JP2021061849A - 組織/器官再生、寿命、およびヘルススパンを増進する方法および製剤 - Google Patents
組織/器官再生、寿命、およびヘルススパンを増進する方法および製剤 Download PDFInfo
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Abstract
Description
本出願は、2012年10月22日に提出された米国仮特許出願第61/716,676号明細書、2012年12月12日に提出された米国仮特許出願第61/736,308号明細書、および2012年12月28日に提出された米国仮特許出願第61/746,787号明細書の利益を主張し、これらの開示は、本明細書において参照によってそれらの全体が組み込まれる。
本発明は、契約番号PO1AG034906、PO1AG034906−01、およびPO1AG020642の下で政府支援によりなされた。政府は、本発明に対して一定の権利を有する。
発明者らの発見は、通常の食事制限およびタンパク質制限の毎週のサイクルが、IGF−1およびIGFBPの循環レベルを調節し、また、タウリン酸化をも低下させ、ADの動物モデルにおいて年齢依存性の記憶障害をも軽減するという証拠を提供する。
食事制限組成物
以下の実験食を使用した:
−通常の食事制限(Harlan Teklad LM−485、Indianapolis、IN、USA)
−タンパク質制限(PR)食(9つのAA:イソロイシン、ロイシン、リシン、メチオニン、フェニルアラニン、トレオニン、トリプトファン、バリン、アルギニンを欠く食事制限)(Teklad、Indianapolis、IN、USA)
3×Tg−ADおよび対応する野生型(WT)(C57BL/6/129S)マウスをこの研究において使用した。3×Tg−ADマウスは、Αβ斑、超リン酸化タウ濃縮体の両方の発達および年齢依存性のアルツハイマー様認知機能障害をもたらす、AD(presenelin−1、APP)および前頭側頭型認知症(タウ)に関連づけられる突然変異を含む3つのヒト遺伝子を過剰発現する(Oddo et al. 2003)。記載されるマウスのコロニーは、実験動物の使用についてのNational Institutes of HealthのガイドラインおよびUniversity of Southern California(Los Angeles、CA) Institutional Animal Care and Use Committeeによって承認されたプロトコールに従って、University of Southern Californiaで飼育し、維持した。雄の3×Tg−ADおよびWTマウスは、食事レジメンの開始の数日前に単一のケージに入れた(食物摂取量をモニターするために)。8〜9月齢時に(この年齢時、作業記憶機能障害などのような認知障害が3×Tg−ADマウスにおいて検出可能である図22A(Rosario et al. 2006))、3×Tg−ADおよびWTの動物は2つの群(群当たり12〜14匹のマウス)に分割し、上記に記載される食事療法レジメンに割り当てた。
グルコースレベルは、Precision Xtra blood glucose monitoring system(Abbott、Abbott Park、IL、USA)を使用して、尾を切って収集した血液について屠殺の前に測定した。
IGF−1、IGFBP−3、およびIGFBP−1測定値
Y−迷路:
群当たり12〜14匹マウスを、Y迷路(40cmの壁を有するアーム21cm(長さ)×4cm(幅))を使用して、作業記憶について試験した。マウスは、8〜9月齢時に食事療法による介入の前におよび12.5〜13.5月齢まで毎月の処置で試験した。試験は迷路のアームのうちの一方にげっ歯動物を置くことによって開始した。マウスに8分間、環境を自由に探索させ、アーム侵入およびアーム選択の総数を記録した。アーム選択は、前足および後足の両方がアームに完全に入ることとして定義した。自発的交替行動(SAB)スコアは、交替の機会の総数に対する交替(前の2回の選択と異なるアーム選択)の割合として計算した(Carroll et al. 2010; Rosario et al. 2006)。
