加水分解酵素の阻害剤（特許文献３）として知られ、またライ麦の栄養阻害効果への関与が示唆されている（非特許文献１１）。しかし、アルキルレゾシノールがサーチュイン蛋白を直接活性化することや老化抑制に貢献することはこれまで知られていなかった。 Alkyl resorcinol is a compound contained in many plants and fungi such as wheat and rye. Alkyl resorcinol is known as an inhibitor of intestinal carbohydrate hydrolase (Patent Document 3) and has been suggested to be involved in the nutritional inhibitory effect of rye (Non-Patent Document 11). However, it has not been known so far that alkylresinol directly activates sirtuin proteins and contributes to aging inhibition.
本発明は、生体の恒常性維持に有効であり、個体の老化を防止して寿命を延長することができ、且つ長期間継続的に摂取しても安全な素材の提供を課題とする。 It is an object of the present invention to provide a material that is effective in maintaining the homeostasis of a living body, can prevent the aging of an individual, extend the life span, and is safe even if ingested continuously for a long period of time.
本発明者は、上記課題を解決すべく鋭意研究を重ねた結果、特定の構造を有するアルキルレゾルシノール類が、サーチュイン活性化作用および老化抑制作用を有し、個体の寿命を延長させる効果をもたらすことを見出し、本発明を完成した。 As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that alkylresorcinols having a specific structure have a sirtuin activating action and an aging-inhibiting action, and an effect of extending the life of an individual. The present invention has been completed.
すなわち、本発明は、下記式（Ｉ）：
で表される化合物を有効成分とするサーチュイン活性化剤を提供する。
また、本発明は、上記式（Ｉ）で表される化合物を有効成分とする老化抑制剤を提供する。
That is, the present invention provides the following formula (I):
The sirtuin activator which uses the compound represented by these as an active ingredient is provided.
Moreover, this invention provides the aging inhibitor which uses the compound represented by the said formula (I) as an active ingredient.
本発明のサーチュイン活性化剤および老化抑制剤によれば、生体の機能や恒常性を維持したまま、寿命を延長させることができる。また当該本発明の剤によれば、個体の老化を抑制し、その寿命を延長させることができる。さらに、当該本発明の剤の有効成分であるアルキルレゾルシノールは、穀物に含まれる成分であるため、連続的に服用しても有害な副作用がなく、安全性が高い。 According to the sirtuin activator and the aging inhibitor of the present invention, the lifespan can be extended while maintaining the functions and homeostasis of the living body. Moreover, according to the agent of the present invention, aging of an individual can be suppressed and its life can be extended. Furthermore, since alkylresorcinol, which is an active ingredient of the agent of the present invention, is an ingredient contained in cereals, there are no harmful side effects even when taken continuously, and safety is high.
本発明のサーチュイン活性化剤または老化抑制剤は、下記式（Ｉ）で表されるアルキルレゾルシノール化合物（本明細書において以下、式（Ｉ）化合物とも称する）を有効成分とする。 The sirtuin activator or aging inhibitor of the present invention comprises an alkylresorcinol compound represented by the following formula (I) (hereinafter, also referred to as formula (I) compound) as an active ingredient.
式（Ｉ）中、Ｒ1は、飽和または不飽和の直鎖または分岐鎖アルキル基を表す。Ｒ1で表されるアルキル基の炭素数は、制限されるものではないが、好ましくは１〜２３、より好ましくは３〜２３、さらに好ましくは５〜２１、なお好ましくは５、７、９、１１、１３、１５、１７、１９および２１である。 In formula (I), R 1 represents a saturated or unsaturated linear or branched alkyl group. The number of carbon atoms of the alkyl group represented by R 1 is not limited, but is preferably 1 to 23, more preferably 3 to 23, still more preferably 5 to 21, still more preferably 5, 7, 9, 11, 13, 15, 17, 19 and 21.
好ましくは、Ｒ1は、飽和または不飽和の直鎖アルキル基であり、より好ましくは飽和直鎖アルキル基である。Ｒ1で表される飽和直鎖アルキル基の例としては、メチル、ｎ−プロピル、ｎ−ペンチル、ｎ−ヘプチル、ｎ−ノニル、ｎ−ウンデシル、ｎ−トリデシル、ｎ−ペンタデシル、ｎ−ヘプタデシル、ｎ−ノナデシル、ｎ−ヘンイコシル、ｎ−トリコシルなどが挙げられる。
Ｒ1で表される不飽和直鎖アルキル基の不飽和結合の位置や数は、特に制限されるものではない。当該不飽和直鎖アルキル基の例としては、上述した飽和直鎖アルキル基の炭素鎖上の任意の位置に不飽和結合を有するアルキル基が挙げられる。
Ｒ1で表される飽和または不飽和の分岐鎖アルキル基の分岐の位置や数、および不飽和結合の位置や数は、特に制限されるものではない。
Preferably, R 1 is a saturated or unsaturated linear alkyl group, more preferably a saturated linear alkyl group. Examples of the saturated linear alkyl group represented by R 1 include methyl, n-propyl, n-pentyl, n-heptyl, n-nonyl, n-undecyl, n-tridecyl, n-pentadecyl, n-heptadecyl, Examples include n-nonadecyl, n-henicosyl, n-tricosyl and the like.
The position and number of unsaturated bonds of the unsaturated linear alkyl group represented by R 1 are not particularly limited. Examples of the unsaturated linear alkyl group include an alkyl group having an unsaturated bond at an arbitrary position on the carbon chain of the above-described saturated linear alkyl group.
