Aging is associated with both overt and subclinical lung fibrosis, which increases risk for mortality from viruses and other respiratory pathogens. The molecular programs that induce fibrosis in the aging lung are not well understood. To overcome this knowledge gap, we undertook multimodal profiling of distal lung samples from healthy human donors across the lifespan. Telomere shortening, a cause of cell senescence and fibrosis, was progressive with age in a sample of 86 lungs and was associated with foci of DNA damage. Bulk RNA sequencing confirmed activation of cellular senescence and pro-fibrotic pathways as well as genes necessary for collagen processing with increasing age. These findings were validated in independent datasets for lung and sun-exposed skin, but not other organs including heart, liver and kidney. Cell type deconvolution analysis revealed a progressive loss of lung epithelial cells and an increasing proportion of fibroblasts. Consistent with the observed pro-fibrotic transcriptional profile, second harmonic imaging demonstrated increased density of interstitial collagen in aged human lungs. Furthermore, regions of parenchymal fibrosis were associated with decreased alveolar expansion and surfactant secretion. These findings reveal the transcriptional and structural features of fibrosis and associated physiologic impairments in normal lung aging.

中文翻译：

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衰老的人肺纤维化变化的分子程序

衰老与明显的和亚临床的肺纤维化有关，这增加了病毒和其他呼吸道病原体致死的风险。在衰老的肺中引起纤维化的分子程序尚未被很好地理解。为了克服这一知识鸿沟，我们对整个生命周期中来自健康人类供体的远端肺部样本进行了多模式分析。端粒缩短是细胞衰老和纤维化的原因，在86个肺部样本中随着年龄的增长逐渐发展，并与DNA损伤灶有关。大量RNA测序证实了细胞衰老和促纤维化途径以及随着年龄增长胶原蛋白加工所必需的基因的激活。这些发现已在针对肺和日晒皮肤的独立数据集中进行了验证，但并未验证其他器官（包括心脏，肝脏和肾脏）。细胞类型反卷积分析显示，肺上皮细胞逐渐丧失，成纤维细胞比例增加。与观察到的促纤维化转录谱一致，二次谐波成像表明老年人肺中间质胶原的密度增加。此外，实质性纤维化区域与肺泡扩张和表面活性剂分泌减少有关。这些发现揭示了正常肺衰老中纤维化的转录和结构特征以及相关的生理损伤。实质性纤维化区域与肺泡扩张和表面活性剂分泌减少有关。这些发现揭示了正常肺衰老中纤维化的转录和结构特征以及相关的生理损伤。实质性纤维化区域与肺泡扩张和表面活性剂分泌减少有关。这些发现揭示了正常肺衰老中纤维化的转录和结构特征以及相关的生理损伤。