Aging and lung Unraveling mechanisms and therapeutic targets

Authors: Yanan Zhou, Gaoying Chen, Xiang Li, Xiaohe Li, Zeqiang Lin, Li Liu, Dan Pu, Jiyuan Chen, Yuqin Chen, Ziying Lin, Zili Zhang, Lingling Zhu, Wenju Lu, Wen Ning, Jian Wang, Songmin Ying, Jing Zhang, Qinghua Zhou, Yuanlin Song

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.

Introduction

Human aging results from the combined effects of weakened natural selection and pleiotropic constraints.^1^^,^^2^ The global elderly population is steadily growing, becoming a major contributor to rising healthcare costs and presenting economic challenges related to medical expenditures.^3^ It is critical to understand the relationship between aging and age-related diseases, which increase in incidence with age and include cancer, diabetes, cardiovascular diseases, neurodegenerative disorders, and chronic obstructive pulmonary disease (COPD).4, 5, 6 Pulmonary diseases that have been extensively studied in the context of aging also include idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), pulmonary hypertension (PH), lung cancer,7, 8, 9 and asthma. Among these conditions, age is a widely reported risk factor for ARDS, with both incidence and mortality rising significantly with age, particularly in individuals over 80 years.10, 11, 12, 13 A prospective longitudinal cohort study showed that the 90-day mortality for young (18–54 years), middle-aged (55–67 years), and elderly (≥ 67 years) patients with ARDS was 30 %, 37 %, and 43 %, respectively, with middle-aged and elderly patients having a significantly higher risk of death than younger patients.^14^ One study demonstrated that long-term sequelae following severe infection, including elevated cytokine levels and decreased functional ability, are also observed during the aging process.^15^ This parallel suggests that aging-related mechanisms (e.g., immunosenescence, chronic inflammation) may underlie or exacerbate the pathogenesis of chronic lung disease following infection. Aging is also one of the most important risk factors for cancerous diseases,^16^ with lung cancer incidence increasing with age^17^ and peaking between ages 85 and 90 years.^18^

Given the high incidence of lung disease and the complexity of lung aging, as well as their potential interrelationship, this review aims to comprehensively summarize the impacts of aging on the occurrence, progression, and treatment response of lung diseases, including IPF, ARDS, PH, asthma, COPD, and lung cancer. Additionally, it explores underlying aging-related mechanisms and clinical intervention strategies tailored to older populations. A deeper understanding of these interactions may lead to the development of more precise, effective, and personalized approaches to patient management.

Aging and IPF

IPF is a progressive, fibrotic, and often lethal interstitial lung disease of unknown etiology, with a mean survival of 2–3 years after diagnosis.^19^ Its primary histopathological feature is a usual interstitial pneumonia (UIP) pattern characterized by a heterogeneous appearance, with areas of subpleural fibrosis and honeycombing alternating with areas of less affected or normal parenchyma.^20^ Aging is an independent risk factor for IPF, with an important influence on its progression.^7^ IPF mainly affects the elderly (≥ 65 years), with incidence increasing with age.21, 22, 23, 24 While its general prevalence is 10–60 cases per 100,000 people, it rises as high as 400 cases per 100,000 in those over 65 years.^25^ Although the pathogenesis of IPF is incompletely understood, a multicellular model is emerging, characterized by injured epithelial cells, hyperactivated fibroblasts, and excessive deposition of extracellular matrix (ECM), which contribute to defective repair resulting in the initiation and progression of pulmonary fibrogenesis.^26^ Recent research found that age-related morphological and physiological changes in the lung caused abnormal alveolar epithelial cell and fibroblast overactivation, dysregulated innate and adaptive immune responses, and increased oxidative stress, thereby increasing susceptibility to disrepair.^7^ In the following sections, we describe the roles of cellular senescence, telomere attrition, mitochondrial dysfunction, and loss of proteostasis in IPF (Fig. 1).Fig. 1Regulatory 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 1

Aging-related pathogenesis of IPF

IPF-related cellular senescence

The pathogenesis of IPF involves the senescence of various cell types, including epithelial cells, fibroblasts, and immune cells. Senescence-related remodeling of lung tissue matrix and profibrotic lesions play a key role in the occurrence and development of IPF. A deeper understanding of the role of cellular senescence in IPF pathogenesis is crucial for the development of related therapeutic strategies.

*Epithelial * Recent studies have shown that senescence of alveolar progenitor cells is a key factor in the progression of IPF.^27^ Alveolar epithelial cells (AECs) of type 1 (AEC1s) are derived from type 2 AECs (AEC2s) via a transition state known as transitional cells, also referred to as damage-associated transitional progenitors.^28^^,^^29^ Single-cell transcriptome analysis of IPF lung tissues revealed transcriptional features of cellular senescence and enrichment of aging-related pathways in distal AECs.^30^ Accumulation of these transitional cells in IPF lungs suggests a connection between senescence and abnormal AEC2 differentiation, indicating a failure to regenerate AECs and restore alveolar structure.31, 32, 33, 34 Meanwhile, these senescent AEC2s also create a profibrotic microenvironment that induces the senescence of neighboring cells through paracrine senescence-associated secretory phenotype (SASP) signaling, further promoting myofibroblast differentiation and collagen deposition, thereby aggravating fibrosis progression.35, 36, 37 Current studies have identified multiple signaling pathways that regulate AEC2 senescence, including a variety of transcription factors and cell cycle-related genes.^38^ The transcription factor p53 (TP53) and retinoblastoma protein (RB) pathways have been widely studied. TP53 mediates cell growth arrest through a variety of effectors, leading to a series of aging phenotypes (e.g., DNA damage, telomere dysfunction, SASP^39^) that cause alveolar stem cell regeneration disorders^40^^,^^41^ and promote aging and fibrosis.^42^ The pRb/p16 pathway also regulates senescence and promotes self-renewal and differentiation of AEC2s.^43^ Additionally, the Sirtuin pathway—which regulates autophagy and mitochondrial function—is closely linked to AEC2 aging, but plays a protective role by mitigating AEC2 senescence and fibrosis through regulation of zinc metabolism.^44^ Other signaling pathways that also regulate AEC2 senescence include WNT/β-catenin, nuclear factor (NF)-κB, insulin-like growth factor, and transforming growth factor (TGF)-β1/interleukin (IL)-11/mitogen-activated protein kinase/extracellular signal-regulated kinase (TIME).45, 46, 47, 48 In conclusion, impaired regenerative functioning of alveolar progenitor cells can lead to aging and the formation of a profibrotic environment, which is a key promotional factor in fibrosis progression.

Fibroblasts: IPF lung fibroblasts exhibit characteristic features of cellular senescence during serial in vitro passaging, such as increased cell size, flattened morphology, reduced division rate, and elevated senescence-associated (SA)-β-galactosidase (SA-β-gal) activity. At the same time, these cells show increased expression levels of cell cycle suppressor proteins p21^waf1^ and p16^ink4D^, as well as telomere shortening and SASP characteristics.^49^ In a mouse model of bleomycin injury, the irreversible pulmonary fibrosis in aged mice may be due to the persistence of aging fibroblasts.^50^ Additionally, studies have shown that antiaging drugs targeting senescent fibroblasts significantly improve pulmonary fibrosis in mice, suggesting that these cells play a detrimental role in disease progression.^51^ Current studies have examined the regulatory mechanisms for the dysfunction of senescent IPF lung fibroblasts, which include oxidative stress, mitochondrial dysfunction, insufficient autophagy, reduced apoptosis, and metabolic reprogramming.^52^ Aging-associated oxidative stress can disrupt the balance between lung damage and repair. Primary lung fibroblasts cultured in an oxidative environment show an enhanced profibrotic phenotype, with fibroblasts from elderly mice being particularly responsive to oxidative stress.^53^ Regarding mitochondrial function, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) 4 is highly expressed in senescent myofibroblasts and can inhibit mitochondrial biological functions through Nrf2- and mitochondrial transcription factor A (TFAM)-dependent pathways.^54^ The mitophagy impairment mediated by Parkin (Prkn) deficiency was associated with increased ECM deposition in IPF lung fibroblasts.^55^ Autophagy-associated markers Beclin1, LC3, and p62 showed reduced activity in IPF lung fibroblasts, representing an autophagy defect that may lead to increased fibroblast invasiveness.^56^ Apoptosis is a genetically controlled form of programmed cell death. Senescent fibroblasts exhibit greater resistance to apoptosis than senescent epithelial cells,^50^ with lung fibroblasts from aged mice showing heightened survival in response to apoptotic stimuli (hydrogen peroxide and tumor necrosis factor [TNF]-α]).^57^ Metabolic reprogramming of IPF lung fibroblasts is characterized by upregulated activity of the glycolytic pathway and dysregulated metabolism of various substances (e.g., amino acids and lipids), driven by multiple signal transduction cascades and interactions within the senescent fibroblasts.^58^ Microenvironmental factors such as hypoxia may further disrupt cellular energy homeostasis. Upregulation of hypoxia-inducible factor-1α (HIF-1α) mediates the overexpression of pyruvate dehydrogenase kinase 1 (PDK1), thereby activating glycolysis and promoting the activation of lung fibroblasts.^59^ Conversely, glycolysis inhibition attenuates lung fibroblast activation and the hyperproliferative phenotype of IPF lung fibroblasts.^60^ As the disease progresses, senescent fibroblasts accumulate, become hyperactivated, and secrete large amounts of ECM, thereby exacerbating fibrosis progression.