The position and number of branches of the saturated or unsaturated branched alkyl group represented by R 1 and the position and number of unsaturated bonds are not particularly limited.
式（Ｉ）中、Ｒ2は、水素原子またはメチル基を表し、好ましくは水素原子である。 In formula (I), R 2 represents a hydrogen atom or a methyl group, preferably a hydrogen atom.
式（Ｉ）中、好ましくはＲ1はＲ2のパラ位に位置する。 In formula (I), R 1 is preferably located in the para position of R 2 .
上記式（Ｉ）化合物の好ましい例としては、以下が挙げられる。
５−ペンチルレゾルシノール［オリベトールまたは１，３−ジヒドロキシ−５−ｎ−ペンチルベンゼン（Ｃ５：０）］
５−ヘプチルレゾルシノール［または１，３−ジヒドロキシ−５−ｎ−ヘプチルベンゼン（Ｃ７：０）］
５−ノニルレゾルシノール［または１，３−ジヒドロキシ−５−ｎ−ノニルベンゼン（Ｃ９：０）］
５−ウンデシルレゾルシノール［または１，３−ジヒドロキシ−５−ｎ−ウンデシルベンゼン（Ｃ１１：０）］
５−トリデシルレゾルシノール［または１，３−ジヒドロキシ−５−ｎ−トリデシルベンゼン（Ｃ１３：０）］
５−ペンタデシルレゾルシノール［または１，３−ジヒドロキシ−５−ｎ−ペンタデシルベンゼン（Ｃ１５：０）］
５−ヘプタデシルレゾルシノール［または１，３−ジヒドロキシ−５−ｎ−ヘプタデシルベンゼン（Ｃ１７：０）］
５−ノナデシルレゾルシノール［または１，３−ジヒドロキシ−５−ｎ−ノナデシルベンゼン（Ｃ１９：０）］
５−ヘンイコシルレゾルシノール［または１，３−ジヒドロキシ−５−ｎ−ヘンイコシルベンゼン（Ｃ２１：０）］
５−トリコシルレゾルシノール［または１，３−ジヒドロキシ−５−ｎ−トリコシルベンゼン（Ｃ２３：０）］
Preferred examples of the compound of formula (I) include the following.
5-pentylresorcinol [olibutol or 1,3-dihydroxy-5-n-pentylbenzene (C5: 0)]
5-heptylresorcinol [or 1,3-dihydroxy-5-n-heptylbenzene (C7: 0)]
5-nonylresorcinol [or 1,3-dihydroxy-5-n-nonylbenzene (C9: 0)]
5-undecylresorcinol [or 1,3-dihydroxy-5-n-undecylbenzene (C11: 0)]
5-tridecylresorcinol [or 1,3-dihydroxy-5-n-tridecylbenzene (C13: 0)]
5-pentadecylresorcinol [or 1,3-dihydroxy-5-n-pentadecylbenzene (C15: 0)]
5-heptadecylresorcinol [or 1,3-dihydroxy-5-n-heptadecylbenzene (C17: 0)]
5-nonadecylresorcinol [or 1,3-dihydroxy-5-n-nonadecylbenzene (C19: 0)]
5-Henicosyl resorcinol [or 1,3-dihydroxy-5-n-henicosylbenzene (C21: 0)]
5-tricosylresorcinol [or 1,3-dihydroxy-5-n-tricosylbenzene (C23: 0)]
上記式（Ｉ）化合物は、市販品を入手することができ、また、植物から常法により抽出することができる。市販品は、ＲｅｓｅａＣｈｅｍ ＧｍｂＨ、ＳＩＧＭＡ−ＡＬＤＲＩＣＨなどから購入することができる。さらに上記式（Ｉ）の化合物は、国際公開ＷＯ２００７／７７７７０号パンフレットなどを参考にして、化学合成法により製造することもできる。 The said formula (I) compound can obtain a commercial item, and can be extracted from a plant by a conventional method. Commercially available products can be purchased from ResearchChem GmbH, SIGMA-ALDRICH, and the like. Furthermore, the compound of the said formula (I) can also be manufactured by a chemical synthesis method with reference to international publication WO2007 / 77770 pamphlet etc.
式（Ｉ）化合物を含有する植物としては、ウルシ科、イチョウ科、ヤマモガシ科、ヤブコウジ科、サクラソウ科、ニクズク科、アヤメ科、サトイモ科、マメ科、イネ科などに属する植物、およびキク科のヨモギが挙げられる。これらの植物の中でも、イネ科植物は、可食部にアルキルレゾルシノールを含有しているため、式（Ｉ）化合物の原料として好ましい。イネ科植物の中でも、小麦およびライ麦がより好ましい。さらに、小麦およびライ麦の糟糠類および全穀粒は、式（Ｉ）化合物を豊富に含有しているため（全粒質量の０．０１５〜０．３質量％程度）、式（Ｉ）化合物の原料のさらに好適な例として挙げられる。イネ科植物の発酵物もまた、式（Ｉ）化合物の原料の好ましい例として挙げられる。 Plants containing the compound of formula (I) include urushiaceae, ginkgoaceae, caterpillaraceae, scorpionaceae, primrose, asteraceae, iris family, taro family, legume family, gramineous family, Artemisia is mentioned. Among these plants, gramineous plants are preferable as a raw material for the compound of formula (I) because they contain alkylresorcinol in the edible part. Among grasses, wheat and rye are more preferable. Furthermore, wheat and rye moss and whole grains contain abundantly the compound of formula (I) (about 0.015 to 0.3% by mass of the total grain mass), so that of the compound of formula (I) A more preferable example of the raw material is mentioned. A fermented product of the grass family is also mentioned as a preferred example of the raw material of the compound of formula (I).
