Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre, Madrid, Spain.
Department of Biochemistry and Molecular Biology, Research Institute "Hospital 12 de Octubre (imas12)," Complutense University, Madrid, Spain.
J Cell Biol. 2020 Oct 5;219(10). doi: 10.1083/jcb.202002120.
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.
短/功能失调的端粒是端粒维持基因突变患者特发性肺纤维化（IPF）的起源。然而，目前尚不清楚生理衰老是否会导致肺部端粒变短，从而导致与衰老相关的 IPF。在这里，我们发现野生型小鼠的生理衰老会导致端粒缩短，肺泡 II 型细胞和 club 细胞的增殖潜力降低，细胞衰老和 DNA 损伤增加，成纤维细胞激活和胶原沉积增加，肺生物物理特性受损，提示存在类似于纤维化的病理学。端粒酶基因治疗可预防野生型和端粒酶缺陷型小鼠发生肺纤维化病理改变。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患者有意义，而且对与生理衰老相关的散发性 IPF 也有意义。
