JPWO2007029730A1 - 老人性貧血を防止又は治療するためのアミノ酸組成物 - Google Patents
老人性貧血を防止又は治療するためのアミノ酸組成物 Download PDFInfo
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Abstract
Description
貧血は単に症状を示すもので、直接的には、赤血球の産生低下、ヘモグロビンの合成低下、赤血球の破壊の亢進などにより生じ、原因はそれぞれ異なっている。
若年性の貧血は鉄欠乏が原因であることが多い。老化による貧血の発生原因は完全には解明されていないが、若年性貧血とは対照的に、骨髄の老化に伴う造血幹細胞の減少、産生される赤血球の寿命の短縮、胃の粘膜の萎縮に伴う栄養の吸収量の減少などが原因として挙げられてきている。
赤血球は造血幹細胞から、赤芽球バースト形成細胞(BFU−E:burst-forming-unit-erythroid)、赤芽球コロニー形成細胞(CFU:colony-forming-unit-erythroid)、前赤芽球、赤芽球、網状赤血球、赤血球と分化して生産されると考えられている。最近では、転写因子GATA-1及びGATA-2の発現量が赤血球の分化段階で異なっており、GATA-1は赤芽球、前赤芽球で発現が見られ、GATA-2は造血幹細胞、骨髄幹細胞などの未分化な細胞で発現が見られることが明らかになっている。赤芽球バースト形成細胞では、GATA-2の発現がGATA-1の発現を上回り、赤芽球コロニー形成細胞では、GATA-1の発現がGATA-2の発現を上回っていると報告されている(実験医学2004年,Vol22,No.3,361-366)。
本願発明者は、特定の組成を有するアミノ酸組成物が老人性貧血の改善に効果的であることを実験的に見出し、更に、これらの改善が老化による赤血球への分化抑制を防止することに起因していることを、関連する遺伝子の発現状況から明らかにした。
本願発明で用いるアミノ酸組成物として、必須アミノ酸Ile、Trp、Thr、Val、His、Phe、Met、Lys及びLeuを含むアミノ酸組成物を有効成分として含有する老人性貧血防止剤、老人性貧血治療剤、細胞老化防止剤、筋肉同化促進剤又は筋肉異化抑制剤を包含する。
本願発明のアミノ酸組成物の使用形態は特に限定されないが、飲食用、栄養補助飲食用としても、医療用としても用いることができる。食用とする場合には、本願アミノ酸組成物は、そのまま食用できるが、各種食品への添加物とすることもできる。また、本願発明の組成物は水に溶解して飲料とすることもでき、その場合には、他の栄養成分、例えば、水溶液ビタミン類、タウリンなどを更に添加することもできる。また、嗜好性の改善のために、塩化ナトリウムなどの塩類、クエン酸等の酸類及び/又は他の適当な風味を加えて飲料とすることもできる。安定性のために、pH調整剤、キレート剤を更に添加することもできる。
(1)老齢マウスの作製及び投与
ICR雄性マウスは20ヶ月齢まで自由飲水、MF飼料(オリエンタル酵母)の自由摂取条件で飼育し、体重により群分けした。20ヶ月齢以降の28ヶ月齢に達するまでの8ヶ月間には試験飼料を投与した。投与では表1に示すように、AIN-93M精製飼料(カゼイン含量14%)を基本飼料とし、14%含まれるカゼインの2%相当分をアミノ酸組成物に置換した飼料を与えた。期間中に飼料は自由摂取とした。投与群では、16種類のアミノ酸を混合したアミノ酸混合1投与群と必須アミノ酸を中心としたアミノ酸混合2投与群の2群とした(表2)。コントロール飼料はAIN-93Mとし、5週齢の同系統のマウスに同期間(8ヶ月)で与えた群(9ヶ月齢)と、2週間で与えた群(1.5ヶ月齢)の2群とした。
投与終了後に脾臓を摘出して遺伝子の発現量を解析した。
(2−1)赤血球関連遺伝の発現量
表3で、減少が認められた遺伝子は赤血球の細胞骨格を形成する主要な糖タンパク質であるスペクトリンやアンキリン、鉄の取り込みやヘム合成に関わる酵素群、酸素交換に関わる酵素などであった。特にヘムの生合成に関わる8つの酵素の全ての遺伝子の発現が若齢マウスに比べて、およそ1/2に減少しており、赤血球造血における機能の低下が推測された。
更に、赤血球系の転写因子で造血幹細胞からの分化誘導に重要であるGATA-1及びGATA-2の発現を検討した。結果を図2に示す。加齢によりGATA-1は半減し、GATA-2は2倍に増加していた(図2)。
また更に、加齢により変化が認められた全遺伝子を、パスウェイ解析ソフト(インジェヌイティ社)を用いて解析した。パスウェイ解析により赤血球細胞に関連した遺伝子の動き以外に、老齢マウスでは細胞周期と染色体複製の低下が強く示唆され、細胞増殖の点でも血液細胞数の低下が予想された。更に、赤血球の分化成熟過程において骨髄性幹細胞から分化した前赤芽球は、これ以降に3〜5回の細胞分裂を行い、8〜32個の赤血球が生じる。したがって、細胞周期と染色体複製の低下は、間接的に赤血球の分化の抑制を示していると考えられる。この点に関しても、アミノ酸の摂取により回復が認められることから、アミノ酸の摂取、特に必須アミノ酸の摂取が加齢による造血機能の低下の抑制には有効である可能性が強いと考えられた。なお、上記解析により、脾臓において老化により低下すると判断された細胞周期及び染色体複製関連の遺伝子を下記の表4に挙げる。