上記植物からの式（Ｉ）化合物の抽出方法としては、上記植物またはその発酵物を常圧または加圧下で室温または加温した抽出溶媒中に必要に応じて攪拌しながら浸漬させる方法、還流抽出法、などが挙げられる。上記植物は、抽出溶媒に添加される前に、必要に応じて切断、粉砕、圧搾、乾燥、またはそれらの組み合わせにかけられてもよい。 As a method for extracting the compound of formula (I) from the above-mentioned plant, a method of immersing the above-mentioned plant or a fermented product thereof in an extraction solvent heated at room temperature or under normal pressure or with stirring as necessary, reflux extraction Law, etc. The plant may be subjected to cutting, crushing, pressing, drying, or combinations thereof as needed before being added to the extraction solvent.
上記抽出溶媒としては、メタノール、エタノール、ｎ−プロパノール、イソプロパノールおよびｎ−ブタノールなどの低級アルコール、および１，３−ブチレングリコール、プロピレングリコール、グリセリンなどの多価アルコールなどの室温で液体であるアルコール類；ジエチルエーテルおよびプロピルエーテルなどのエーテル類；酢酸ブチルおよび酢酸エチルなどのエステル類；アセトンおよびエチルメチルケトンなどのケトン類；ヘキサン；ならびにクロロホルム、などの有機溶媒が挙げられる。これらの溶媒は単独で用いてもよいし、２種以上を組み合わせて用いてもよい。上記の溶媒のうち、操作性や環境に対する影響などの点から、室温で液体であるアルコール類、例えば、炭素原子数１〜４の低級アルコールを用いるのが好ましく、残留溶媒による安全性の観点からはエタノールを用いるのがより好ましい。 Examples of the extraction solvent include alcohols that are liquid at room temperature, such as lower alcohols such as methanol, ethanol, n-propanol, isopropanol, and n-butanol, and polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, and glycerin. Ethers such as diethyl ether and propyl ether; esters such as butyl acetate and ethyl acetate; ketones such as acetone and ethyl methyl ketone; hexane; and organic solvents such as chloroform. These solvents may be used alone or in combination of two or more. Of the above solvents, alcohols that are liquid at room temperature, for example, lower alcohols having 1 to 4 carbon atoms, are preferably used from the viewpoint of operability and environmental impact, and from the viewpoint of safety due to residual solvents. More preferably, ethanol is used.
上記有機溶媒には、さらに水性成分が含まれている含水有機溶媒も包含され得る。抽出効率を高く保持する観点からは、上記含水有機溶媒中の水性成分の含有量は、通常５０体積％以下、好ましくは３０体積％以下、より好ましくは２０体積％以下であるのが望ましい。含水有機溶媒としては、好ましくは上記のような室温で液体であるアルコール類にさらに水性成分が含まれている含水アルコール、より好ましくは含水エタノールが挙げられる。 The organic solvent may further include a water-containing organic solvent containing an aqueous component. From the viewpoint of maintaining high extraction efficiency, the content of the aqueous component in the water-containing organic solvent is usually 50% by volume or less, preferably 30% by volume or less, more preferably 20% by volume or less. Examples of the water-containing organic solvent include a water-containing alcohol in which an aqueous component is further contained in the alcohol that is liquid at room temperature as described above, and more preferably water-containing ethanol.
抽出のための温度および時間は、使用する抽出溶媒の種類や抽出条件などによって適宜設定することができるが、抽出温度は２〜１００℃、抽出時間は３０分〜６０時間程度とするのが好ましい。抽出溶媒の量は、上記イネ科植物またはその発酵物１００質量部に対し、好ましくは２００〜２０００質量部程度にすればよい。 The temperature and time for extraction can be appropriately set depending on the type of extraction solvent used and the extraction conditions, but the extraction temperature is preferably 2 to 100 ° C. and the extraction time is preferably about 30 minutes to 60 hours. . The amount of the extraction solvent is preferably about 200 to 2000 parts by mass with respect to 100 parts by mass of the Gramineae plant or its fermented product.
次いで、抽出液および残渣を含む混合物を、必要に応じて濾過または遠心分離などに供し、残渣である固形成分を除去して、式（Ｉ）化合物を含む抽出物を得る。なお、除去した固形成分を再度、抽出溶媒を用いた抽出操作に供することもでき、さらにこの操作を何回か繰り返してもよい。また得られた抽出物を、さらに液体クロマトグラフィー等により精製することが好ましい。このようにして得られた式（Ｉ）化合物を含む抽出物は、そのまま、または必要に応じて、さらに濃縮、凍結乾燥、熱風乾燥、粉砕、粉末化、分級、希釈、加水混合などの処理を施した後、本発明に使用することができる。 Next, the mixture containing the extract and the residue is subjected to filtration or centrifugation as necessary, and the solid component that is the residue is removed to obtain an extract containing the compound of formula (I). It should be noted that the removed solid component can be subjected again to an extraction operation using an extraction solvent, and this operation may be repeated several times. The obtained extract is preferably further purified by liquid chromatography or the like. The extract containing the compound of formula (I) thus obtained is subjected to further treatment such as concentration, freeze-drying, hot-air drying, pulverization, pulverization, classification, dilution, and water mixing as it is or as necessary. Once applied, it can be used in the present invention.