*Immune * In IPF, abnormal repair of AECs leads to the recruitment and activation of relevant immune cells, resulting in local immune dysfunction that promotes sustained myofibroblast activation and accelerates fibroblast foci formation.^61^ Thus, promoter epithelial cells, effector fibroblasts, and regulatory innate/adaptive immune cells together constitute the “immunofibrotic niche” in IPF.^26^ Senescence of immune cells could lead to the impairment of the immune surveillance ability, which is responsible for the accumulation of senescent cells in the lungs.^62^ Senescent cells that are not cleared in time continue to accumulate and elevates SASP mediator levels in fibrotic lesions, which in turn recruits immune cells and perpetuates chronic inflammation and fibrosis.^63^ Macrophage senescence leads to phenotypic transformation and an increased release of inflammatory cytokines, thus promoting the formation of a chronic inflammatory microenvironment.^64^ The presence of p16^Ink4a^/β-galactosidase-positive senescent macrophages in pulmonary fibrosis could explain the accumulation of senescent cells, because these macrophages lose the ability to eliminate them.^65^ In addition to IPF, the same immune cell senescence phenotype also exists in progressive pulmonary fibrosis diseases such as radiation-induced pulmonary fibrosis. In a mouse model of ionizing radiation-induced pulmonary fibrosis, macrophages were found to be positive for SA-β-gal, with markedly elevated expression of senescence markers (p16, p21, b-cell lymphoma 2 [Bcl-2], and b-cell lymphoma-extra large [Bcl-xl]), profibrotic mediators (TGF-β1 and arginase-1 [Arg-1]), proinflammatory cytokines (TNF-α and interleukin [IL]−6), and SASP-associated chemokines and matrix metalloproteinases (MMPs). These factors collectively stimulate a fibrotic phenotype in lung fibroblasts.^66^ Research has also shown that mitochondria in aging macrophages from IPF lung tissue are damaged,^67^^,^^68^ leading to the accumulation of reactive oxygen species (ROS) and activation of mitophagy through protein kinase Bα (Akt 1).^69^ This process regulates apoptotic resistance and promotes fibrosis progression.^69^ Aging macrophages also exhibit heightened sensitivity to harmful stimuli via activation of the nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin domain protein 3 (NLRP3) inflammasome, further promoting a profibrotic phenotype.^70^

Telomere attrition

Telomeres are tandem repeat sequences at the ends of chromosomes, and their length affects cell replication and senescence.^71^ Proteins that bind to telomeres include telomeric repeat-binding factor (TRF) 1 and TRF2, which play important roles in maintaining telomere structure, protecting chromosome ends, and regulating telomere length, while also influencing cell division, apoptosis, immortalization, and carcinogenesis. Studies in mice have shown that the absence of TRF1 in AEC2s leads to severe telomere dysfunction in the lungs, inducing pulmonary fibrosis via DNA damage and upregulating the cell cycle suppressor protein p21/p53.^72^ Telomeric repeat sequences are added by telomerase through the actions of two telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC). When telomere length becomes severely shortened and falls below a functional threshold, it sends a p53-dependent DNA damage response (DDR) signal, triggering apoptosis or cellular senescence.^73^ Studies have shown that mothers against decapentaplegic homolog 3 (SMAD3)-mediated TERT inhibition and telomere shortening are crucial for TGF-β-induced pathological fibrosis.^74^ Collectively, these studies indicate that telomere dysfunction is the key driving factor of IPF.

Mitochondrial dysfunction

Mitochondrial dysfunction is a key aging indicator,^75^ closely related to various aging-related diseases, including IPF. In IPF, pathogenic mitochondrial dysfunction mainly involves imbalances in mitochondrial ROS levels and the electron transport chain, altered mitochondrial DNA (mtDNA), and reduced mitochondrial-mediated autophagy. PTEN-induced putative kinase 1 (PINK1)—a key factor in mitochondrial autophagy—plays a crucial role in IPF pathogenesis. Bueno et al^76^ found that significantly decreased PINK1 expression in the AECs of fibrotic aging mice resulted in defective mitochondrial autophagy, induced epithelial cell senescence, and increased susceptibility to virus-mediated fibrosis.

Loss of proteostasis

Impaired protein homeostasis has been found to significantly induce aging and age-related diseases. Evidence of protein homeostasis alterations in IPF includes protein misfolding, endoplasmic reticulum (ER) stress, autophagy defects, and impaired proteasome activity.^77^^,^^78^ The ER processes proteins and mediates their folding, assembly, transport, and degradation. ER homeostasis is regulated by various factors, including cellular metabolism, redox balance, and calcium homeostasis. Alterations in these factors can induce ER stress and activate the unfolded protein response (UPR).^79^ Studies have demonstrated that ER stress can regulate AEC2 apoptosis,^80^ via phosphofurin acidic cluster sorting protein 2 (PACS2)-transient receptor potential cation channel subfamily V member 1 (TRPV1) axis, while the UPR can promote pulmonary fibrosis by upregulating profibrotic mediators.^81^ Reports have shown an association between ER stress and increased levels of p16 and p21 in lung epithelial cells of elderly patients with IPF.^49^ Torres-Gonzalez et al^82^ found that ER stress markers in AEC2s were significantly elevated in aged mice compared with those in young mice in a pulmonary fibrosis model. Previous studies have demonstrated that fibroblasts treated with ER stress inducers show increased susceptibility to myofibroblast differentiation induced by TGF-β.^83^ Additionally, knockdown of the ER chaperone calreticulin (CALR) using small interfering RNA in mouse and human IPF fibroblasts reduces the TGF-β1-induced production of collagen and fibronectin.^84^ Therefore, protein homeostasis imbalance also plays an important role in age-related pulmonary fibrosis.

Therapeutic strategies targeting aging mechanisms in IPF

The occurrence and progression of IPF are highly correlated with senescence, making senescence-targeting therapies a promising avenue for treatment. Broadly, these therapies are classified as senomorphic or senolytic (Supplementary Fig. 1): senomorphics target pathological SASP signaling, while senolytics target senescent cells that potentially release SASP factors.^85^ In senolytic therapy, drugs targeting senescent AECs lead to reduced expression of profibrotic markers and enhanced epithelial cell function, thereby ameliorating disease progression in animal models of pulmonary fibrosis.^86^ Furthermore, a combination of two senolytics—the Src kinase inhibitor dasatinib plus the flavonoid quercetin—has entered clinical trials.^87^ Quercetin alone similarly targets senescent fibroblasts to alleviate pulmonary fibrosis.^50^ By modulating bone morphogenetic protein (BMP) 4, the mitophagy of senescent lung fibroblasts can be enhanced, inhibiting pulmonary fibrosis.^88^ Citrus alkaline extracts can be utilized to target senescent lung fibroblasts by inhibiting the expression of senescence markers p16 and p21 and profibrotic marker alpha-smooth muscle actin (α-SMA), thereby ameliorating lung fibrosis in mice via activation of cyclooxygenase-2 (COX-2).^89^ Hesperidin alone can also target senescent fibroblasts to alleviate pulmonary fibrosis.^90^ Currently, the antifibrotic drug nintedanib has shown no significant effect on the pathological phenotypes of senescent fibroblasts and epithelial cells.^91^^,^^92^ However, targeting senescent cells remains a promising strategy for developing more effective IPF therapies.

Aging and ARDS

ARDS is an acute respiratory condition characterized by hypoxemia and noncardiogenic pulmonary edema leading to bilateral chest radiographic opacities.^93^ The primary causes of death in ARDS are sepsis and multiple organ failure^94^; however, estimating the mortality directly attributable to ARDS is challenging and requires consideration of factors such as underlying etiology, severity, age, and sex. The emergence of the COVID-19 pandemic has underscored the impact of age as a significant mortality predictor.^95^ Follow-up data from COVID-19 patients at 1 year post-discharge revealed that those with longer stays in the intensive care unit, and those requiring invasive mechanical ventilation, had shorter relative telomere length in peripheral blood, increasing their susceptibility to cellular senescence and pulmonary-related complications.^96^ Following the onset of ARDS, the lungs exhibit damage to the alveolar–capillary barrier, which comprises a thin layer of AECs and capillary endothelial cells. This involves gaps between endothelial cells, upregulation of adhesion molecules and injurious mediators, the occurrence and resolution of pulmonary inflammatory responses, dysregulated coagulation and fibrinolysis, and subsequent repair processes.^97^ Clinical evidence linking age to the incidence and mortality of ARDS, along with potential overlaps between normal aging and pathological processes in the lungs, further suggests a correlation between aging and ARDS. In the following sections, we describe the roles of cellular senescence, mitochondrial dysfunction, inflammatory and immune responses, and dysregulated coagulation and fibrinolysis in ARDS (Fig. 2).Fig. 2Regulatory 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 2

Aging-related pathogenesis of ARDS

ARDS-related cellular senescence

The senescence of various cell types, including epithelial cells, endothelial cells, fibroblasts, and a range of immune cells, is frequently discussed in the context of ARDS progression. The persistent activation of senescence pathways in these cells not only contributes to sustained inflammation and impaired tissue repair, but also promotes fibrosis and weakens the structural integrity of the alveolar–capillary barrier. This collective dysfunction increases the lung’s susceptibility to injury.^98^ Therefore, elucidating the role of cellular senescence in ARDS pathogenesis is crucial for developing age-related and senescence-targeted therapeutic strategies, particularly given the shared mechanisms underlying lung aging and ARDS progression.

