Short/dysfunctional telomeres are at the origin of idiopathic pulmonary fibrosis (IPF) in patients mutant for telomere maintenance genes. However, it remains unknown whether physiological aging leads to short telomeres in the lung, thus leading to IPF with aging. Here, we find that physiological aging in wild-type mice leads to telomere shortening and a reduced proliferative potential of alveolar type II cells and club cells, increased cellular senescence and DNA damage, increased fibroblast activation and collagen deposits, and impaired lung biophysics, suggestive of a fibrosis-like pathology. Treatment of both wild-type and telomerase-deficient mice with telomerase gene therapy prevented the onset of lung profibrotic pathologies. These findings suggest that short telomeres associated with physiological aging are at the origin of IPF and that a potential treatment for IPF based on telomerase activation would be of interest not only for patients with telomerase mutations but also for sporadic cases of IPF associated with physiological aging.

中文翻译：

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端粒酶治疗可预防与生理衰老相关的肺纤维化病变

端粒短/功能失调是端粒维持基因突变患者特发性肺纤维化（IPF）的根源。然而，目前尚不清楚生理衰老是否会导致肺部端粒变短，从而导致随年龄增长而发生的特发性肺纤维化（IPF）。在这里，我们发现野生型小鼠的生理衰老导致端粒缩短、肺泡 II 型细胞和俱乐部细胞增殖潜力降低、细胞衰老和 DNA 损伤增加、成纤维细胞活化和胶原蛋白沉积增加以及肺生物物理学受损，提示纤维化样病理学。用端粒酶基因疗法治疗野生型和端粒酶缺陷小鼠可预防肺纤维化病变的发生。这些发现表明，与生理衰老相关的短端粒是 IPF 的起源，基于端粒酶激活的 IPF 潜在治疗方法不仅对端粒酶突变的患者感兴趣，而且对与生理衰老相关的 IPF 散发病例也感兴趣。