[実施例2]
アミノ酸摂取によるヘモグロビン値の増加
老齢マウス及び若齢マウス各群の尾静脈より採血して、末梢血のヘモグロビン量をヘモグロビンB-テスト・ワコーにて測定した。若齢マウスは5週齢、老齢マウスは各群とも20ヶ月齢であった。若齢マウスはn=9、老齢マウスは各群ともn=15である。統計解析にはStudent-t-テストを用い、若齢マウスに対する有意差検定を行った。結果を図3に示す。図3中、老齢マウスのカッコ内のAAM1は、アミノ酸混合1を投与する予定の群、AAM2はアミノ酸混合2を投与する予定の群を示す。
アミノ酸摂取による筋肉同化の維持促進効果
5週齢及び23ヶ月齢の雄性ICRマウスに対して、3種類のアミノ酸混合物を4ヶ月間、投与した。投与したアミノ酸混合物は、表5に示す通りであり、前出のアミノ酸混合2(AAM2)、必須アミノ酸のみからなるアミノ酸混合3(AAM3)及びVal、Leu、Ile、Arg、Glnの5種類のアミノ酸の混合物であるアミノ酸混合4(AVM)である。投与を終了した後に、各マウスより腓腹筋を採取して、重量を測定した。
比較実験1 若齢マウスに対するアミノ酸組成物の投与がヘモグロビン量に与える影響
5週齢の雌性ICRマウスに実施例2と同様の飼料を5ヶ月間、摂取させた後に、腹部大静脈より採血して、ヘモグロビンB-テスト・ワコーにより、ヘモグロビン量を測定した(図5)。
5週齢の雄性ICRマウスに対して、3種類のアミノ酸混合物を4ヶ月間、投与した。投与したアミノ酸混合物は、実施例3と同じく表5に示す通りであり、前出のアミノ酸混合2(AAM2)、必須アミノ酸のみからなるアミノ酸混合3(AAM3)およびVal、Leu、Ile、Arg、Glnの5種類のアミノ酸の混合物であるアミノ酸混合4(AVM)である。
Claims (18)
- Ile、Trp、Thr、Val、His、Phe、Met、Lys及びLeuからなるアミノ酸組成物を有効成分とする老人性貧血防止剤又は老人性貧血治療剤。
- アミノ酸組成物が更に、Arg、Glu及びProからなる群から選ばれる1以上のアミノ酸を含む請求項1記載の老人性貧血防止剤又は老人性貧血治療剤。
- アミノ酸組成物がArg、Ile、Glu、Trp、Thr、Val、His、Phe、Pro、Met、Lys及びLeuからなる請求項2記載の老人性貧血防止剤又は老人性貧血治療剤。
- アミノ酸組成物が更に、Asp、Ala、Gly、Ser及びTyrからなる群から選ばれる1以上のアミノ酸を含む請求項2又は3記載の老人性貧血防止剤又は老人性貧血治療剤。
- アミノ酸組成物がAsp、Ala、Arg、Ile、Gly、Glu、Ser、Tyr、Trp、Thr、Val、His、Phe、Pro、Met、Lys及びLeuからなる請求項4記載の老人性貧血防止剤又は老人性貧血治療剤。
- 請求項1から5のいずれか1項記載の老人性貧血防止剤又は老人性貧血治療剤を含有する飲食品。
- Ile、Trp、Thr、Val、His、Phe、Met、Lys及びLeuからなるアミノ酸組成物を有効成分とする細胞老化防止剤。
- アミノ酸組成物が更に、Arg、Glu及びProからなる群から選ばれる1以上のアミノ酸を含む請求項7記載の細胞老化防止剤。
- アミノ酸組成物がArg、Ile、Glu、Trp、Thr、Val、His、Phe、Pro、Met、Lys及びLeuからなる請求項8記載の細胞老化防止剤。
- アミノ酸組成物が更に、Asp、Ala、Gly、Ser及びTyrからなる群から選ばれる1以上のアミノ酸を含む請求項8又は9記載の細胞老化防止剤。
- アミノ酸組成物がAsp、Ala、Arg、Ile、Gly、Glu、Ser、Tyr、Trp、Thr、Val、His、Phe、Pro、Met、Lys及びLeuからなる請求項10記載の細胞老化防止剤。
- 請求項7から11のいずれか1項記載の細胞老化防止剤を含有する飲食品。
- アミノ酸組成物がIle、Trp、Thr、Val、His、Phe、Met、Lys及びLeuからなるアミノ酸組成物を有効成分とする筋肉同化促進剤又は筋肉異化抑制剤。
- アミノ酸組成物が更に、Arg、Glu及びProからなる群から選ばれる1以上のアミノ酸を含む請求項13記載の筋肉同化促進剤又は筋肉異化抑制剤。
- アミノ酸組成物がArg、Ile、Glu、Trp、Thr、Val、His、Phe、Pro、Met、Lys及びLeuからなる請求項14記載の筋肉同化促進剤又は筋肉異化抑制剤。
- アミノ酸組成物が更に、Asp、Ala、Gly、Ser及びTyrからなる群から選ばれる1以上のアミノ酸を含む請求項14又は15記載の筋肉同化促進剤又は筋肉異化抑制剤。
- アミノ酸組成物がAsp、Ala、Arg、Ile、Gly、Glu、Ser、Tyr、Trp、Thr、Val、His、Phe、Pro、Met、Lys及びLeuからなる請求項16記載の筋肉同化促進剤又は筋肉異化抑制剤。
- 請求項13から17のいずれか1項記載の筋肉同化促進剤又は筋肉異化抑制剤を含有する飲食品。
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