Aging in a Dish: Pulmonary Organoids as Models of Lung Aging

Dissecting Lung Aging Through Organoid Models: From Mechanisms to Therapeutic Targets Aging of the lung is characterized by progressive alterations in epithelial integrity, stem cell renewal, immune surveillance, and tissue repair. These changes compromise pulmonary function and increase susceptibility to chronic lung diseases, including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), as well as respiratory infections that disproportionately affect older individuals. Mechanistically, lung aging arises from cell-intrinsic dysfunction, impaired intercellular communication, and disrupted homeostasis. Understanding mechanisms driving lung aging remains a critical challenge for preserving respiratory health in the elderly. To address this challenge, advanced in vitro models like lung organoids have emerged as powerful tools to study respiratory aging. Organoids are three-dimensional (3D) cultures derived from lung stem or progenitor cells. Lung organoids enable investigation of aging phenotypes, including impaired self-renewal, differentiation, epigenetic alterations, oxidative stress, and senescence. They can model interactions between epithelial, stromal, and immune cells while recapitulating key microenvironmental influences such as inflammation, fibrosis, and toxin exposure. Together, these features position organoids as a versatile platform to dissect cellular crosstalk and signaling pathways driving lung aging and related pathologies. This review highlights the use of lung organoids to investigate age-related lung diseases. We discuss how organoid systems have been used to study epithelial dysfunction, impaired regeneration and immune-epithelial crosstalk in the aging lung. Furthermore, we emphasize how integration with multi-omics approaches can reveal novel mechanisms and targets. Finally, we consider the translational potential of organoid-based models for drug discovery, target validation, and interventions to mitigate age-related decline in lung function.