式（Ｉ）化合物は、後述の実施例に示すように、サーチュイン蛋白ＳＩＲＴ１を活性化する作用を有し、また動物個体の寿命を延長する作用を有する。したがって、式（Ｉ）化合物は、サーチュイン活性化、寿命の延長、老化抑制、加齢とともに生じ得る疾患や状態の予防もしくは改善、等のために使用することができる。 The compound of formula (I) has an action of activating the sirtuin protein SIRT1 and an action of extending the life of an individual animal, as shown in the Examples described later. Therefore, the compound of formula (I) can be used for sirtuin activation, prolongation of life span, suppression of aging, prevention or improvement of diseases and conditions that may occur with aging, and the like.
従って、本発明は、式（Ｉ）化合物を有効成分とするサーチュイン活性化剤を提供する。また本発明は、式（Ｉ）化合物を有効成分とする老化抑制剤を提供する。また本発明は、式（Ｉ）化合物を有効成分とする寿命延長剤を提供する。また本発明は、式（Ｉ）化合物を有効成分とする、加齢とともに生じ得る疾患や状態の予防もしくは改善剤を提供する。一実施形態において、上記の剤は、式（Ｉ）化合物から本質的に構成されていてもよい。別の実施形態において、上記の剤は、式（Ｉ）で示される化合物を含有する植物抽出物、好ましくは小麦またはライ麦抽出物を含む。 Accordingly, the present invention provides a sirtuin activator comprising a compound of formula (I) as an active ingredient. The present invention also provides an aging inhibitor comprising a compound of formula (I) as an active ingredient. The present invention also provides a life extending agent comprising a compound of formula (I) as an active ingredient. The present invention also provides a preventive or ameliorating agent for a disease or condition that can occur with aging, comprising a compound of formula (I) as an active ingredient. In one embodiment, the agent may consist essentially of a compound of formula (I). In another embodiment, the agent comprises a plant extract containing a compound of formula (I), preferably a wheat or rye extract.
本明細書において、「老化」としては、加齢とともに生じる動物個体の生理機能低下、例えば、視力または聴力の低下、運動能力の低下、恒常性維持機能の低下、免疫機能の低下、記憶障害等の脳機能の低下、生体内の各臓器の機能低下などが挙げられる。本明細書において、「老化抑制」とは、上記加齢とともに生じる動物個体の生理機能低下の抑制、当該生理機能低下に起因する疾患や障害の抑制、および老化の進行による個体の死の抑制（すなわち、寿命の延長）を含む概念である。
また本明細書において「加齢とともに生じ得る疾患や状態」としては、上述の加齢とともに生じる動物個体の生理機能低下に起因する種々の疾患や状態、例えば、自己免疫による障害、テロメア遺伝子の不具合に起因する細胞増殖の不具合、神経変性に起因する障害（例えば、パーキンソン病、アルツハイマー病、ハンチントン病、筋萎縮性側索硬化症）、脳における神経栄養因子遺伝子の機能低下、学習、記憶能力の低下等が挙げられる。
In the present specification, “aging” refers to a decrease in the physiological function of an animal individual that occurs with aging, for example, a decrease in visual acuity or hearing, a decrease in motor ability, a decrease in homeostatic function, a decrease in immune function, memory impairment, etc. Decrease in brain function, and decrease in function of each organ in the living body. In the present specification, “aging suppression” refers to suppression of decrease in physiological function of an animal individual that occurs with the above-mentioned aging, suppression of diseases and disorders caused by the decrease in physiological function, and suppression of death of an individual due to progress of aging ( That is, it is a concept that includes the extension of life.
In addition, in the present specification, the “disease or condition that can occur with aging” refers to various diseases and conditions that are caused by the above-described decrease in physiological function of the animal individual that occurs with aging, for example, disorders due to autoimmunity, telomere gene defects Cell proliferation defects caused by neuropathy, disorders caused by neurodegeneration (eg Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis), impaired neurotrophic factor gene function in the brain, learning, memory ability A drop etc. are mentioned.
式（Ｉ）化合物は、食経験が豊富な小麦やライムギに含まれている成分であることから、長期間継続的摂取しても生体に有害な作用をもたらす懸念が少ない、安全な化合物である。したがって、式（Ｉ）化合物は、健常者や成人だけでなく、本発明を特に必要とする高齢者または病弱者にも、安全且つ継続的に接種され得る。したがって、式（Ｉ）化合物は、ヒトまたは動物用の医薬、飲食品、飼料等として、あるいはそれらを製造するために有用である。 Since the compound of formula (I) is a component contained in wheat and rye with abundant dietary experience, it is a safe compound with little fear of causing harmful effects on the living body even if taken continuously for a long period of time. . Therefore, the compound of the formula (I) can be safely and continuously inoculated not only for healthy persons and adults but also for elderly persons or sick persons who particularly need the present invention. Accordingly, the compound of formula (I) is useful as a human or animal medicine, food and drink, feed, or the like, or for producing them.
よって、本発明はまた、式（Ｉ）化合物を有効成分として含有する医薬、飲食品、および飼料を提供する。当該医薬、飲食品、および飼料は、サーチュイン活性化、寿命の延長、老化抑制、加齢とともに生じ得る疾患や状態の予防もしくは改善、等のために使用することができる。 Therefore, this invention also provides the pharmaceutical, food-drinks, and feed which contain a compound of Formula (I) as an active ingredient. The said medicine, food-drinks, and feed can be used for sirtuin activation, life extension, aging inhibition, prevention or improvement of diseases and conditions that may occur with aging, and the like.