*Epithelial * The age-related decline in pulmonary epithelial cell turnover is associated with increased apoptosis in bronchiolar epithelial cells, AECs, and basal cells, alongside reduced proliferation of Clara cells.99, 100, 101, 102 Among these, abnormally activated AECs produce many of the growth factors and chemokines responsible for the proliferation, migration, and activation of fibroblasts. During the early stages of fibrosis, excessive AEC activation involves mechanisms such as aberrant reactivation of developmental pathways, defects in molecules essential for epithelial integrity, and accelerated senescence-associated characteristics.^103^ One marker of AEC damage, the receptor for advanced glycation end-products (RAGE), promotes the progression of both the exudative and fibroproliferative phases of ARDS. RAGE also serves as a biomarker for ARDS severity and mortality, although this association may be modulated by aging.104, 105, 106, 107 Tissue remodeling related to ARDS, driven by alveolar epithelial injury, primarily occurs in the lung parenchyma. Senescence of AEC2s can increase the vulnerability of the lung parenchyma to injury by impairing re-epithelialization.^8^ The causes of AEC2 damage include increased apoptosis, elevated ROS production, DNA damage, reduced autophagy, and dysregulation of the UPR—all of which can exacerbate ARDS prognosis.108, 109, 110 As cellular senescence progresses, age-related dysfunction in AEC2s contributes to a highly proinflammatory and oxidative environment within the lungs.^111^

*Endothelial * Pulmonary capillary endothelial cells constitute a vital component of the blood–gas barrier. In particular, senescent pulmonary endothelium plays a crucial role in the pathogenesis and progression of ARDS, which can be categorized into three main aspects. Firstly, senescent pulmonary endothelium exhibits increased susceptibility to oxidative stress. Oxidative stress arises from an overproduction of ROS and/or a decline in antioxidant defenses, leading to a disrupted redox balance. In ARDS, senescent pulmonary endothelial cells display heightened vascular permeability, a response that is further aggravated by the upregulation of NADPH oxidase—the primary cellular source of ROS.^112^^,^^113^ Secondly, endothelial senescence impairs nitric oxide (NO) signaling, a pathway critically involved in ARDS pathophysiology. Elevated ROS levels in senescent pulmonary endothelial cells have been shown to downregulate NO signaling, thereby compromising endothelial-dependent vasodilation and vascular homeostasis.^114^ Thirdly, senescent pulmonary endothelium shows heightened vulnerability to infection. Age-related decline in zinc metalloproteinase STE24 (ZMPSTE24), for example, may enhance the susceptibility of vascular endothelial cells to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, thereby promoting ARDS development in the elderly.^115^

Fibroblasts: Fibroblasts, which are widely distributed throughout the lung interstitium, play a central role in localized responses and tissue repair processes. These cells primarily contribute to the structural organization and remodeling of the ECM by secreting glycoproteins, MMPs, and other components.^7^ In normal lung aging, the ECM undergoes changes characterized by increased collagen, which promotes age-related alterations in tissue elasticity and expansion of air spaces. Aged ECM also exhibits reduced diversity of structural proteins.^116^ In lung injury, the production of a fibrotic matrix is heightened by the increased recruitment of circulating multipotent mesenchymal progenitor cells.^117^ While this leads to increased matrix deposition, the repair process becomes maladaptive. Specifically, upregulated MMP expression in aged or senescent fibroblasts further influences ECM composition and function by degrading critical structural components, such as collagen and elastin.^118^^,^^119^ This degradation not only compromises ECM integrity but thereby also exacerbates tissue damage and fibrosis, particularly in ARDS-like conditions. In addition to losing their regenerative potential, senescent fibroblasts adopt a profibrotic and inflammatory phenotype that can lead to excessive ECM deposition.

*Immune * Immune cell activation plays a central role in the inflammatory processes of ARDS. Crucially, the function of nearly all these immune cell types declines with age, creating a pervasive state of immune dysregulation that underpins the increased severity of ARDS in the elderly. Alveolar macrophages, the resident immune cells in the airways, are critical for both initiating and resolving inflammation. However, their initial response to microbial and other inflammatory stimuli decreases with age.120, 121, 122 Elderly populations show reduced macrophage phagocytic capacity and impaired clearance of apoptotic cells, leading to prolonged inflammatory responses following infection.^123^^,^^124^ These declines in older individuals are primarily attributable to altered TLR signaling pathways and increased negative feedback signaling related to chronic inflammation.^125^ Neutrophils, which play a key role in clearing pathogens during the early stages of lung infections through various antimicrobial mechanisms, also exhibit a functional decline with aging. For example, elderly mice show reduced infiltration and delayed chemokine production by neutrophils during early infections.^126^ In ARDS, markers involved in neutrophil responses, such as IL-6 and IL-8, show an age-dependent increase in their levels.^127^ The effects of aging on neutrophils may vary depending on the type of stimulus. For instance, neutrophils exhibit an age-related reduction in ROS production in response to stimulation with Staphylococcus aureus, but not Escherichia coli.^128^ These pathogen-specific responses imply that the underlying mechanisms of aging could also vary in ARDS triggered by different microbes. Dendritic cells (DCs) in older mice exhibit impaired phagocytic and endocytic functions in vitro, reducing their ability to activate T cells in lymph nodes following viral infections.129, 130, 131 It has been suggested that age-related mitochondrial dysfunction in DCs contributes to these declines in phagocytic and antigen-presenting capacities.^132^ Innate lymphoid cells (ILCs), which assist with regulating immune and inflammatory responses and restoring airway epithelial integrity, may also exhibit age-related changes in function and frequency.^7^ Beyond ILCs, the frequency and cytokine production of natural killer (NK) cells in the lung post-infection decrease with age, although the specific mechanisms remain unclear.^133^^,^^134^ In parallel, the adaptive immune system is affected, as CD8^+^ T-cell counts decline with age, leading to impaired immunity associated with poor ARDS prognosis.^135^ Furthermore, monocytes—key participants in the cytokine storms of severe COVID-19—also exhibit age-related functional and phenotypic changes.^136^ These findings demonstrate that aging distinctively compromises both innate and adaptive immune cells, which collectively contributes to the increased vulnerability to ARDS and other lung diseases in older populations.

Mitochondrial dysfunction

Mitochondrial dysfunction and cellular senescence are interrelated processes. Senescence activation involves both pro-oxidative and proinflammatory axes closely linked to peroxisome proliferator-activated receptor gamma (PPARG) coactivator 1 beta (PGC-1β)-mediated mitochondrial biogenesis, with pathways involving ROS and DDR.^137^ Older populations show declines in both mitochondrial oxidative phosphorylation (ATP production) and antioxidant defenses, leading to increased ROS production. The excess ROS can damage DNA and key mitochondrial components, thereby accelerating cellular senescence.^138^ The effects of aging on mitochondrial structure and function include enlargement, cristae disintegration, and inner membrane disruption—all of which impair energy production.^76^^,^^139^^,^^140^ Critically, in the context of trauma or sepsis, this age-associated mitochondrial dysfunction contributes to the release of mtDNA damage-associated molecular patterns (DAMPs), which have been shown to exacerbate the inflammatory responses driving ARDS progression in elderly patients.^141^

Inflammaging and the immune response

In ARDS, the inflammatory response is characterized by systemic increases in inflammatory cytokines and oxidative stress. This reflects not only sustained activation of the innate immune system, but is also profoundly exacerbated by the engagement of various aging-related mechanisms.^142^^,^^143^ Senescent immune and nonimmune cells can enhance the production of inflammatory mediators through SASP signaling.^8^ In elderly individuals, particularly those with pneumonia, circulating monocytes produce elevated levels of IL-6 and TNF-α, both at baseline and in response to endotoxin stimulation.^144^ This inflammatory shift is not isolated; elevated circulating TNF-α acts as a driver, promoting a senescent monocyte phenotype and the premature release of immature monocytes from the bone marrow.^8^ Moreover, the aging process generates DAMPs, including DNA and misfolded proteins. These DAMPs sustain inflammation by binding to pattern recognition receptors on innate immune cells like monocytes, thereby locking them into a state of chronic, low-grade activation.^8^^,^^142^ Studies have shown that the immune system of younger individuals, which maintains a balance between proinflammatory and anti-inflammatory cytokine networks, can limit the progression of ARDS. In contrast, with advancing age, the immune system loses this balance and enters a mildly inflammatory state.^145^ This age-related “inflammaging” is exacerbated by the activation of the DDR and the acquisition of the SASP, which together promote a proinflammatory environment. Crucially, inflammation-associated microRNAs (miR-146, miR-155, miR-21) serve as key regulators that interconnect DDR, cellular senescence, and the chronic inflammatory state.^146^

Dysregulated coagulation and fibrinolysis

The coagulation and fibrinolytic systems play critical roles in both hemostasis and tissue repair. Abundant extravascular fibrin and coagulation factors in the lung interstitium and alveolar spaces is a hallmark of diseases such as IPF and ARDS.^147^^,^^148^ Elderly populations exhibit significant increases in markers of coagulation and fibrinolytic system activation in the bloodstream, which are closely linked with systemic inflammatory responses. These associations may be regulated by various components of the SASP. For instance, PAI-1, a key fibrinolysis inhibitor, is a canonical SASP factor that directly promotes a procoagulant state by inhibiting clot breakdown and has been implicated in inducing alveolar cell senescence.^149^ Similarly, the SASP cytokine IL-6 exacerbates coagulopathy by serving as a potent inducer of tissue factor, thus activating the extrinsic coagulation pathway. These examples illustrate how the SASP mechanistically bridges aging, inflammation, and coagulation dysfunction.^150^ Further research into these SASP-mediated pathways is essential to identify therapeutic targets for ARDS.

Therapeutic strategies targeting aging mechanisms in ARDS

The clinical heterogeneity of ARDS necessitates therapies tailored to specific subphenotypes. Targeting aging mechanisms has emerged as a key strategy, supported by several distinct yet complementary approaches. This includes directly targeting key molecular regulators of aging—such as the epigenetic enzymes PARP1/SIRT1 and the transcription factor IRF1—to address upstream drivers of senescence and inflammation.^151^^,^^152^ Another approach involves pharmacological intervention with “anti-aging” compounds like SIRT1 activators and senolytics, which show promise in preclinical models.^153^ A third strategy utilizes cellular and biomolecular tools, such as mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs), to modulate the tissue microenvironment, with efficacy linked to the donor’s biological age.^154^ Together, these approaches provide a multi-faceted framework for developing precise ARDS treatments by intervening at different levels of the aging process.

