Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually lethal disease associated with aging. However, the molecular mechanisms of the aging process that contribute to the pathogenesis of IPF have not been elucidated. IPF is characterized by abundant foci of highly active fibroblasts and myofibroblasts resistant to apoptosis. Remarkably, the role of aging in the autophagy activity of lung fibroblasts and its relationship with apoptosis, as adaptive responses, has not been evaluated previously in this disease. In the present study, we analyzed the dynamics of autophagy in primary lung fibroblasts from IPF compared to young and age‐matched normal lung fibroblasts. Our results showed that aging contributes for a lower induction of autophagy on basal conditions and under starvation which is mediated by mTOR pathway activation. Treatment with rapamycin and PP242, that target the PI3K/AKT/mTOR signaling pathway, modified starvation‐induced autophagy and apoptosis in IPF fibroblasts. Interestingly, we found a persistent activation of this pathway under starvation that contributes to the apoptosis resistance in IPF fibroblasts. These findings indicate that aging affects adaptive responses to stress decreasing autophagy through activation of mTORC1 in lung fibroblasts. The activation of this pathway also contributes to the resistance to cell death in IPF lung fibroblasts.

中文翻译：

---

mTORC1激活减少衰老和特发性肺纤维化中的自噬，并有助于IPF成纤维细胞的凋亡抗性。

特发性肺纤维化（IPF）是一种与衰老相关的慢性，进行性疾病，通常是致死性疾病。但是，尚不清楚导致IPF发病机理的衰老过程的分子机制。IPF的特征在于高活性的成纤维细胞和成纤维细胞对细胞凋亡具有抗性。值得注意的是，该疾病以前尚未评估衰老在肺成纤维细胞自噬活性中的作用及其与细胞凋亡的关系，作为适应性反应。在本研究中，我们分析了与年轻和年龄匹配的正常肺成纤维细胞相比，IPF的原代肺成纤维细胞自噬的动力学。我们的结果表明，衰老有助于在基础条件下和在饥饿状态下通过mTOR途径激活介导的自噬诱导作用降低。雷帕霉素和PP242的治疗靶向PI3K / AKT / mTOR信号通路，改善了饥饿诱导的自噬和IPF成纤维细胞的凋亡。有趣的是，我们发现该途径在饥饿状态下持续激活，这有助于IPF成纤维细胞的凋亡抗性。这些发现表明，衰老通过激活肺成纤维细胞中的mTORC1来影响对应激减轻自噬的适应性反应。该途径的激活还有助于抵抗IPF肺成纤维细胞中的细胞死亡。这些发现表明，衰老通过激活肺成纤维细胞中的mTORC1来影响对应激减轻自噬的适应性反应。该途径的激活还有助于抵抗IPF肺成纤维细胞中的细胞死亡。这些发现表明，衰老通过激活肺成纤维细胞中的mTORC1来影响对应激减轻自噬的适应性反应。该途径的激活还有助于抵抗IPF肺成纤维细胞中的细胞死亡。