上記医薬は、式（Ｉ）化合物を有効成分として含有するサーチュイン活性化薬、寿命延長薬、老化抑制薬、加齢とともに生じ得る疾患や状態の予防もしくは改善薬、等であり得る。上記医薬の剤型としては、例えば、錠剤、カプセル剤、顆粒剤、散剤、シロップ剤、ドライシロップ剤、液剤、懸濁剤等の経口剤、および吸入剤、経皮製剤、坐剤等の経腸製剤、点滴剤、注射剤等の非経口剤が挙げられる。上記液剤、懸濁剤等の液体製剤は、服用直前に水または他の適当な媒体に溶解または懸濁する形であってもよく、上記錠剤および顆粒剤は周知の方法でその表面をコーティングされていてもよい。また上記注射剤は、必要に応じて溶解補助剤を含む式（Ｉ）化合物の滅菌蒸留水または滅菌生理食塩水の溶液であり得る。 The medicament may be a sirtuin activator containing a compound of formula (I) as an active ingredient, a life extension agent, an aging inhibitor, a preventive or ameliorating agent for diseases and conditions that may occur with aging, and the like. Examples of the pharmaceutical dosage form include oral preparations such as tablets, capsules, granules, powders, syrups, dry syrups, liquids and suspensions, and enteral preparations such as inhalants, transdermal preparations, and suppositories. Examples include parenteral preparations such as preparations, instillations, and injections. Liquid preparations such as the above-mentioned liquids and suspensions may be in the form of being dissolved or suspended in water or other suitable medium immediately before taking, and the tablets and granules are coated on the surface by a well-known method. It may be. The injection may be a solution of the compound of formula (I) in sterile distilled water or sterile physiological saline containing a solubilizing agent as necessary.
上記医薬は、有効成分である式（Ｉ）化合物に加えて、必要に応じて薬学的に許容される種々の担体、例えば賦形剤、安定化剤、その他の添加剤等を含有していてもよく、あるいは、さらに他の薬効成分、例えば各種ビタミン類、ミネラル類、生薬等を含有していてもよい。当該医薬は、式（Ｉ）化合物またそれを含有する植物抽出物に、上述の担体および他の薬効成分を配合し、常法に従って製造することができる。 In addition to the compound of formula (I) which is an active ingredient, the medicament contains various pharmaceutically acceptable carriers, for example, excipients, stabilizers, other additives and the like as necessary. Alternatively, it may further contain other medicinal ingredients such as various vitamins, minerals, herbal medicines and the like. The said pharmaceutical can be manufactured in accordance with a conventional method by mix | blending the above-mentioned carrier and other medicinal ingredients with the formula (I) compound or a plant extract containing it.
上記飲食品または飼料は、式（Ｉ）化合物を有効成分として含有し、且つサーチュイン活性化、寿命の延長、老化抑制、加齢とともに生じ得る疾患や状態の予防もしくは改善、等の効果を企図して、その旨を表示した健康食品、機能性飲食品、特定保健用飲食品、病者用飲食品、家畜、競走馬、鑑賞動物等のための飼料、ペットフード等であり得る。 The above-mentioned food or drink or feed contains the compound of formula (I) as an active ingredient, and intends effects such as sirtuin activation, life extension, aging inhibition, prevention or improvement of diseases and conditions that may occur with aging, etc. In addition, health food, functional food and drink, food and drink for specified health use, food and drink for the sick, livestock, racehorse, feed for appreciation animals, pet food, etc.
上記飲食品および飼料の形態は特に制限されず、式（Ｉ）化合物を配合できる全ての形態が含まれる。例えば当該形態としては、固形、半固形または液状であり得、あるいは、錠剤、チュアブル錠、粉剤、カプセル、顆粒、ドリンク、ゲル、シロップ、経管経腸栄養用流動食等の各種形態が挙げられる。 The form of the said food-drinks and feed is not restrict | limited in particular, All the forms which can mix | blend a formula (I) compound are contained. For example, the form may be solid, semi-solid or liquid, or various forms such as tablets, chewable tablets, powders, capsules, granules, drinks, gels, syrups, liquid foods for enteral nutrition. .
具体的な飲食品の形態の例としては、緑茶、ウーロン茶や紅茶等の茶飲料、コーヒー飲料、清涼飲料、ゼリー飲料、スポーツ飲料、乳飲料、炭酸飲料、果汁飲料、乳酸菌飲料、発酵乳飲料、粉末飲料、ココア飲料、アルコール飲料、精製水等の飲料、バター、ジャム、ふりかけ、マーガリン等のスプレッド類、マヨネーズ、ショートニング、クリーム、ドレッシング類、パン類、米飯類、麺類、パスタ、味噌汁、豆腐、牛乳、ヨーグルト、スープまたはソース類、菓子（例えばビスケットやクッキー類、チョコレート、キャンディ、ケーキ、アイスクリーム、チューインガム、タブレット）等が挙げられる。
上記飼料は上記飲食品とほぼ同様の組成や形態で利用できることから、本明細書における飲食品に関する記載は、飼料についても同様に当てはめることが出来る。
Specific examples of the form of food and drink include tea drinks such as green tea, oolong tea and tea, coffee drinks, soft drinks, jelly drinks, sports drinks, milk drinks, carbonated drinks, fruit juice drinks, lactic acid bacteria drinks, fermented milk drinks, Powdered beverages, cocoa beverages, alcoholic beverages, beverages such as purified water, butter, jam, sprinkles, margarine spreads, mayonnaise, shortening, cream, dressings, breads, cooked rice, noodles, pasta, miso soup, tofu, Examples include milk, yogurt, soup or sauce, confectionery (for example, biscuits and cookies, chocolate, candy, cake, ice cream, chewing gum, and tablet).
