Aging and lung diseases: Unraveling mechanisms and therapeutic targets

Abstract

As life expectancy increases globally, the prevalence of various age-related diseases among the elderly is rising. Advancing age is associated with both the incidence and mortality of a variety of respiratory diseases; however, the specific correlations and underlying mechanisms remain incompletely understood. This review summarizes changes in lung physiology and structure, as well as the biology of immune system cells, in relation to idiopathic pulmonary fibrosis, acute respiratory distress syndrome, pulmonary hypertension, asthma, chronic obstructive pulmonary disease, and lung cancer. It also offers a comprehensive discussion of the relationships between these lung diseases and aging, along with potential mechanistic insights. Finally, the review underscores that the association between aging and lung disease supports the development of personalized intervention strategies, with particular consideration of disease heterogeneity. Future research should prioritize the identification and validation of robust aging biomarkers and aging-related disease phenotypes.

Keywords: Acute respiratory distress syndrome; Asthma; Cellular senescence; Chronic obstructive pulmonary disease; Idiopathic pulmonary fibrosis; Immune senescence; Lung aging; Lung cancer; Pulmonary hypertension; Treatment strategy.

Fig. 1

Regulatory mechanisms of aging involved in IPF. Close relationships between the age-related phenotypes of key cell types—alveolar epithelial cells, fibroblasts, and macrophages—and IPF pathogenesis. Akt: Protein kinase B; Arg-1: Arginase-1; Bcl-2: B-cell lymphoma-2; ERK: Extracellular signal-regulated kinase; HIF-1α: Hypoxia-inducible factor-1α; IGFBP2: Insulin-like growth factor binding protein 2; IL-11: Interleukin-11; IL-6: Interleukin-6; MEK: Mitogen-activated protein kinase; NF-κΒ: Nuclear factor kappa-B; NOX4: Recombinant nicotinamide adenine dinucleotide phosphate oxidase 4; Nrf2: Nuclear factor erythroid 2-related factor 2; PAI-1: Plasminogen activator inhibitor 1; PDK1: Pyruvate dehydrogenase kinase 1; PINK1: PTEN-induced putative kinase 1; pRb: Retinoblastoma protein; PTEN: Phosphatase and tensin homolog; RB: Retinoblastoma protein; TFAM: Mitochondrial transcription factor A; TGF-β1: Transforming growth factor-β1; TNF-α: Tumor necrosis factor-α; TP53: Transcription factor p53.

Fig. 2

Regulatory mechanism of ARDS-related aging. This schematic illustrates the aging phenotypes of key cell types closely related to ARDS pathogenesis, with possible involvement in mitochondrial disorders, inflammatory responses, and coagulation and fibrinolysis. ARDS: Acute respiratory distress syndrome; ROS: Reactive oxygen species; IL: Interleukin; INF-γ: Interferon-γ; TNF-α: Tumor necrosis factor-α. Created with BioRender.com.

Fig. 3

Dysregulation of mTOR and TGF-β/SMAD signaling in the cellular senescence of PH. Normal cells (left) maintain balanced signaling of the mTOR and TGF-β/SMAD pathways. Senescent cells (right) exhibit DNA damage response activation (ATM/CHK2/p53/p21), permanent cell cycle arrest, mTOR dysregulation, and SASP formation, establishing feedback loops that promote neighboring cell senescence and tissue dysfunction. AKT: Protein kinase B; ATM: Ataxia telangiectasia mutated; CHK2: Checkpoint kinase 2; CDK2: Cyclin-dependent kinase 2; CDK4/6: Cyclin-dependent kinase 4/6; DSB: Double-strand break; G1: Gap 1 phase; G2: Gap 2 phase; M: Mitotic phase; mTOR: Mammalian target of rapamycin; P: Phosphorylation; PI3K: Phosphatidylinositol 3-kinase; PH: Pulmonary hypertension; RB: Retinoblastoma protein; ROS: Reactive oxygen species; RTK: Receptor tyrosine kinase; S: Synthesis phase; SARA: Smad anchor for receptor activation; SASP: Senescence-associated secretory phenotype; SMAD2/3/4: Small mothers against decapentaplegic homolog 2/3/4; TGF-β: Transforming growth factor-β. Created with BioRender.com.

