Ten years on, nearly every hallmark of ageing is linked to chronic lung disease
A decade after their first review, lung researchers say almost all ageing hallmarks drive COPD, IPF and lung cancer, and early trials now target them.
Summary
Marking ten years since their original review, the authors update the hallmarks of the ageing lung and argue that nearly all 13 recognised hallmarks of ageing contribute to chronic lung diseases such as COPD, idiopathic pulmonary fibrosis (IPF) and lung cancer. Extracellular matrix dysregulation, which they proposed as a lung hallmark in 2015, is now considered integral. In COPD, evidence implicates DNA damage, telomere dysfunction, epigenetic and miRNA changes, impaired proteostasis, altered autophagy and mTOR-driven nutrient sensing. Cigarette and wildfire smoke accelerate these processes. Extracellular vesicles and the microbiome are emerging themes, and early clinical studies are testing therapies such as senescence-targeting approaches. Whether the hallmarks cause disease or result from it remains unresolved in many cases.
Detailed Summary
Ageing is the single biggest risk factor for chronic lung disease, which affected more than 500 million people in 2017 and is the third leading cause of death. The WHO projects the share of people over 60 will rise from 12% to 22% between 2015 and 2050. People over 65 have roughly a five-fold higher COPD risk than those under 40. This review revisits the authors' 2015 European Respiratory Journal paper to ask how far ageing biology explains lung disease.
This is a narrative review, not a new study. The authors build on the expanded framework of 13 hallmarks of ageing and cover findings supported by descriptive or genetic evidence from multiple clinical cohorts or at least two laboratories, or by genetic mouse models or pharmacological targeting in diseased animals. They note more than 16,000 PubMed articles on the topic since 2015. They also distinguish biological from chronological lung ageing, which reflects genetics, epigenetics, environmental exposures, lifestyle and early-life injury. The text available for this summary covers the introduction and the COPD sections up to deregulated nutrient sensing. Statements about IPF, lung cancer, extracellular vesicles, the microbiome and clinical trials come from the abstract only.
In COPD, described as a disease of accelerated ageing, the authors report evidence for most hallmarks. FEV1 declines by 50–100 mL per year in COPD versus about 20 mL per year in healthy people. DNA repair genes are altered, and clonal haematopoiesis of indeterminate potential (CHIP) is more common. Accelerated telomere shortening predicted worse lung function over 10 years in one prospective study. Epigenetic work includes shared methylation patterns between smoke-exposed fetal lung and adult COPD lung, and PRMT7 loss reduced emphysema in mice. Several miRNAs (miR-34a, miR-570) promote senescence via sirtuin-1 downregulation. Proteostasis is disrupted through ER stress, altered proteasome function and compromised immunoproteasome activity. Autophagy findings are mixed and may depend on cell type and exposure duration. mTOR activity is raised in COPD and drives senescence in smooth muscle and endothelial cells. mTOR inhibition protected smoke-exposed mice, and metformin use in COPDGene participants was associated with slower emphysema progression.
The broader message is that chronic lung diseases share common ageing mechanisms, which opens the way to shared diagnostics and therapies. Per the abstract, smoke exposure accelerates ageing-related change, and in lung cancer, ageing contributes to genomic alterations, immune evasion and treatment resistance. Early clinical studies are targeting hallmarks such as cellular senescence.
Key caveats: for many hallmarks it is unclear whether they cause COPD or are consequences of it, and genetic evidence in COPD is limited. Several findings, such as the metformin association, are observational or come from animal models. The review does not follow a systematic search method.
Key Findings
- Nearly all 13 recognised hallmarks of ageing are implicated in chronic lung diseases including COPD, IPF and lung cancer.
- COPD shows accelerated decline: FEV1 falls 50–100 mL per year versus about 20 mL per year in healthy ageing.
- Smoke exposure drives DNA damage, telomere dysfunction, ER stress and senescence, and in utero smoke leaves COPD-like methylation patterns.
- mTOR activity is elevated in COPD; mTOR inhibition protected smoke-exposed mice, and metformin use was linked to slower emphysema progression.
- Early clinical studies are now targeting ageing hallmarks such as cellular senescence to reduce age-related lung pathology.
Methodology
Narrative review updating the authors' 2015 paper, using the 13-hallmark framework of ageing. Included evidence required multiple clinical cohorts, two or more laboratories, or support from genetic mouse models or pharmacological targeting in disease models. No systematic search or quantitative synthesis is described.
Study Limitations
The review does not establish whether many hallmarks cause disease or result from it, and genetic evidence in COPD is limited. Much supporting data come from animal models, small cohorts or observational associations such as the metformin finding. The text provided ended partway through the COPD section, so IPF, lung cancer, microbiome and trial details are summarised from the abstract only.
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