群当たり12〜14匹マウスを、新規な物体認識(NOR)試験を使用して、短期間の空間記憶について試験した。マウスは、12.5〜13.5月齢時に食事療法処置の終了時に一度試験した。迷路は、61cm(長さ)×36cm(幅)×30cm(高さ)の不透明のプラスチック箱で構成される。試験はGulinelloおよび共同研究者によって記載されるプロトコールに基づく(Gulinello et al. 2009)。手短に言えば、試験の第1日目(慣らしの日)に、マウスを箱に置き、5分間フィールドを探索させた。24時間後(試験の日)、慣らしたマウスを、2つの同一の無毒性の物体が存在する箱に再び置き、5分間、それらを自由に探索させた(治験1)。物体を探索するのに費やされた時間を記録し、物体とのあらゆる物理的な接触および/または5cm以内のそれに対する明白な方向を伴う接近を探索と見なした。治験1の終了時に、動物をホームケージに戻した。3分後、マウスを、見慣れた物体のうちの一方が新規な物体と交換された試験フィールドに戻した。マウスに5分間、活動領域を探索させ、物体を探索する時間を再びモニターした。認識インデックス(RI)は、動物が、両方の物体を探索するのに費やされた全時間に対して新規な物体を探索するのに費やされた時間として計算した。
群当たり12〜14匹のマウスを高架式十字迷路(EPM)を使用して、不安について試験した。マウスは、8〜9月齢時に食事療法による介入の前におよび12.5〜13.5月齢まで毎月の処置で試験した。EPMは、中央のプラットフォームから伸びる2つの交互のオープンアームおよび2つの交互のクローズドアームによって形成された十字形の形状を有し、それぞれのアームは長さが30cm、幅が5cm、高さが15cmである(Carroll et al. 2010)。試験は、オープンスペースに対する自然なげっ歯動物の嫌悪によってバランスをとった、げっ歯動物探索行動に基づく。高いオープンアームの回避は、強度の不安の徴候である。試験の間に、マウスを中央のフィールドに置き、5分間迷路を自由に探索させ、より低い不安レベルに対応する、オープンアームにおいて費やされた時間を測定した。
群当たりの8〜10の固定した半脳を、vibratome Leica V1000S (Leica)を使用して、水平面で完全に切片にし(40μm)、次いで、免疫組織化学的検査のために処理した。7枚ごとの切片(脳当たり10枚)をΑβ(71−5800 Αβ、Zymed Laboratories、San Francisco、CA、USA)、超リン酸化タウ(AT8、Pierce、Rockford、IL、USA)、またはCD11b(MCA711、Serotec、Kidlmgton、UK)に対して向けられる抗体により、ABC Vector EliteキットおよびDABキット(Vector Laboratories、Burlingame、CA、USA)を使用して免疫染色した。すべての実験について、免疫反応性の定量化は、サンプル特徴について盲目の2人の観察者によって評価し、値を平均した。
Αβ免疫反応性(IR)を増強するために、切片は99%ギ酸中で5分間すすいだ。Αβ IRは、負荷値として計算した。手短に言えば、海馬の重複しない免疫標識切片の選択したフィールド(海馬台について2つのフィールドおよびCA1−アンモン角エリア1−について3つ)をとらえ、顕微鏡につながれたビデオキャプチャーシステムを使用してデジタル化した。NIH Scion image 1.62Cソフトウェアを使用して、画像を二進数/負のデータに変換し、陽性のピクセル(IRエリアに等価)を定量化した(Carroll et al. 2010)。また、Αβ斑を、神経細胞内のΑβ IRとは異なる球状の形状および形態を示す細胞外Αβ免疫反応性沈着物として定義した(Rosario et al. 2006)。定量化のために、上記に定義される切片からの海馬のCA1および海馬台領域の組み合わせを光学顕微鏡下で検査し、細胞外斑の総数を数えた。それぞれの斑の面積はImageJソフトウェアを使用して定量化した。
AT8免疫反応性の神経細胞は、ほとんどの細胞表面にわたって強いAT8免疫標識を示す細胞として定義した。陽性の細胞は、海馬CA1および海馬台領域を組み合わせた範囲内で数えた(Carroll et al. 2010)。
CD11b−免疫反応性(ir)陽性ミクログリア細胞は、細胞体および突起にわたってCD11b免疫染色することによってカバーされた細胞として定義した。CD11b−ir細胞は、海馬の海馬台およびCA1領域を組み合わせた2つの隣接した重複しない免疫標識切片(合計5つの切片)において数えた。さらに、細胞活性化の段階はそれらの形態によって同定した。手短に言えば、発明者らは、ミクログリア活性化の4つの段階を定義した(Zhang et al. 2011):
・段階1:休止ミクログリア。多くの長く薄い分枝型突起を有する杆体状の体細胞。
・段階2:活性化分枝型ミクログリア。長方形の細胞体、突起はより厚い。
・段階3:著しい細胞の肥大および短く厚い突起を示すアメーバ状のミクログリア
