Hutchinson-Gilford progeria syndrome (HGPS) is a rare accelerated aging disorder most notably characterized by cardiovascular disease and premature death from myocardial infarction or stroke. The majority of cases are caused by a de novo single nucleotide mutation in the LMNA gene that activates a cryptic splice donor site, resulting in production of a toxic form of lamin A with a 50 amino acid internal deletion, termed progerin. We previously reported the generation of a transgenic murine model of progeria carrying a human BAC harboring the common mutation, G608G, which in the single-copy state develops features of HGPS that are limited to the vascular system. Here, we report the phenotype of mice bred to carry two copies of the BAC, which more completely recapitulate the phenotypic features of HGPS in skin, adipose, skeletal, and vascular tissues. We further show that genetic reduction of the mechanistic target of rapamycin (mTOR) significantly extends lifespan in these mice, providing a rationale for pharmacologic inhibition of the mTOR pathway in the treatment of HGPS.

中文翻译：

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mTOR 基因减少可延长 Hutchinson-Gilford 早衰症小鼠模型的寿命

哈钦森-吉尔福德早衰综合征 (HGPS) 是一种罕见的加速衰老疾病，最显着的特征是心血管疾病和心肌梗塞或中风导致的过早死亡。大多数病例是由LMNA中的从头单核苷酸突变引起的激活隐秘剪接供体位点的基因，导致产生具有 50 个氨基酸内部缺失的有毒形式的核纤层蛋白 A，称为早老素。我们之前报道了携带人类 BAC 的早衰转基因鼠模型的产生，该模型携带具有常见突变 G608G，其在单拷贝状态下发展出仅限于血管系统的 HGPS 特征。在这里，我们报告了携带两个 BAC 拷贝的小鼠的表型，这更完整地概括了 HGPS 在皮肤、脂肪、骨骼和血管组织中的表型特征。我们进一步表明，雷帕霉素（mTOR）机制靶点的遗传减少显着延长了这些小鼠的寿命，为治疗 HGPS 的药物抑制 mTOR 通路提供了理论依据。