Since the said feed can be utilized by the composition and form substantially the same as the said food / beverage products, the description regarding the food / beverage products in this specification can be applied similarly to feed.
上記飲食品および飼料は、式（Ｉ）化合物またそれを含有する植物抽出物に飲食品や飼料の製造に用いられる他の飲食品素材、各種栄養素、各種ビタミン、ミネラル、アミノ酸、各種油脂、種々の添加剤（たとえば呈味成分、甘味料、有機酸等の酸味料、界面活性剤、ｐＨ調整剤、安定剤、酸化防止剤、色素、フレーバー）等を配合して、常法に従って製造することができる。あるいは、通常食されている飲食品または飼料に式（Ｉ）化合物またそれを含有する植物抽出物を配合することにより、本発明に係る飲食品または飼料を製造することができる。 The above food and drink and the formula (I) compound or a plant extract containing the compound, other food and drink materials used in the production of food and drink and feed, various nutrients, various vitamins, minerals, amino acids, various fats and oils, various And other additives (for example, flavoring ingredients, sweeteners, acidulants such as organic acids, surfactants, pH adjusters, stabilizers, antioxidants, pigments, flavors), etc. Can do. Or the food / beverage products or feed concerning this invention can be manufactured by mix | blending a formula (I) compound or the plant extract containing it with the food / beverage products or feed currently eaten normally.
上記医薬、飲食品または飼料における式（Ｉ）化合物の含有量は、所望のサーチュイン活性化効果、寿命延長効果、老化抑制効果等の効果が得られる量であればよく、医薬の剤型や食品の形態、投与または摂取する個体の種、症状、年齢、性別などに応じて適宜変更され得る。ヒトを対象とする場合、通常、式（Ｉ）化合物の好ましい投与量は、成人１人１日当たり０．０１〜１０ｇであり得る。当該１日投与量は、１回で投与されてもよいが、数回に分けて投与されてもよい。上記医薬の剤型もしくは投与レジメン、または上記飲食品もしくは飼料の形態は、当該投与量を適切に管理できるような形であることが望ましい。 The content of the compound of formula (I) in the above-mentioned medicine, food or drink or feed may be an amount that can provide the desired sirtuin activation effect, life extension effect, aging inhibitory effect, etc. The form may be appropriately changed depending on the type, symptom, age, sex, etc. of the individual to be administered or ingested. When targeting humans, the preferred dosage of the compound of formula (I) is usually 0.01 to 10 g per day per adult. The daily dose may be administered once, but may be divided into several times. The pharmaceutical dosage form or administration regimen, or the form of the food or drink or feed is preferably in a form that allows the dosage to be appropriately managed.
以下の実施例により本発明を具体的に説明するが、本発明はこれらの実施例に限定されるものではない。 The present invention will be specifically described by the following examples, but the present invention is not limited to these examples.
製造例１ 式（Ｉ）化合物を含有するライ麦抽出物の製造
ライ麦外皮２ｇを、マルチビーズショッカー（多検体細胞破砕機／ＭＢ３０１（Ｓ）：安井器械株式会社製）で粉砕した後、５倍量のエタノールを添加して、１５０ｒｐｍ、室温の条件で２時間振とう抽出し、次いで、３５００ｒｐｍ、室温の条件で１５分間遠心分離し、上清を遠心濃縮機で乾燥して、ライ麦外皮エタノール抽出物を得た。この抽出物を高速液体クロマトグラフィーを用いて精製し、分析したところ、１，３−ジヒドロキシ−５−ｎ−ペンタデシルベンゼン（Ｃ１５：０）、１，３−ジヒドロキシ−５−ｎ−ヘプタデシルベンゼン（Ｃ１７：０）、１，３−ジヒドロキシ−５−ｎ−ノナデシルベンゼン（Ｃ１９：０）、および１，３−ジヒドロキシ−５−ｎ−ヘンイコシルベンゼン（Ｃ２１：０）を合計で約８０％含有していた。
Production Example 1 Production of rye extract containing compound of formula (I) 2 g of rye husk was pulverized with a multi-bead shocker (multi-sample cell crusher / MB301 (S): manufactured by Yasui Kikai Co., Ltd.). Of ethanol, and extracted by shaking for 2 hours at 150 rpm and room temperature, then centrifuged for 15 minutes at 3500 rpm and room temperature, and the supernatant was dried with a centrifugal concentrator to obtain an extract of rye hull ethanol. Got. When this extract was purified and analyzed using high performance liquid chromatography, 1,3-dihydroxy-5-n-pentadecylbenzene (C15: 0), 1,3-dihydroxy-5-n-heptadecylbenzene was analyzed. (C17: 0), 1,3-dihydroxy-5-n-nonadecylbenzene (C19: 0), and 1,3-dihydroxy-5-n-henicosylbenzene (C21: 0) in a total of about 80 % Content.