・段階4:食細胞。円形細胞および突起は検出可能ではない。
異なる活性化段階におけるCD11b−ir細胞を数え、総ir細胞数のパーセンテージとしてプロットした。
長い間にわたる体重およびカロリー摂取量の変化を反復測定ANOVA、その後に続くNewman−Keuls検定によって分析した。生の行動データは、一元配置ANOVA、その後に続く、Fisherの最小有意差検定を使用するグループ間の比較によって分析した。t−検定は適している場合に使用した。データはすべて平均値+/−SEMを示す。
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Claims (1)
- 食餌療法を必要とする対象を同定するステップと、
第1の期間に対象に第1の食事制限を施すステップであって、前記第1の食事制限が、第1日に対象1ポンド当たり4.5〜7キロカロリーおよび前記第1の食事制限の第2〜第5日に1日当たり対象1ポンド当たり3〜5キロカロリーを提供し、前記第1の食事制限が、
第1日に30g未満の糖、
第2〜第5日に20g未満の糖、
第1日に28g未満のタンパク質、
第2〜第5日に18g未満のタンパク質、
第1日に20〜30グラムの一価不飽和脂肪、
第2〜第5日に10〜15グラムの一価不飽和脂肪、
第1日に6〜10グラムの多価不飽和脂肪、
第2〜第5日に3〜5グラムの多価不飽和脂肪、
第1日に12g未満の飽和脂肪、
第2〜第5日に6グラム未満の飽和脂肪、および
第2〜第5日に1日当たり12〜25グラムのグリセロール
を含むステップと
を含むことを特徴とする方法。
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EP3016528A4 (en) | 2013-07-01 | 2017-01-04 | University of Southern California | Fasting condition as dietary treatment of diabetes |
US10172839B2 (en) | 2014-03-06 | 2019-01-08 | University Of Southern California | Use of short term starvation regimen in combination with kinase inhibitors to enhance traditional chemo-drug efficacy and feasibility and reverse side effects of kinases in normal cells and tissues |
WO2015153850A2 (en) * | 2014-04-02 | 2015-10-08 | University Of Southern California | Autoimmunity and multiple sclerosis treatment |
EP3291693A4 (en) * | 2015-05-06 | 2019-04-03 | University of Southern California | FASTENIMITIER AND IMPROVING DIET FOR THE TREATMENT OF HYPERTENSION AND LIPID DISORDER |
CN108463121A (zh) * | 2016-01-12 | 2018-08-28 | 南加利福尼亚大学 | 长期禁食模仿作为多发性骨髓瘤和其它癌症的膳食治疗的用途 |
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IT202000008740A1 (it) | 2020-04-23 | 2021-10-23 | L Nutra Inc | Composizione dietetica per l’incremento della massa magra e della massa muscolare |
IT202000016957A1 (it) | 2020-07-13 | 2022-01-13 | Univ Degli Studi Di Palermo | Composizione dietetica per il trattamento della depressione |
CN116096251A (zh) * | 2020-09-23 | 2023-05-09 | 氨基维他有限公司 | 癌症的代谢疗法 |
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