Additionally, lifestyle interventions to improve symptoms has become an important focus in research on aging. For example, exercise and caloric restriction offer promising approaches for alleviating various mitochondrial dysfunctions.^6^ Food components, including curcumin, resveratrol, and genistein, can serve as adjunctive treatment for ARDS, most likely through accelerating immune cell recruitment and tissue repair, as well as anti-oxidant properties.^155^

Future research should bridge aging biology and ARDS therapy through two core translational efforts. First, a mechanism-driven approach should validate key targets (e.g., PARP1/SIRT1, IRF1) and optimize interventions like MSC-derived therapies using multi-omics and preclinical models. Second, a synergistic therapeutic approach should be explored, combining senolytic clearance, immunomodulation, and lifestyle interventions to enhance resilience. Advancing these innovations will require cross-disciplinary collaboration to ensure their translation into effective clinical applications.

Aging and PH

PH is a chronic vascular disease involving the abnormal proliferation of pulmonary artery endothelial cells (PAECs), pulmonary artery smooth muscle cells (PASMCs), and fibroblasts. It is characterized by increased pulmonary vascular resistance, and the most significant histopathological feature is vascular remodeling.^156^ PH prevalence increases significantly with age, from an estimated 1 % in the general population to approximately 10 % in individuals over 65 years of age. In the elderly, pulmonary hypertension associated with left heart disease (WHO Group 2) is the predominant etiology.^157^ This aging trend indicates that elderly patients differ significantly from younger patients in etiology and clinical features, suggesting aging may contribute to pulmonary hypertension development through specific pathophysiological mechanisms. Recent research has established cellular senescence as a significant and previously underappreciated risk factor in PH pathogenesis. The levels of senescence markers p16 and p21 are elevated in the lung tissue of PH patients,^158^ with increased p16 staining observed in both PASMCs and PAECs.^159^ Studies have shown the involvement of cellular senescence at various stages of pulmonary arterial hypertension (PAH).^160^ Supporting this connection, rats with PH induced by monocrotaline (MCT) exhibit downregulation of the antisenescence protein klotho.^161^ Triggers that induce senescence also promote PH, and DNA damage accumulation in PAECs and PASMCs is a common factor in vascular aging and PH.^162^ The morphological and functional manifestations of pulmonary vascular aging further underscore this relationship. Morphologically, aging is characterized by endothelial deterioration, increased collagen fiber content, and enhanced ECM deposition. Functionally, this aging process manifests as vascular wall stiffening, decreased sensitivity to vasodilator factors, increased responsiveness to vasoconstrictor agents, and diminished angiogenic capacity.^163^ Mechanistically, senescent vascular endothelial cells increase ROS generation, thereby initiating the inflammatory response.^164^ Endothelial cells may also develop oxidative stress and DNA damage in response to hypoxia, leading to cellular senescence.^165^ These senescent cells then act in an autocrine or paracrine manner through the SASP,^166^ creating a complex interplay of cellular senescence and vascular dysfunction that underscores the intricate relationship between aging and pulmonary vascular pathology.

Aging-related pathogenesis of PH

PH-related cellular senescence

Cellular senescence in PH manifests distinctly across different pulmonary vascular cell types, each contributing uniquely to disease pathogenesis through cell-specific mechanisms and secretory profiles.

PAECs: Pulmonary vascular endothelial dysfunction is considered an early or stimulating event in vascular remodeling of PH. Therefore, senescent endothelial cells play an important initiating and promoting role in the pathophysiology of PH. The levels of senescence marker, p16 and SA-β-gal, are higher in PAECs isolated from IPAH patients compared to those from healthy individuals.^167^ Single-cell RNA sequencing data from aged mouse and human lung tissues further reveal that most senescent lung cells are endothelial cells. Importantly, in the short term after senescent cell clearance, vascular structure remains relatively intact. However, genetic elimination of senescent endothelial cells in aged mice leads to distal pulmonary capillary loss and stimulates remodeling of larger vessels, thereby promoting the development or exacerbation of PH.^168^

PH and senescence share common pathogenic pathways. These senescence phenomena are closely associated with dysregulation of key signaling pathways (Fig. 3).^158^ Among these, the mTOR pathway plays a particularly important role in promoting cellular senescence. Activation of the mTOR pathway increases the expression of cell cycle inhibitors such as p16 and p21, disrupts cell cycle regulation, and contributes to vascular remodeling.^169^ Conversely, mTOR inhibition alleviates senescence phenotypes, reduces the secretion of SASP factors, and prevents morphological changes in PAECs.^170^^,^^171^ Complementarily, mTOR kinase leads to PTEN-loss-induced cellular senescence by phosphorylating p53,^172^ where p53 activation triggers downstream targets, ultimately resulting in cell cycle arrest. Beyond mTOR, TGF-β signaling plays a critical dual role as both a senescence inducer and a SASP component, creating a pathogenic feedback loop.^173^ In PAECs from PAH patients, TGF-β binding to transforming growth factor-β receptor type I/II (TβRI/TβRII) receptors activates small mothers against decapentaplegic (SMAD) 2/3/4 complexes, which directly upregulate cyclin-dependent kinase inhibitors p16, p21, p15, and p27, while suppressing proliferation factors including c-Myc.^174^^,^^175^ Additionally, TGF-β indirectly increases ROS levels and suppresses telomerase activity in PAECs, accelerating the senescent phenotype. This pro-senescent effect establishes a vicious cycle in which senescent PAECs secrete additional TGF-β as part of their SASP,^176^ further promoting senescence in neighboring cells and contributing to pulmonary vascular remodeling in PAH.Fig. 3Dysregulation 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/ 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/ Small mothers against decapentaplegic homolog 2/3/4; TGF-β: Transforming growth factor-β. Created with BioRender.com.Fig 3

Complementing these pathways, oxidative stress represents another critical mechanism driving PAEC senescence. PAECs from PAH patients exhibit increased susceptibility to apoptosis and senescence,^177^^,^^178^ closely linked with oxidative stress and endothelial dysfunction.^179^ At the molecular level, the thrombospondin-1 (TSP1)-CD47-nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1) signaling axis mediates enhanced PAEC senescence. Studies demonstrate increased abundance of TSP1 and NOX1 in lung tissue from elderly PAH patients. Activation of this axis leads to the generation of ROS, which activate the p53/p21/Rb pathway, induce cell cycle arrest, and promote the SASP. Inhibition of NOX1 blocks this process and protects against PAEC senescence,^180^ confirming that the TSP1-NOX1 axis is a key regulatory mechanism in pulmonary vascular aging and PAH pathogenesis. The oxidative stress induced by these pathways leads to critical functional impairments in PAECs. Specifically, oxidative stress reduces the expression and activity of endothelial nitric oxide synthase (eNOS), thereby impairing NO bioavailability, a key regulator of pulmonary vasodilation.^181^ These findings explain how senescence contributes to the enlargement of PAECs, characterized by Golgi dysfunction and aberrant trafficking of eNOS, which dissociates from the plasma membrane and accumulates in the cytoplasm.^182^ Supporting this mechanism, senescence marker protein (SMP) 30 is an antisenescence protein involved in the development of hypoxia-induced PH via impaired eNOS activity, and its deficiency in SMP30 knockout mice increases susceptibility to PH.^183^ PAEC senescence is also linked to mitochondrial respiratory chain dysfunction, which amplifies oxidative stress. In senescent PAECs, the catalytic activity of complex IV and relative protein levels of complex IV subunits I and IV are decreased by 84 % and 91 %, respectively, compared with those in young cells.^184^ This mitochondrial impairment not only compromises cellular energy metabolism but also contributes to increased ROS production, creating a feed-forward loop that further exacerbates oxidative stress and eNOS dysfunction.

An imbalance in various regulatory molecules fine-tunes the senescent state. Sirtuin 1 (SIRT1), an endogenous inhibitor of the Notch signaling pathway,^185^ plays a protective role against senescence. Knockout of SIRT1 activates the Notch signaling pathway, leading to a decrease in angiogenesis.^186^ In PAECs, downregulating SIRT1 expression increased the acetylation level of p53 and decreased the expression of eNOS, promoting the occurrence of senescence.187, 188, 189 MicroRNAs also play important regulatory roles. miR-21, which regulates inflammation and leads to endothelial cell senescence, was found to be upregulated and to impair the function of PAECs in lung tissues of patients with smoking-induced PH by activating phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mTOR signaling. Knockout of miR-21 in mice exposed to cigarette smoke attenuated this change.^190^ Similarly, miR-22 promoted senescence and reduced the angiogenic ability of endothelial cells by inhibiting the expression of AKT3.^191^ Conversely, upregulation of miR-214 can delay senescence of endothelial cells and enhance their ability to promote angiogenesis.^192^ These findings highlight the complex regulatory network involving multiple microRNAs in controlling PAEC senescence and angiogenic function.

