Disease pathogenicity in Hutchinson–Gilford progeria syndrome mice: insights from lung-associated alterations

TL;DR

This study explores lung changes in mice with a rare aging disease, revealing new insights into how the lungs are affected and their role in disease progression.

Contribution

The study highlights previously overlooked lung pathologies in HGPS and identifies specific molecular and histological changes.

Findings

Lung tissues showed elevated Progerin, abnormal NAD metabolism, and cellular senescence markers.

Transcriptomic analysis revealed down-regulated genes linked to extracellular space and immune response.

Lung fibrosis, inflammation, and alveolar wall thickening were observed in HGPS mouse models.

Abstract

Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by accelerated aging, impaired growth, disrupted lipid metabolism, and reduced lifespan.

Prior research has primarily focused on cardiovascular manifestations, our research sheds light on multiple organs that underwent significant age-related changes validated by tissue cross-sections H&E, Masson's trichrome, and β-galactosidase staining.

Among these pathologies tissues, the lung was severely affected and substantiated by clinical data of pulmonary anomalies from our HGPS patients. Biochemical and histological analyses of lung tissue from the HGPS mouse model revealed elevated Progerin expression, abnormal NAD metabolism, cellular senescence markers (higher level of p16 and p27, lower level of ki67), and various age-related morphology changes, including fibrosis, inflammation, and thickening of alveolar walls. Transcriptomic analyses of lung tissue indicated that down-regulated genes (Thy1, Tnc, Cspg4, Ccr1) were associated with extracellular space, immune response, calcium signaling pathway, osteoclast differentiation, and lipid binding pathway.

This study unveiled the previously overlooked organs involved in HGPS pathogenesis and suggested a specific emphasis on the lung. Our findings suggest that pulmonary abnormalities may contribute to disease progression, warranting further investigation into their role in HGPS monitoring and management.

The online version contains supplementary material available at 10.1186/s10020-025-01165-x.

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