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首页> 外文期刊>Nature >Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice
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Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice

机译：端粒酶激活可逆转衰老端粒酶缺陷小鼠的组织变性

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摘要

An ageing world population has fuelled interest in regenerative remedies that may stem declining organ function and maintain fitness. Unanswered is whether elimination of intrinsic instigators driving age-associated degeneration can reverse, as opposed to simply arrest, various afflictions of the aged. Such instigators include progressively damaged genomes. Telomerase-deficient mice have served as a model system to study the adverse cellular and organismal consequences of wide-spread endogenous DNA damage signalling activation in vivo. Telomere loss and uncapping provokes progressive tissue atrophy, stem cell depletion, organ system failure and impaired tissue injury responses. Here, we sought to determine whether entrenched multi-system degenera-tion in adult mice with severe telomere dysfunction can be halted or possibly reversed by reactivation of endogenous telomerase activity. To this end, we engineered a knock-in allele encoding a 4-hydroxytamoxifen (4-OHT)-inducible telomerase reverse tran-scriptase-oestrogen receptor (TERT-ER) under transcriptional con-trol of the endogenous TERT promoter. Homozygous TERT-ER mice have short dysfunctional telomeres and sustain increased DNA damage signalling and classical degenerative phenotypes upon successive generational matings and advancing age. Telomerase reactivation in such late generation TERT-ER mice extends telo-meres, reduces DNA damage signalling and associated cellular checkpoint responses, allows resumption of proliferation in qui-escent cultures, and eliminates degenerative phenotypes across multiple organs including testes, spleens and intestines. Notably, somatic telomerase reactivation reversed neurodegeneration with restoration of proliferating Sox2~+ neural progenitors, Dcx~+ new-born neurons, and Olig2~+ oligodendrocyte populations. Consistent with the integral role of subventricular zone neural progenitors in generation and maintenance of olfactory bulb interneurons, this wave of telomerase-dependent neurogenesis resulted in alleviation of hyposmia and recovery of innate olfactory avoidance responses. Accumulating evidence implicating telomere damage as a driver of age-associated organ decline and disease risk and the marked reversal of systemic degenerative phenotypes in adult mice observed here support the development of regenerative strategies designed to restore telomere integrity.
机译：世界人口老龄化引起人们对再生疗法的兴趣，该疗法可能会阻止器官功能下降并保持健康。尚无答案是消除与年龄相关的退化导致内在的煽动者是否能够扭转（而不是简单地逮捕）老年人的各种痛苦。这样的煽动者包括逐渐受损的基因组。端粒酶缺陷型小鼠已成为研究体内广泛分布的内源性DNA损伤信号转导激活的不利细胞和机体后果的模型系统。端粒丢失和解开会引起进行性组织萎缩，干细胞耗竭，器官系统衰竭和组织损伤反应受损。在这里，我们试图确定具有严重端粒功能障碍的成年小鼠中根深蒂固的多系统变性是否可以通过内源性端粒酶活性的重新激活而停止或逆转。为此，我们在内源性TERT启动子的转录控制下设计了一种编码4-羟基他莫昔芬（4-OHT）可诱导的端粒酶逆转录酶-雌激素受体（TERT-ER）的敲入等位基因。纯合的TERT-ER小鼠具有短的功能失调端粒，并且在连续的世代交配和成年后，会维持增加的DNA损伤信号传导和经典的退化表型。在这种晚世代TERT-ER小鼠中端粒酶的激活扩展了端粒，降低了DNA损伤信号传导和相关的细胞检查点反应，允许在静态培养物中恢复增殖，并消除了包括睾丸，脾脏和肠道在内的多个器官的变性表型。值得注意的是，体细胞端粒酶再激活可逆转神经变性，恢复增殖的Sox2〜+神经祖细胞，Dcx〜+新生神经元和Olig2〜+少突胶质细胞群。与脑室下区神经祖细胞在嗅球中神经元的产生和维持中所起的整体作用一致，端粒酶依赖性神经发生浪潮减轻了低渗症并恢复了先天性嗅觉回避反应。越来越多的证据表明端粒损伤是与年龄相关的器官衰弱和疾病风险的驱动因素，而成年小鼠中系统退化表型的显着逆转在此观察到，这支持旨在恢复端粒完整性的再生策略的发展。

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  • 来源
    《Nature》 |2011年第7328期|p.102-106|共5页
  • 作者

    Mariela Jaskelioff; Florian L. Muller; Ji-Hye Paik; Emily Thomas; Shan Jiang; Andrew C. Adams; Ergun Sahin; Maria Kost-Alimova; Alexei Protopopov; Juan Cadifianos; James W. Horner; Eleftheria Maratos-Flier; Ronald A. DePinho;

  • 作者单位

    Belfer Institute for Applied Cancer Science and Departments of Medical Oncology, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Belfer Institute for Applied Cancer Science and Departments of Medical Oncology, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Belfer Institute for Applied Cancer Science and Departments of Medical Oncology, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Belfer Institute for Applied Cancer Science and Departments of Medical Oncology, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Belfer Institute for Applied Cancer Science and Departments of Medical Oncology, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Division of Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA;

    Belfer Institute for Applied Cancer Science and Departments of Medical Oncology, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Belfer Institute for Applied Cancer Science and Departments of Medical Oncology, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Belfer Institute for Applied Cancer Science and Departments of Medical Oncology, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Belfer Institute for Applied Cancer Science and Departments of Medical Oncology, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Belfer Institute for Applied Cancer Science and Departments of Medical Oncology, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Division of Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA;

    Belfer Institute for Applied Cancer Science and Departments of Medical Oncology, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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