PASMCs: PASMC senescence is an important contributor to the process of pulmonary vascular remodeling that underlies pulmonary hypertension in chronic lung disease.^193^ Senescent PASMCs exhibit elevated SA-β-gal activity and increased expression of senescence markers such as p16 and p21. A key mechanism by which senescent PASMCs drive disease pathology is through the SASP.^194^ Via secretion of both soluble factors (such as IL-6) and insoluble extracellular matrix components, senescent PASMCs stimulate the growth and migration of neighboring normal PASMCs, thereby promoting vascular remodeling.^195^^,^^196^ Mechanistically, activation of the mTOR/ribosomal protein S6 kinase beta-1 (S6K1) pathway in senescent PASMCs enhances IL-6 secretion. This IL-6, in turn, acts on both senescent and normal PASMCs in a paracrine manner, promoting their proliferation and further activation. This creates a self-reinforcing pathological cycle wherein senescent cells continuously activate neighboring cells, progressively accelerating vascular remodeling and disease progression.^197^

Multiple molecular pathways critically regulate PASMC senescence, with the mTOR pathway playing a central role. The mTOR pathway is closely associated with PASMC proliferation and pulmonary vascular remodeling.^198^ Supporting this mechanism, substantial activation of PI3K/Akt/mTOR signaling has been observed in senescent vascular smooth muscle cells but not in young cells.^199^ Conversely, mTOR inhibitors can alleviate senescence phenotypes and reduce the secretion of SASP factors. Although multiple signaling pathways are involved in cellular senescence, the p53/p16 axis plays a central role in PASMC senescence regulation. Experimental evidence demonstrates that nutlin-3a, an mouse double minute 2 (MDM2) antagonist and p53 activator, induces growth arrest and senescence in human PASMCs.^200^ Further supporting this axis, transglutaminase 2 (TG2), upregulated in hypoxia-induced PH and senescent PASMCs, promotes senescence via mitogen-activated protein kinase 14 (MAPK14) mediated p16/p21 upregulation. Senescent PASMCs show markedly increased TG2 expression, and silencing of TG2 significantly reduces p16 and p21 levels, switching PASMCs from a growth-arrested state to an activated cell cycle state, thereby mitigating senescence.^201^ This demonstrates the reversibility of the senescent phenotype through targeted molecular intervention.

Senescence in PASMCs is further driven by several fundamental cellular and molecular dysfunctions. DDR dysfunction represents a critical underlying mechanism. PAH-PASMCs exhibit increased DNA damage markers (53BP1 and γH2AX foci) alongside poly (ADP-ribose) polymerase-1 (PARP-1) overexpression, which drove miR-204 downregulation.^202^ This DDR dysfunction contributes to genomic instability and altered cellular phenotypes, potentially facilitating disease progression.^203^ Moreover, senescent cells release nuclear DNA fragments into the cytoplasm, inducing synthesis of the second messenger cyclic GMP-AMP (cGAMP) via cGAMP synthase (cGAS). This activates the stimulator of interferon genes (STING) protein and its downstream effectors, including NF-κB, resulting in inflammation.^204^ Consequently, researchers proposed that vascular smooth muscle cell senescence may exert its main impact through inflammation rather than through direct effects on proliferative capacity.^204^ In pulmonary hypertension, telomere shortening—a biomarker of accelerated systemic aging—is also implicated. In IPAH cells with a population doubling level (PDL) below 30, telomeres were consistently longer than those in control cells, but their length gradually shortened as PDL increased.^205^ Beyond that, mitochondrial dysfunction contributes to PASMC senescence through metabolic dysregulation. Hypoxia-induced suppression of peroxisome proliferator-activated receptor gamma (PPARγ) and PPARγ coactivator 1 alpha (PGC1α) expression in PASMCs leads to mitochondrial abnormalities and impaired metabolic homeostasis. Notably, PGC1α helps prevent senescence by regulating transcription of the longevity gene SIRT1 through Forkhead box O1 (Foxo1), thereby linking mitochondrial integrity to cellular senescence resistance.^206^

Pulmonary artery adventitial fibroblasts (PAFs): Adventitial fibroblasts, which increase in number with age, are responsible for the production and deposition of collagens I and III.^207^ PAFs also exhibit cellular senescence in MCT-induced PH model rats. The molecular regulation of PAF senescence is centrally controlled by the B-cell specific Moloney murine leukemia virus integration site 1 (Bmi-1) pathway. In PH rats, lung tissues exhibit reduced expression of Bmi-1, a key regulator that normally suppresses oxidative stress, DDR, and cellular senescence. The reduction is primarily localized to PAFs. Mechanistically, Bmi-1 exerts a biphasic protective effect during PH progression.^208^ In early stage PH, Bmi-1 provides protection by eliminating ROS and maintaining vascular homeostasis. However, as the disease progresses, persistent pathological stimuli lead to decreased Bmi-1 expression, resulting in adventitial fibroblast senescence. The loss of Bmi-1′s protective function allows ROS accumulation, which directly promotes cellular senescence through oxidative damage. Importantly, these senescent fibroblasts then promote PASMC proliferation via paracrine SASP signaling, creating a pathological cycle that drives PH progression. Additional regulatory mechanisms further modulate PAF senescence through complementary pathways. Studies have demonstrated that SIRT6 plays a protective role against adventitial fibroblast senescence.^193^ Lentiviral-mediated SIRT6 reduction enhances the senescence phenotype in adventitial fibroblasts, which is consistent with findings that SIRT6 alleviates vascular adventitial aging by blocking the NF-κB pathway.^209^ This suggests that maintaining SIRT6 expression is critical for preserving adventitial health and preventing premature senescence. Conversely, extracellular heat shock protein (HSP) 90α (eHSP90α) promotes adventitial fibroblast senescence through a distinct mechanism. eHSP90α activates TGF-β signaling, which in turn promotes transcription of the senescence-associated genes p53 and p21. Increased eHSP90α levels mediate fibroblast senescence and promote mitochondrial dysfunction.^209^ Notably, HSP90 inhibitors reportedly play a novel role in aging processes, suggesting potential therapeutic avenues for targeting senescence-related pathologies in PH.^210^

Genome instability

In PH, excessive pulmonary blood flow initially causes persistent endothelial damage,^211^ which gradually evolves into severe vascular pathological changes through the interplay of multiple aging markers. Sustained mechanical stress and exposure to inflammatory mediators induce DNA double-strand breaks and genomic instability that trigger cellular senescence in pulmonary vascular cells,212, 213, 214 creating a chronic inflammatory environment through SASP factor release that drives PH progression. DNA damage is markedly increased in PAH patients’ lungs and vascular cells, indicating systemic genomic instability. PAH patients display impaired DNA repair due to DNA topoisomerase II binding protein 1 (TopBP1) and bone morphogenetic protein receptor type II (BMPR2)-mediated breast cancer type 1 susceptibility protein (BRCA1) downregulation, promoting persistent DDR activation and cellular senescence through p53/p21 pathway induction.^162^

Mitochondrial dysfunction

Mitochondrial dysfunction serves as both an initiating factor and amplifying mechanism in PH-associated cellular senescence. Mitochondrial dysfunction promotes cellular senescence in PH through excessive mitochondrial ROS (mt-ROS) generation, impaired antioxidant defenses, and metabolic reprogramming that creates a pro-aging cellular environment. PAH patients exhibit aberrant mt-ROS production coupled with reduced antioxidant capacity,^215^ particularly manganese superoxide dismutase (MnSOD) inhibition, leading to oxidative damage and mtDNA injury which may trigger senescence pathways. Additionally, mitochondrial dysfunction drives metabolic alterations that further amplify oxidative stress. The metabolic shift from mitochondrial respiration to aerobic glycolysis promotes NADPH oxidase 4 (NOX4) upregulation, and abnormal NOX4 expression can contribute to cellular senescence through enhanced oxidative stress.^216^^,^^217^

Loss of proteostasis

Proteostasis, the dynamic equilibrium between protein synthesis, folding, and degradation, progressively deteriorates with age.^218^ A major driver of this decline is age-related oxidative stress, in which excessive ROS generation directly damages the structural integrity of the cell membrane and the conformation of proteins, disrupting their folding, modification, and degradation, and further exacerbating cellular dysfunction.219, 220, 221 In aging-associated PH, the combination of oxidative damage and impairment of the proteasome and autophagy lysosome degradation pathways^222^ leads to the accumulation of misfolded proteins and aggregates, ultimately contributing to pulmonary vascular cell dysfunction and vascular remodeling.

Chronic inflammation

Additionally, the proinflammatory microenvironment created by the SASP can directly damage vascular structures,^223^ amplify inflammatory responses via activation of multiple signaling pathways, particularly the NF-κB, Janus kinase–signal transducer and activator of transcription (JAK–STAT) and mitogen-activated protein kinase (MAPK) (extracellular signal-regulated kinase [ERK]/JNK/p38) cascades that collectively orchestrate the transcription of proinflammatory mediators and perpetuate inflammatory signaling,224, 225, 226 and sustain a persistent low-grade inflammatory state. This chronic inflammation further promotes oxidative stress, endothelial dysfunction, and vascular remodeling, reinforcing a positive feedback loop with other aging-associated markers.^227^

Stem cell exhaustion

Continuous damage and an inflammatory environment may impair the function of stem and progenitor cells responsible for repair and regeneration in the pulmonary vasculature,228, 229, 230 through both cell-intrinsic and cell-extrinsic mechanisms that exhibit extensive cross-talk. Chronic inflammation disrupts stem cell niche homeostasis, while sustained exposure to pro-inflammatory cytokines induces premature senescence through oxidative stress and DNA damage responses. Critical regulatory pathways, particularly mTOR (which regulates ROS levels and autophagy) and sirtuin-mediated mitochondrial function, become dysregulated during aging.^231^^,^^232^ The accumulation of stem cell-autonomous damage (DNA and protein damage from toxic metabolites) combined with non-autonomous stresses from extracellular signals impairs stem cell function,^233^ thereby weakening its intrinsic repair capacity and rendering the structural damage irreversible. The progressive depletion of regenerative cell populations, coupled with fibrotic tissue formation that promotes pathological vascular remodeling, ultimately compromises the ability to maintain pulmonary vascular homeostasis (Supplementary Fig. 2).