試験例１ 式（Ｉ）化合物によるサーチュイン活性化−１
試験化合物として、１，３−ジヒドロキシ−５−ｎ−ヘプタデシルベンゼン（Ｃ１７：０）（ＲｅｓｅａＣｈｅｍ ＧｍｂＨ社より購入）を使用した。サーチュインＳＩＲＴ１の活性化を、ＳＩＲＴ１／Ｓｉｒ２ Ｄｅａｃｅｔｙｌａｓｅ Ｆｌｕｏｒｏｍｅｔｒｉｃ Ａｓｓａｙ Ｋｉｔ（サイクレックス社）を使用して以下に示す方法により測定した。エタノールにより各濃度に調整した試験化合物の溶液に、終濃度で５０ｍＭのＴｒｉｓ−ＨＣｌ（ｐＨ８．８）、０．５ｍＭのＤＴＴ、０．２５ｍＡＵ／ｍｌのＬｙｓｙｌｅｎｄｏｐｅｐｔｉｄａｓｅ、１μＭのＴｒｉｃｈｏｓｔａｔｉｎ Ａ、２００μＭのＮＡＤ、２０μＭの蛍光基質ペプチド、および０．０２Ｕ／ｍＬのＳＩＲＴ１酵素を添加混合した。対照として、試験化合物溶液の代わりにエタノールのみを添加した。当該混合物の蛍光を、２５℃にて６０分間、蛍光プレートリーダーにより、励起波長３５０ｎｍ、発光波長４５０ｎｍにてカイネティックス測定した。
Test Example 1 Sirtuin Activation-1 by Compound (I)
As a test compound, 1,3-dihydroxy-5-n-heptadecylbenzene (C17: 0) (purchased from ResearchChem GmbH) was used. The activation of sirtuin SIRT1 was measured by the method shown below using SIRT1 / Sir2 Decelacease Fluorometric Assay Kit (Cyclex). A solution of the test compound adjusted to each concentration with ethanol was added to a final concentration of 50 mM Tris-HCl (pH 8.8), 0.5 mM DTT, 0.25 mAU / ml lysylepteptidase, 1 μM Trichostatin A, 200 μM NAD, 20 μM fluorescent substrate peptide and 0.02 U / mL SIRT1 enzyme were added and mixed. As a control, ethanol alone was added instead of the test compound solution. The fluorescence of the mixture was measured at 25 ° C. for 60 minutes using a fluorescent plate reader at an excitation wavelength of 350 nm and an emission wavelength of 450 nm.
試験化合物（終濃度１０μＭ）によるＳＩＲＴ１活性化のカイネティックスカーブを図１に示す。対照と比べて、試験化合物による蛍光強度の変化の初速は増加していることから、試験化合物がＳＩＲＴ１酵素活性を直接的に活性化したことが確認された。 The kinetics curve of SIRT1 activation by the test compound (final concentration 10 μM) is shown in FIG. Compared to the control, the initial rate of change in fluorescence intensity by the test compound was increased, confirming that the test compound directly activated the SIRT1 enzyme activity.
試験例２ 式（Ｉ）化合物によるサーチュイン活性化−２
試験化合物として、オリベトール［１，３−ジヒドロキシ−５−ｎ−ペンチルベンゼン（Ｃ５：０）］（ＳＩＧＭＡ−ＡＬＤＲＩＣＨより購入）を使用し、試験例１と同様の手順で蛍光のカイネティックス測定を行い、ＳＩＲＴ１酵素活性を評価した。試験化合物の最終濃度は１、１０および１００μＭとした。反応時間１０００秒における、蛍光強度の対照（エタノール）に対する増加率を図２に示す。試験化合物により濃度依存的にＳＩＲＴ１酵素活性が増強されたことが示された。
Test Example 2 Sirtuin Activation-2 by Formula (I) Compound
As a test compound, olivetol [1,3-dihydroxy-5-n-pentylbenzene (C5: 0)] (purchased from SIGMA-ALDRICH) was used, and fluorescence kinetics was measured in the same procedure as in Test Example 1. And SIRT1 enzyme activity was evaluated. Final concentrations of test compounds were 1, 10 and 100 μM. The increase rate of the fluorescence intensity with respect to the control (ethanol) at a reaction time of 1000 seconds is shown in FIG. It was shown that SIRT1 enzyme activity was enhanced in a concentration-dependent manner by the test compound.