Fig. 4

Aging-associated mechanisms and anti-aging treatments of asthma. Aging contributes to the onset and progression of asthma by initiating a series of fundamental biological processes, including DNA damage, mitochondrial dysfunction, loss of proteostasis, epigenetic alterations, and stem cell exhaustion, among others. Collectively, these factors lead to irreversible airway inflammation, remodeling, and impaired barrier function. Targeting these mechanisms through senomorphic and senolytic interventions, as well as regenerative stem cell therapies, represents a highly promising novel approach for asthma treatment. ATP; cGAS: cGAMP synthase; EMT: Epithelial-mesenchymal transition; IL-6: Interleukin-6; IRE1β: Inositol-requiring enzyme 1 beta; MMPs: Matrix metalloproteinases; mtDNA: Mitochondrial DNA; NF-κB: Nuclear factor kappa B; p21: Cyclin-dependent kinase inhibitor 1; p53: Tumor protein p53; ROS: Reactive oxygen species; SASP: Senescence-associated secretory phenotype; STING: Stimulator of interferon genes; TGF-β1: Transforming growth factor beta 1; UPR: Unfolded protein response; XBP1s: Spliced X-box binding protein. Created with BioRender.com.

Fig. 5

Regulatory mechanisms of premature lung aging in COPD. Premature lung aging is driven by the combined effects of age, environmental exposures, and genetic predisposition. Key mechanisms of cellular senescence includes telomere shortening, oxidative stress, mitochondrial dysfunction, immunosenescence, stem cell exhaustion, epigenetic alterations, and impaired anti-aging systems. ATM: Ataxia-telangiectasia mutated kinases; ATR: Ataxia telangiectasia and Rad3-related protein; CDK: Cyclin-dependent kinase; CHK2/1: Checkpoint kinase 2/1; Foxo: Forkhead box O; GATA: GATA binding protein; MMPs: Matrix metalloproteinases; MAPK: Mitogen-activated protein kinase; mTOR: Mechanistic target of rapamycin; NF-κB: Nuclear factor kappa B; pRb: Retinoblastoma protein; ROS: Reactive oxygen species; SASP: Senescence-associated secretory phenotype; SIRT1: Sirtuin 1.

Fig. 6

Schematic diagram illustrating the dual role of aging in lung cancer initiation and progression. Cellular stressors (oncogene activation, DNA damage, telomere shortening, therapy, etc.) drive cancer cells into senescence, leading to growth arrest and immune-mediated clearance by CTLs and NK cells, while senescence escape via p53 pathway inactivation, TERT reactivation and oncogenic rewiring confers replicative immortality. During organismal aging, lung tissues accumulate genomic and metabolic damage and senescent stromal/epithelial cells release SASP factors (e.g., IL-6, IL-8, TGF-β, MMPs, growth factors) that expand premalignant clones, recruit immunosuppressive cells (Tregs, TAMs, TANs), and remodel the ECM, creating a pro-tumor microenvironment that promotes tumor development and progression. Thus, aging functions as a double-edged sword, cell-autonomous senescence restricts tumor growth, whereas the aged, senescent microenvironment fuels lung cancer evolution. CTL: Cytotoxic T lymphocyte; ECM: extracellular matrix; IL-6: Interleukin-6; MMP-1: Matrix metalloproteinase-1; mTOR: mammalian target of rapamycin; NK: Natural killer cell; PAR-1: Protease-activated receptor-1; PI3K: Phosphatidylinositol 3-kinase; ROS: Reactive oxygen species; SASP: Senescence-associated secretory phenotype; STAT3: Signal transducer and activator of transcription 3; TAMs: Tumor-associated macrophages; TANs: Tumor-associated neutrophils; TERT: Telomerase reverse transcriptase; TGF-β: Transforming growth factor-beta; Tregs: Regulatory T cells; Ub: Ubiquitin; USP5: Ubiquitin specific peptidase 5.