Therapeutic strategies targeting aging mechanisms in PH

Therapeutic approaches targeting senescence in PH have made significant strides. One key senotherapeutic strategy is senolysis, the selective elimination of senescent cells using agents such as combination of dasatinib and quercetin. However, it should be noted that dasatinib can induce pulmonary vascular toxicity.^234^ Studies have determined that HSP90 inhibitors are senolytic, capable of halting the progression of senescence and eliminating senescent cells. Most importantly, these inhibitors improve vascular remodeling in experimental MCT-PAH.^235^ As previously mentioned, senescent PASMCs increase paracrine IL-6 levels. IL-6 recruits and activates proinflammatory M1 macrophages, which further amplify IL-6 secretion.^236^ Prolonged exposure to this inflammatory milieu induces senescence in the recruited macrophages through oxidative stress and DNA damage. This creates a harmful feedback loop, as these senescent (p16-positive) macrophages produce their own SASP factors, further contributing to the inflammatory microenvironment and propagating senescence to adjacent vascular cells through paracrine signaling. Senolytic therapy can break this cycle by eliminating both p16-positive macrophages and senescent vascular cells, thereby reversing vascular remodeling. Furthermore, senolytics such as ABT263 or the forkhead box protein O4 peptide Foxo4-DRI have been shown to promote tissue regeneration following the clearance of senescent cells.^237^ Notably, ABT263, which induces apoptosis, has demonstrated efficacy in reversing pulmonary vascular remodeling and mitigating PH progression by selectively targeting senescent cells.^178^ There are also studies reporting that ABT263 induces apoptosis in senescent endothelial cells, but not in nonsenescent endothelial cells.^178^ Another promising antisenescence therapy is SASP suppression. Unlike senolytic therapy which eliminates senescent cells, this approach focuses on reducing the harmful secretory profile of existing senescent cells. While senolytic therapy can be administered intermittently, SASP suppression typically requires continual administration to maintain therapeutic benefit.^238^ This strategy targets the intracellular signaling pathways that control SASP production. A central regulator of SASP is mTORC1, which orchestrates the synthesis and secretion of inflammatory cytokines by promoting IL-1A translation and activating NF-κB transcriptional activity.^225^^,^^239^ Studies show that mechanistic target of rapamycin complex 1 (mTORC1) activity increases with age and drives the secretion of proinflammatory cytokines from senescent cells.^240^ Targeting this pathway with the mTOR inhibitor rapamycin reduces SASP factor secretion and inhibits PASMC senescence, thus both suppressing the harmful inflammatory secretion and preventing hypoxia-induced PASMC proliferation.^197^ Interestingly, intermittent doses of mTOR inhibitors can enhance rather than suppress immune function, therefore, reducing the amount of dietary protein or specific amino acids such as methionine and branched-chain amino acids (leucine, isoleucine, and valine) that stimulate mTORC1 activity has been explored for aging prevention.^241^ The latest research indicates that endogenous SIRT6 is an inhibitor of senescent vascular smooth muscle cells (VSMCs). Overexpression of SIRT6 can preserve the integrity of telomeres, delay cell aging, and reduce the expression of inflammatory cytokines.^242^ Additionally, icariin assists in delaying cell senescence by elevating SIRT6 expression and inhibiting NF-κB activity.^243^ Antioxidant strategies aim to prevent senescence by reducing oxidative stress and DNA damage. For instance, antiaging strategies using resveratrol focus on reducing oxidative stress, alleviating inflammatory reactions, improving mitochondrial function, and regulating apoptosis.^244^

Lifestyle interventions that reduce oxidative stress and DNA damage are being investigated as complementary approaches. Exercise training, for instance, has been shown to upregulate endogenous antioxidant defenses and improve DNA repair mechanisms.^245^ In PAH patients, supervised exercise programs have demonstrated benefits in terms of exercise capacity and quality of life, although their direct impact on cellular senescence remains to be fully elucidated. Currently, gene therapy and immunotherapy are also being actively explored.^238^ The CDKN2A locus encodes two important cell cycle p16 (a key senescence marker) and p19ARF (a tumor suppressor that activates p53-mediated growth arrest). During aging, accumulation of cells expressing p16 and p19ARF drives tissue dysfunction by enforcing irreversible growth arrest and promoting inflammatory SASP production.^246^^,^^247^ Eliminating the p19ARF reversibly restored lung function in 12-month-old mice, while deletion of the of the p16 gene extended their lifespan.^248^ However, it is important to note that senescent cell clearance may exacerbate vascular remodeling through the removal of senescent PAECs, increased proliferation of PASMCs in large vessels, and loss of pulmonary capillaries.^168^ Transgenic mice depleted in p53, p21, or p16 suffer more severe PH than their control counterparts.^249^

In conclusion, while significant progress has been made in developing senescence-targeted therapies for PH, further research is needed to develop targeted treatments based on the specific mechanisms underlying PH pathogenesis. Additionally, to optimize therapeutic strategies and minimize potential adverse effects, it is crucial to evaluate how current antisenescence agents affect multiple cell types involved in PH pathogenesis.

Aging and asthma

Asthma is a common chronic inflammatory disease of the airways, distinguished by airway hyperresponsiveness (AHR) and changes in airway structure. Airway inflammation, the hallmark of asthma, manifests as a sustained inflammatory state within the airway epithelium. This condition is predominantly driven by a variety of inflammatory cells, including eosinophils, T cells, macrophages, and mast cells, alongside their secreted inflammatory mediators IL-4, IL-5, IL-13, and TNF-α. AHR refers to the increased sensitivity of the airways to different stimuli, including allergens, infections, and physical exertion. Exaggerated responsiveness leads to bronchoconstriction, which subsequently presents as wheezing and dyspnea. Airway remodeling encompasses long-term structural alterations, including airway smooth muscle hyperplasia, basement membrane thickening, and collagen deposition, which collectively contribute to airway narrowing and instability.^250^ The airway remodeling feature of asthma has been associated with cellular senescence and immunosenescence. Aging-associated pulmonary degeneration, marked by alveolar dilation, reduced elastic recoil, thickened basement membranes, and excessive ECM deposition, comprises key pathological characteristics of airway remodeling in asthma.^251^ This process strongly correlates with the clinical presentation of late-onset asthma.^252^ Furthermore, imaging studies in elderly populations have demonstrated characteristic airway wall thickening and fibrosis as part of age-related airway remodeling, which leads to diminished lung tissue elasticity and impaired elastic recoil.^253^ This array of pathological changes can impair the efficacy of pulmonary gas exchange and exacerbate the disease of older individuals with asthma.

Aging-related pathogenesis of asthma

Asthma-related cellular senescence

Research has revealed that cellular senescence plays an important role in asthma among the elderly. Senescent features are evident in airway epithelial cells, smooth muscle cells, stromal cells, and various immune cell types. These persistently active senescence pathways lead to airway remodeling and hyperresponsiveness via sustained airway inflammation. Cell senescence contributes to detrimental changes within lung tissue, including heightened airway sensitivity to allergens and pathogens. These effects are mediated through enhanced remodeling and injury of the airway epithelial barrier, along with augmented fibrotic processes. A deeper understanding of the precise pathological processes linked to cellular senescence is needed to devise individualized preventive and therapeutic strategies tailored to older people.

*Airway epithelial * Airway epithelial cells serve as key innate immune sensors; however, during senescence, their dysregulated signalling becomes a major contributor to asthma pathobiology.^254^ Age-related ciliary ultrastructural abnormalities—particularly microtubule disintegration and dynein ATPase dysregulation—directly impair ciliogenesis by disrupting the formation of axonemal motor complexes.^255^ Simultaneously, there is age-related epithelial barrier dysfunction (EBD), characterized by tight junction rupture and mucociliary failure, which is worsened by goblet cell metaplasia.^256^^,^^257^ Disruption of tight junctions increases the risk of barrier invasion by environmental allergens, pollutants, and other harmful extrinsic factors. Combined EBD and impaired ciliary structure facilitate pathogen entry into the bronchial submucosa, increasing susceptibility to infections and inducing both airway remodeling and AHR.^258^ Additionally, aged airways exhibit reduced production of cytokines that promote cell repair, such as hepatocyte growth factor (HGF)^259^ and epidermal growth factor (EGF).^260^ Mucociliary dysfunction results in impaired mucus clearance and retention, thereby stimulating goblet cell metaplasia and excessive mucin secretion. This renders the mucus more viscous, which further exacerbates ciliary dysfunction and establishes a vicious cycle. Therefore, progressive airway remodeling in aging involves three pathologic loss of parenchymal elasticity, excessive mucin production, and impaired mucus clearance. These changes promote the formation of a mucous plug, eventually leading to bronchial airflow obstruction and fostering a pro-infective environment that drives chronic inflammation and structural damage.

Airway smooth muscle cells (SMCs): Senescent airway SMCs substantially contribute to airway remodeling through two primary mechanisms. First, these cells exhibit increased synthesis of ECM proteins, including collagen, elastin, and glycosaminoglycans, which directly contribute to pathological thickening and stiffening of the airway walls. Second, through the SASP, airway SMCs secrete a variety of growth factors and cytokines, including TGF-β, platelet-derived growth factor, and fibroblast growth factor. This secretory activity functions through both autocrine and paracrine mechanisms, promoting the proliferation of senescent cells and activating adjacent structural cells, thereby exacerbating airway smooth muscle hypertrophy, an important feature of airway remodeling.^261^ Furthermore, the reduced elasticity and narrowing resulting from airway remodeling may diminish the efficacy of bronchodilators such as β2-agonists, which primarily function by promoting smooth muscle relaxation.

