Background Lung ageing, a significant risk factor for chronic human lung diseases such as COPD and emphysema, is characterised by airspace enlargement and decreasing lung function. Likewise, in prematurely ageing telomerase null (terc−/−) mice, p53 stabilisation within diminishing numbers of alveolar epithelial type 2 cells (AEC2) accompanies reduced lung function. Resveratrol (RSL) is a plant phytoalexin that has previously showed efficacy in enhancing invertebrate longevity and supporting mammalian muscle metabolism when delivered orally. Here, we tested whether inhaled RSL could protect young, terc−/− mice from accelerated ageing of the lung.
Methods terc−/− mice aged 2 months inhaled 1 mg/kg RSL that was instilled intratracheally once per month for 3 months. One month after the last inhalation, whole lung function, structure and cellular DNA damage were evaluated and AEC2 survival was assessed by western blotting for survival pathway gene expression.
Results RSL treatments delayed the loss of lung compliance (p<0.05), maintained lung structure (p<0.001) and blocked parenchymal cell DNA damage as measured by TdT Nick-End Labeling (TUNEL). RSL, a known agonist of deacetylase SIRT1, supported AEC2 survival by stimulating SIRT1 expression, promoting p53 destabilisation and decreasing Bax expression and by maintaining expression levels of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), activated p-Akt and p-Mdm2 and inactivated Phospho-Phosphatase and tensin homolog (p-PTEN).
Conclusions RSL prophylaxis by inhalation is a potential approach for slowing ageing-related deterioration of lung function and structure by maintaining AEC2 integrity.
- Airway Epithelium
- COPD Pathology
- Lung Physiology
- Respiratory Measurement
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Contributors SN collaborated on study design, performed all experiments with the exception of western blotting, performed data analyses and cowrote the manuscript. RR performed western blots. JL performed mouse breeding and colony management. DW reviewed and revised the manuscript. BD conceived the project, collaborated on study design, performed data analysis and cowrote the manuscript.
Funding This work was supported by NIH/NHLBI R01 HL65352 and funding from the Pasadena Guild Endowment and the Garland Fund to BD and funding from the Pasadena Guild Endowment and the Garland Fund to DW. SN was supported by NIH/NIDCR T90 training grant DE021982.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.