HUMAN lung ageing involves complex cellular changes that may help explain why older adults are more vulnerable to respiratory diseases. A new multi-omic study using single-cell sequencing has mapped how the lung’s cellular landscape shifts with age, revealing that some cell types undergo far greater changes than others.
Age is one of the strongest risk factors for lung diseases such as COPD, pulmonary fibrosis, and respiratory infections. However, the biological processes underlying lung ageing have remained poorly defined. To investigate this, researchers from Yale School of Medicine created the largest human lung ageing atlas to date, integrating single-cell RNA sequencing data with genomic analyses across multiple independent datasets.
Human Lung Ageing Shows Cell-Type Differences
The analysis revealed that lung ageing does not affect all cells equally. Instead, it appears cell-type dyssynchronous, meaning some cells undergo substantial molecular shifts while others remain relatively stable.
Two cell groups showed the most pronounced changes: alveolar epithelial cells, which line the air sacs and help maintain lung function, and endothelial cells, which form the lining of lung blood vessels. Within the alveolar epithelium, the researchers observed a decline in surfactant-producing cells known as SPChigh type-2 alveolar cells. These cells play a crucial role in keeping the air sacs open and supporting lung repair.
Loss of these cells may contribute to reduced lung resilience with age and could help explain the higher susceptibility to respiratory disease in older adults.
Mutation Accumulation in Ageing Lung Cells
Beyond transcriptional changes, the study also found that somatic mutations, genetic alterations acquired over a lifetime, accumulated more frequently in ageing lung cells. Alveolar epithelial and endothelial cells carried the highest mutation burdens, accompanied by activation of DNA damage response pathways.
Researchers also detected increased transcriptional entropy, a measure of gene expression variability that reflects declining cellular organisation. Importantly, this entropy measure independently predicted biological ageing within lung tissue.
Rethinking Cellular Senescence in Lung Ageing
Surprisingly, cells carrying widely used molecular signatures of cellular senescence did not increase with age. Senescence refers to a state in which cells permanently stop dividing and is often considered a hallmark of ageing tissues.
Instead, the analysis suggested that senescence-related markers appear in diverse cell types in different ways, challenging the idea that a single senescence signature explains lung ageing.
Implications for Respiratory Disease Research
By integrating genomic, transcriptional, and cellular data, the researchers have created a publicly accessible lung ageing atlas to support future research. Understanding how specific lung cells change with age may help scientists identify mechanisms that predispose older individuals to respiratory diseases.
Ultimately, these insights could guide the development of therapies aimed at preserving lung function and improving resilience against age-related respiratory conditions.
Reference
De Man R et al. Single-cell atlas of human lung aging identifies cell type dyssynchrony and increased transcriptional entropy. Nat Commun. 2026;17(1):2095.
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