*Matrix * Similar to airway SMCs, matrix cells (e.g., fibroblasts) critically regulate ECM homeostasis through balanced synthesis and degradation. Cellular senescence in these stromal populations disrupts ECM equilibrium, as evidenced by pathological overexpression of collagen types I, III, and V alongside the accumulation of fibronectin subadjacent to the basement membrane. This aberrant deposition progressively reduces airway tissue compliance through diminished elastin content and increased cross-linking, driving parenchymal fibrosis. The resulting structural rigidity enhances airflow obstruction and bronchial hyperreactivity, which clinically presents as persistent wheezing.^262^ Consequently, such irreversible ECM alterations fundamentally compromise therapeutic responsiveness in asthma management.

*Immune * Aging-induced impairment of immune function is a hallmark of pulmonary aging.^263^ This process fundamentally alters asthma pathogenesis in older adults through a self-perpetuating cycle mediated by cellular senescence and its effector phenotype, the SASP, accompanied by an increased risk of bacterial and viral lung infections. Senescent immune cells, including neutrophils, eosinophils, and T cells, secrete excessive SASP factors, including IL-6, TNF-α, IL-1β, and C-X-C motif chemokine ligand (CXCL) 8. These factors perpetuate a cycle of cellular senescence and chronic inflammation driven by persistent SASP signaling. This, in turn, induces pathological airway remodeling via fibroblast activation, thickening of the airway smooth muscle layer, and abnormal basement membrane deposition, all of which trigger the release of DAMPs.^264^ These DAMPs reactivate immune responses, perpetuating a pathological loop that intensifies pulmonary aging and accelerates asthma progression in older individuals.^265^

Neutrophil dysfunction contributes significantly to disease impaired NETosis reduces microbial clearance,^266^ leading to respiratory dysbiosis that amplifies neutrophilic inflammation and tissue remodeling.^267^ Concurrently, delayed apoptosis and an imbalance in the helper T cell (Th)17/regulatory T cell (Treg) axis promote pathological neutrophil accumulation,^268^ while elevated ROS and SASP secretion further exacerbate epithelial damage and Th17-driven inflammatory responses.^269^ Collectively, these mechanisms lead to elevated sputum neutrophilia and increased inflammatory biomarkers in elderly asthma patients,^270^ both of which are associated with severe, late-onset disease phenotypes.^271^ Parallel alterations in eosinophils—including reduced responsiveness to IL-5, diminished degranulation capacity, and impaired superoxide production—weaken antiparasitic defenses while sustaining inflammation through SASP factor secretion, although their specific roles across asthma phenotypes remain poorly understood.^272^^,^^273^

Underlying these immune alterations is thymic involution, which diminishes naïve T-cell output and T-cell receptor diversity while promoting the expansion of memory T-cell populations. This state of T-cell exhaustion is characterized by distinct immunological impairments, including reduced cytotoxic T-lymphocyte (CTL) activity, impaired Th function,^274^^,^^275^ and dysregulated B-cell responses.^276^ DCs exhibit biphasic dysregulation, characterized by impaired antigen responsiveness and migratory capacity, alongside enhanced self-reactivity mediated through the NF-κB signaling pathway. This leads to increased secretion of IL-6 and IFN-α, as well as sustained release of TNF-α and a disintegrin and metalloprotease (ADAM) proteases, which in turn induce airway epithelial chemokines such as CXCL-10, C-C motif chemokine ligand (CCL)-20, and CCL-26—ultimately compromising epithelial barrier integrity.^277^ NK cells display reduced cytotoxic activity and diminished production of key cytokines, including IFN-γ, perforin, and granzyme. These impairments result from phenotypic alterations—specifically, a decrease in CD56^+^ bright subsets and an expansion of CD56^+^ dim subsets expressing inhibitory receptors such as killer cell lectin-like receptor G1 (KLRG1) and natural killer group 2A (NKG2A)—contributing to the accumulation of senescent cells.^278^^,^^279^

Aged monocytes exhibit decreased expression of TLR1 alongside increased expression of TLR3, whereas macrophages maintain relatively stable levels of TLR2 and TLR4. These receptor expression changes impair TLR-induced cytokine production, particularly of IL-6 and TNF-α.^280^ In the lungs, macrophages decline in number and undergo transcriptional reprogramming, marked by downregulation of cell cycle pathways and upregulation of inflammatory mediators including substance P, prostaglandin E2 (PGE2), and IL-8. Functionally, aged lung macrophages exhibit defective phagocytosis, mitochondrial dysfunction marked by reduced ATP production and elevated ROS generation, and impaired antioxidant responses. Paradoxically, these cells hypersecrete proinflammatory cytokines during infection by pathogens (e.g., Mycobacterium tuberculosis) while displaying attenuated IFN-γ responsiveness.^281^^,^^282^ Collectively, these deficits undermine both antiviral and antiallergen immune defenses. This plastic reprogramming of macrophages sustains chronic airway inflammation^283^ while contributing to the development of corticosteroid resistance,^284^ thereby providing a mechanistic explanation for the high incidence of refractory exacerbations observed in geriatric asthma.

Genome instability

Genomic instability is an important trigger of asthmatic genotoxic insults from oxidative stress and/or pathogen activity induce DNA damage, which activates the p53/p21 axis.^285^ This, in turn, promotes senescence and epithelial cell detachment through dysregulated tight junctions, thereby reducing epidermal barrier integrity and exacerbating asthma-related AHR.^286^^,^^287^ Additionally, DNA damage in immune cells leads to aberrant production of inflammatory cytokines, promoting a proinflammatory environment characterized by neutrophil entry and driving the development of a more severe asthma phenotype with increased eosinophilic prevalence.^288^

Telomere attrition and stem cell exhaustion

Increased telomere attrition due to prolonged chronic inflammation and oxidative stress reduces the proliferative capacity of airway epithelial stem cells, ultimately leading to stem cell exhaustion.^289^ When this phenomenon occurs in the lungs, it establishes a detrimental feedback loop with the persistent inflammatory microenvironment disrupts the activation of regenerative signaling pathways within airway stem cells. This can negatively impact tissue repair and disrupt the integrity and stabilization of the airway epithelial barrier. As senescent or depleted stem cells are unable to sufficiently restore this barrier and regulate immune responses, delayed epithelial regeneration and fibrotic scarring ensue.^290^ These processes further exacerbate airway inflammation and remodeling. Moreover, dysregulated differentiation fosters mucus plug formation and goblet cell hyperplasia, which contribute to functional impairment and structural damage within the airway epithelium.^291^ Additionally, telomere shortening, in turn, activates p16/JAK/STAT signaling, leading to disrupted glucocorticoid receptor function,^292^ reduced corticosteroid responsiveness, progressive lung function decline, and increased frequency of exacerbations. Collectively, these mechanisms culminate in more severe asthma phenotypes that are resistant to treatment.

Epigenetic alteration

In asthma, epigenetic changes can mediate a chronic proinflammatory state, where hypomethylation of important inflammatory genes results in continuous production of the Th2 cytokine.^293^ Additionally, dysregulated histone modifications facilitate sustained SASP expression,^294^ which disrupts the suppressive function of Tregs, thereby promoting increased AHR and eosinophilic inflammation.^295^

Loss of proteostasis

Lack of proteostasis worsens disease progression.^296^ Aging leads to errors in protein synthesis, a decline in the functionality of degradation systems (such as the proteasome and autophagy), and diminished activity of molecular chaperones. These changes culminate in a widespread disruption of cellular proteostasis. Consequently, there is a persistent accumulation of unfolded or misfolded proteins, which triggers chronic ER stress. This stress compels the sustained activation of the UPR, transforming it from an adaptive protective mechanism into a central pathogenic driver.^297^^,^^298^ The chronically activated UPR exacerbates airway inflammation by engaging inflammatory signaling pathways such as inositol-requiring enzyme 1 (IRE1)-NF-κB, PKR-like endoplasmic reticulum kinase (PERK)-NF-κB, and activating transcription factor 6 (ATF6)-NF-κB.298, 299, 300, 301 This engagement results in the substantial release of inflammatory factors (e.g., IL-6, TNF-α).^302^ Additionally, it directly upregulates mucin gene expression (e.g., MUC5AC) through the IRE1β/spliced X-box binding protein 1 (XBP1) pathway, leading to mucus hypersecretion^297^^,^^303^; disrupts immune homeostasis by interfering with dendritic cell and T cell functions while promoting Th2/Th17-type responses^297^; and induces apoptosis in airway cells alongside activation and proliferation of fibroblasts via the CCAAT/enhancer-binding protein homologous protein (CHOP)-JNK-caspase pathway.^304^ Concurrently, proteasome dysfunction can cause a buildup of cyclins,^305^^,^^306^ increasing the proliferation of airway SMCs and contributing to subepithelial basement membrane thickening. Collectively, these mechanisms contribute significantly to airway remodeling. Ultimately, these processes synergize to facilitate both the pathogenesis and refractory phenotype associated with asthma.

