Idiopathic pulmonary fibrosis (IPF) is a fatal chronic lung disease characterized by progressive scarring of the lung tissue, leading to respiratory failure. There is no cure for IPF, and current anti-fibrotic treatments modestly arrest its further progression. IPF prevalence and incidence increase with age, which is a recognized risk factor. Intense clinical and basic research over the last fifteen years has shown that hallmarks of accelerated aging are present in the lungs of patients with IPF. Different cell types in IPF lungs exhibit premature hallmarks of aging, including telomere attrition and cellular senescence. In this Review, we discuss recent insights into the mechanisms behind these age-related alterations and their contribution to the development of lung fibrosis. We focus on the genetic and molecular basis of telomere attrition in alveolar type II epithelial cells, which promote cellular senescence and lung fibrosis. Mechanistically, senescent cells secrete pro-fibrotic factors that activate scar-forming myofibroblasts. Ultimately, senescent alveolar epithelial cells lose their regenerative capacity, impeding fibrosis resolution. In addition, mitochondrial dysfunction is strongly associated with the appearance of senescent epithelial cells and senescent myofibroblasts in IPF, which persist in the fibrotic tissue by adapting their metabolic pathways and becoming resistant to apoptosis. We discuss emerging novel therapeutic strategies to treat IPF by targeting cellular senescence with the so-called senotherapeutics.

中文翻译：

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疗法：针对特发性肺纤维化的衰老。

特发性肺纤维化（IPF）是一种致命的慢性肺部疾病，其特征是肺组织进行性瘢痕形成，导致呼吸衰竭。IPF无法治愈，目前的抗纤维化治疗只能适度阻止其进一步发展。IPF患病率和发病率随年龄增长而增加，这是公认的危险因素。在过去的十五年中，大量的临床和基础研究表明，IPF患者的肺部存在加速衰老的标志。IPF肺中的不同细胞类型表现出过早的衰老标志，包括端粒磨损和细胞衰老。在这篇综述中，我们讨论了有关这些年龄相关性改变背后的机制及其对肺纤维化发展的贡献的最新见解。我们专注于II型肺泡上皮细胞端粒磨损的遗传和分子基础，它可促进细胞衰老和肺纤维化。从机制上讲，衰老细胞会分泌促纤维化因子，从而激活形成疤痕的成肌纤维细胞。最终，衰老的肺泡上皮细胞失去了再生能力，阻碍了纤维化的解决。此外，线粒体功能障碍与IPF中衰老的上皮细胞和衰老的成纤维细胞的出现密切相关，后者通过适应其代谢途径并变得对细胞凋亡具有抵抗力，从而持续存在于纤维化组织中。我们讨论了新兴的新型治疗策略，即通过靶向细胞衰老与所谓的senotherapeutics来治疗IPF。从机制上讲，衰老细胞分泌促纤维化因子，从而激活形成疤痕的成肌纤维细胞。最终，衰老的肺泡上皮细胞失去了再生能力，阻碍了纤维化的解决。此外，线粒体功能障碍与IPF中衰老的上皮细胞和衰老的成纤维细胞的出现密切相关，后者通过适应其代谢途径并变得对细胞凋亡具有抵抗力，从而持续存在于纤维化组织中。我们讨论了新兴的新型治疗策略，即通过靶向细胞衰老与所谓的senotherapeutics来治疗IPF。从机制上讲，衰老细胞分泌促纤维化因子，从而激活形成疤痕的成肌纤维细胞。最终，衰老的肺泡上皮细胞失去了再生能力，阻碍了纤维化的解决。此外，线粒体功能障碍与IPF中衰老的上皮细胞和衰老的成纤维细胞的出现密切相关，后者通过适应其代谢途径并变得对细胞凋亡具有抵抗力，从而持续存在于纤维化组织中。我们讨论了新兴的新型治疗策略，即通过靶向细胞衰老与所谓的senotherapeutics来治疗IPF。线粒体功能障碍与IPF中衰老上皮细胞和衰老的成肌纤维细胞的出现密切相关，后者通过适应它们的代谢途径并变得对凋亡具有抵抗力，从而持续存在于纤维化组织中。我们讨论了新兴的新型治疗策略，通过靶向细胞衰老与所谓的“ senotherapeutics”来治疗IPF。线粒体功能障碍与IPF中衰老上皮细胞和衰老的成肌纤维细胞的出现密切相关，后者通过适应其代谢途径并变得对凋亡具有抵抗力，从而持续存在于纤维化组织中。我们讨论了新兴的新型治疗策略，即通过靶向细胞衰老与所谓的senotherapeutics来治疗IPF。