試験例３ 式（Ｉ）化合物によるショウジョウバエの生存期間延長
（ショウジョウバエの準備）
被験対象として、多くのショウジョウバエ研究で野生型相当として扱われる系統であり、Magwire et al, PLoS Genet, 6:e1001037, 2010 他に記載されている系統であるDrosophila melanogaster Ｗ１１１８を、ショウジョウバエ遺伝資源センター（京都市右京区嵯峨一本木町1、京都工芸繊維大学内）より入手して使用した。ショウジョウバエの継代飼育には、通常培地（１０％Ｄ−グルコース、７％コーンミール、４％エビオス、０．５５％寒天、および防腐剤として０．３％プロピオン酸、０．３５％ｐ−ｂｕｔｙｌ ｐ−ｈｙｄｒｏｘｙｂｅｎｚｏａｔｅを含む）を用いた。
培地を敷いた飼育容器（バイアル瓶：直径３ｃｍ×高さ９ｃｍ）内にショウジョウバエの成虫を放ち、室温２５℃、１２時間明暗、湿度５０％に保たれた部屋で飼育を行った。成虫は培地上に産卵し、孵化した幼虫はバイアル瓶の側面に這い上がり蛹になる。蛹から羽化した成虫を新たな飼育容器に移し継代を行った。なお、４〜５日毎に培地の交換を行った。
（試験培地）
上記通常培地に製造例１で調製したライ麦外皮エタノール抽出物の精製物を、式（Ｉ）化合物（Ｃ１５：０、Ｃ１７：０、Ｃ１９：０、Ｃ２１：０の混合物）として０．０７質量％になるよう添加した培地を、試験培地とした。陽性対照として、上記通常培地に１００μＭレスベラトロールを添加し調製した通常培地を、陰性対照として、化合物非添加の通常培地を使用した。
（生存期間測定）
本試験例におけるショウジョウバエ生存期間測定の手順は、ショウジョウバエ成虫個体の生存期間を測定するための一般的な方法（例えば、Muffat et al, Proc Natl Acad Sci U S A, 105:7088-7093, 2008などに記載の方法）に準拠した。各培地を敷いたバイアル瓶に、羽化直後のショウジョウバエ成虫を１バイアルにつき雄２０匹または雌２０匹を入れて飼育した。バイアル瓶は雌雄各２４バイアル作製した。ハエを週に２回新鮮な培地に移し、死亡したハエの数を培地交換のときに計数した。雄および雌のそれぞれについて全個体の生存日数の平均値を求め、平均寿命とした。
Test Example 3 Extending Drosophila Survival by Formula (I) Compound (Preparation of Drosophila)
As a test subject, Drosophila melanogaster W1118, which is a strain treated as a wild type equivalent in many Drosophila studies and described in Magwire et al, PLoS Genet, 6: e1001037, 2010, etc., was used in the Drosophila Genetic Resource Center ( Used in Kyoto City Ukyo-ku, Kyoichi Hongi-cho, Kyoto Institute of Technology). For passage of Drosophila, normal media (10% D-glucose, 7% corn meal, 4% ebios, 0.55% agar, and 0.3% propionic acid, 0.35% p-butyl as preservatives) are used. p-hydroxybenzoate was used).
Drosophila adults were released into a breeding container (vial bottle: diameter 3 cm × height 9 cm) on which the medium was spread, and reared in a room kept at room temperature 25 ° C., 12 hours light and dark, and humidity 50%. Adults lay eggs on the medium, and hatched larvae crawl on the side of the vial and become pupae. Adults emerged from the pupae were transferred to a new breeding container and subcultured. The medium was changed every 4 to 5 days.
(Test medium)
0.07% by mass of the purified rye shell ethanol extract prepared in Production Example 1 in the above normal medium as a compound of formula (I) (mixture of C15: 0, C17: 0, C19: 0, C21: 0) The medium added to become the test medium. As a positive control, a normal medium prepared by adding 100 μM resveratrol to the normal medium was used, and a normal medium without compound was used as a negative control.
(Lifetime measurement)
The procedure for measuring the Drosophila survival time in this test example is described in a general method for measuring the survival time of adult Drosophila individuals (for example, Muffat et al, Proc Natl Acad Sci USA, 105: 7088-7093, 2008). Method). 20 males or 20 females were bred in each vial and placed in a vial with each medium, and adult Drosophila immediately after emergence. 24 vials of male and female were prepared. The flies were transferred to fresh medium twice a week and the number of dead flies was counted at the time of medium change. For each of males and females, the average value of the survival days of all individuals was determined and used as the average life span.
図３に雄ショウジョウバエの生存曲線を、図４に雌ショウジョウバエの生存曲線を示す。雄雌のショウジョウバエともに、陰性対照に比べて、式（Ｉ）化合物を含む試験培地群では生存期間が延長した。試験培地群の生存期間は、雄では、陽性対照（レスベラトロール）群と同程度またはそれ以上に延長されており、雌では、陽性対照群での生存期間延長が顕著ではなかったが、陽性対照群と比べて大幅に延長されていた。雄および雌ショウジョウバエの平均寿命を、それぞれ図５および図６に示す。試験培地群の平均寿命は、陰性対照に比べて１０日程度延長した。雄では、試験培地群、陽性対照群共に、有意（P≦0.005）に平均寿命を延長した。雌では、試験培地群が陰性対照群に比べて有意（P≦0.005）に平均寿命を延長した。 FIG. 3 shows the survival curve of male Drosophila, and FIG. 4 shows the survival curve of female Drosophila. In both male and female Drosophila, the survival time was prolonged in the test medium group containing the compound of formula (I) as compared to the negative control. The survival time of the test medium group was extended to the same level or higher in males as in the positive control (resveratrol) group, while in females, the survival period in the positive control group was not significant, but positive It was significantly extended compared to the control group. The average life spans of male and female Drosophila are shown in FIGS. 5 and 6, respectively. The average life span of the test medium group was extended by about 10 days compared to the negative control. In males, both the test medium group and the positive control group significantly extended the average life span (P ≦ 0.005). In females, the test media group significantly (P ≦ 0.005) extended the average lifespan compared to the negative control group.
Claims (7)
で示される化合物を有効成分とするサーチュイン活性化剤（ただしＮＦκＢ阻害剤として皮膚老化抑制に使用する場合を除く）。 Formula (I)
A sirtuin activator comprising as an active ingredient the compound represented by (except when used as an NFκB inhibitor for the suppression of skin aging) .
で示される化合物を有効成分とする老化抑制剤（ただしＮＦκＢ阻害剤として皮膚老化抑制に使用する場合を除く）。 Formula (I)
An anti-aging agent comprising the compound represented by (except when used as an NFκB inhibitor for inhibiting skin aging) .
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