*Mitochondrial * Aging results in a decline in mitochondrial function, and mitochondrial dysfunction primarily drives the pathogenesis and progression of asthma through four core mechanisms. First, reduced ATP production leads to an inadequate energy supply in airway epithelial cells, impairing their ciliary clearance function and facilitating the retention of foreign particles and mucus.^307^ Second, excessive production of ROS triggers oxidative stress, leading to oxidative damage to lipids, proteins, and DNA while promoting apoptosis.^308^ ROS serve as critical mediators of airway inflammation in asthma by facilitating the release of inflammatory cytokines such as IL-4, IL-5, and IL-13 through the activation of signaling pathways like NF-κB and the NLRP3 inflammasome.^309^ This activation subsequently drives eosinophil infiltration and mucus hypersecretion.^310^^,^^311^ Furthermore, ROS activate the TGF-β1 signaling pathway, which induces epithelial-mesenchymal transition (EMT) within the airways.^312^ This process culminates in smooth muscle proliferation, thickening of the basement membrane, ultimately resulting in irreversible airflow obstruction. Thirdly, disruption of calcium ion (Ca^2+^) homeostasis leads to abnormal excitation and contraction of airway smooth muscle cells, significantly exacerbating airway hyperresponsiveness.^313^^,^^314^ Finally, leakage of mtDNA from damaged mitochondria activates the mitochondrial permeability transition pore (mPTP)-cGAS-STING signaling pathway that persistently amplifies Th2/Th17-type inflammatory responses while chronicizing airway inflammation.^315^^,^^316^ These four processes are interconnected and mutually reinforcing; together they form a key mechanism by which mitochondrial dysfunction contributes to pathological changes observed in asthma (Fig. 4).Fig. 4Aging-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; Cyclin-dependent kinase inhibitor 1; 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 4

Therapeutic strategies targeting aging mechanisms in asthma

The mechanism of cellular senescence, which contributes to chronic airway inflammation and remodeling in asthma, represents a key therapeutic target. Current approaches to treat asthma focus on three senolytics to eliminate senescent cells, senomorphics to suppress the pro-inflammatory SASP, and regenerative therapies.

Senolytics remove senescent cells by blocking anti-apoptotic pathways (e.g., PI3K/AKT, Bcl-2 family, HIF-1α) with greater efficacy than agents targeting the corresponding signaling pathways. Dasatinib combined with quercetin may exert synergistic inhibition of the PI3K/Bcl-2 axis, thereby reducing airway inflammation,^317^ remodeling, and steroid resistance in asthma. Additional senolytic mechanisms have been fisetin reduced M1 macrophage polarization and suppressed ferroptosis in neutrophilic inflammation^318^; ABT-263 decreased mucus hyperplasia and fibrosis via clearance of senescent cells^168^; epigllocatechin gallate (EGCG) inhibited HIF-1α/vascular endothelial growth factor A (VEGFA)-mediated M1 macrophage skewing^319^; and azithromycin eliminated pulmonary senescent cells while modulating PI3K/Akt/mTOR/HIF-1α to attenuate remodeling.^320^ Pharmacologically tractable senolytic pathways directly linked to asthma pathogenesis provide promising therapeutic opportunities.

Senomorphic therapy uses two complementary strategies that target asthma pathophysiology.^321^^,^^322^ The first involves pharmacological inhibition of SASP regulatory pathways, including NF-κB, JAK/STAT, SIRT1/SIRT3, Wnt/β-catenin, and Nrf2/PTEN-induced putative kinase 1 (PINK). These pathways exacerbate asthma progression and contribute to airway hyperresponsiveness. For example, MitoQ, a mitochondria-targeted antioxidant, prevented the rise in AHR in both lean and obese murine models.^323^ Melatonin suppressed NF-κB-mediated eosinophilic inflammation,^324^ whereas metformin modulated the AMPKα/NF-κB pathway to reduce airway remodeling.^328^ Emerging strategies include the SIRT1 activator SRT1720,^325^ the JAK inhibitor ruxolitinib,^326^ and the Wnt antagonist ICG-001.^327^ The second approach uses biotherapeutics that neutralize SASP effector molecules.^322^ These include TSLP blockers such as tezepelumab and ecleralimab, which target senescent epithelial and Th2 inflammatory cells, along with established cytokine-targeted biologics directed against IL-4Rα, IL-5/interleukin-5 receptor (IL-5R), IL-33, and immunoglobulin E (IgE). Targeted therapeutic agents against type 2 inflammatory cytokines such as IL-4, IL-5, and TSLP, as well as IgE-targeting therapies, have been clinically validated. These include the IL-4R monoclonal antibody (mAb) dupilumab, IL-5 mAbs reslizumab and mepolizumab, the IL-5Rα mAb benralizumab, the anti-IgE mAb omalizumab, and TSLP-targeting mAbs tezepelumab and ecleralimab.

Stem cell-derived therapies and regenerative medicine strategies are designed to intervene in the aging process at the cellular level. The fundamental premise of these approaches centers on supplementing exogenous stem cells, such as MSCs derived from umbilical cord or adipose tissue, or leveraging their secreted bioactive factors and exosomes to mitigate the age-related decline in cellular repair functions.^328^ Stem cell-derived therapies and regenerative strategies provide a novel perspective for chronic asthma by simultaneously correcting the persistent inflammatory state and promoting regeneration of damaged airways. The first phase I trial (ChiCTR2500105903) used inhaled exosomes derived from MSCs for the treatment of moderate-to-severe asthma began in 2025 at Yantai Yuhuangding Hospital and is currently ongoing. This study demonstrated a reduced systemic risk through non-invasive delivery methods. Concurrent research showed that baicalein-pretreated exosomes suppressed the TLR4/MyD88/NF-κB signaling cascade, while reducing collagen deposition and attenuating airway hyperresponsiveness in mice.^329^ Additionally, autologous mesenchymal stromal cells reduced the need for inhalers by nearly 90 % among adults with long-term severe asthma in the United States.^330^

Overall, “senotherapy”—a therapeutic strategy that involves selectively eliminating senescent cells (senolytics) or modulating their deleterious secretory phenotype (senomorphics)—represents one of the most promising and rapidly advancing areas in asthma research. It has the potential to transform the current treatment paradigm for asthma. However, the safety profile, therapeutic efficacy, and long-term consequences of these interventions in human populations must be thoroughly evaluated through extensive clinical studies.

Aging and COPD

COPD is a heterogeneous respiratory disorder characterized by persistent airflow limitation due to structural abnormalities in the airways and/or alveoli. As one of the leading causes of global morbidity and mortality among chronic diseases,^331^^,^^332^ its prevalence greatly increases with age. Epidemiological data show substantially higher rates among individuals over 40 years of age, peaking beyond age 60.^333^ Due to population aging worldwide, the burden of COPD is projected to rise in the coming decades.^334^ COPD develops as a consequence of complex gene–environment interactions across the lifespan (GETomics), resulting in lung injury and the disruption of normal developmental and aging processes.^335^ Physiological lung aging involves a series of molecular and structural changes, including functional decline, architectural remodeling, diminished regenerative capacity, and heightened susceptibility to respiratory diseases.^7^ Evidence of premature lung aging has been documented in COPD.^336^ Therefore, elucidation of the intricate relationship between aging and COPD, and clarification regarding how aging contributes to the onset and progression of the disease, may yield new strategies for prevention and treatment.

Age-related changes in the structure, function, and regulation of the respiratory system substantially increase susceptibility to COPD in older adults. Lung function gradually declines with age and is accompanied by structural alterations at multiple levels,^337^ including reduced alveolar distensibility and lung tissue compliance.^338^ Ultimately, this degradation of the extracellular matrix leads to a loss of supportive tissue and consequent dilation of air spaces, without initial destruction of the alveolar walls—a phenomenon observed in both COPD patients and age-matched nonsmokers^7^ These findings suggest that physiological lung aging contributes to COPD progression. A study by Rule et al^339^ defined tissue age using six body composition biomarkers derived from abdominal CT scans analyzed through a combined statistical model. The researchers evaluated the associations of tissue age with chronic disease and mortality risk. The results showed that tissue age exceeding chronological age was correlated with COPD, indicating the presence of premature biological aging in COPD patients. Accelerated aging, where tissue age surpasses chronological age, is linked to impaired lung function and COPD.^339^^,^^340^ Bioinformatic analyses comparing gene expression profiles between COPD samples and healthy controls revealed that differentially expressed genes were primarily associated with apoptosis and aging processes.^341^ Aging can be regarded as the accumulation of unrepaired random molecular damage, which leads to cellular dysfunction and tissue impairment. The breakdown of essential cellular mechanisms—including stem cell exhaustion, genomic instability, telomere attrition, epigenetic alterations, dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, disrupted intercellular communication, and extracellular matrix remodeling—is thought to accelerate the aging process. There is evidence that these mechanisms undergo pathological deterioration in COPD beyond the scope of normal aging.^342^ The following sections describe the roles of lung aging and cellular senescence in COPD (Fig. 5).Fig. 5Regulatory 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/ 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 5

Aging-related pathogenesis of COPD

COPD-related cellular senescence

Continuous exposure to noxious stimuli, including cigarette smoke (CS) and particulate matter, induces cycles of injury and repair that ultimately disrupt cellular function and intercellular communication. CS, the predominant environmental risk factor for COPD, promotes senescence across multiple pulmonary cell types, including epithelial and endothelial cells, whose normal functions and signaling networks are impaired.343, 344, 345, 346 Senescent cells further influence neighboring cells through the release of SASP. An important question is whether a specific pulmonary cell type exhibits heightened sensitivity to aging, subsequently becoming a primary trigger for senescence and accelerating COPD development. Among nonsmokers, air pollution is a major risk factor for COPD.^347^ Studies have shown that fine particulate matter (PM2.5) induces expression of p21^CIP1/WAF1^, leading to cellular injury and senescence.^348^^,^^349^ Moreover, smokers with COPD who reside in households with elevated indoor PM concentrations experience accelerated loss of lung function,^350^ suggesting a synergistic effect of smoking and particulate pollution on pulmonary aging.

*Epithelial * The senescence of pulmonary epithelial cells constitutes a central mechanism underlying COPD pathology. Chronic exposure to injurious stimuli induces telomere shortening, mitochondrial dysfunction, and DNA damage accumulation, which activate senescence-related pathways and trigger irreversible cell-cycle arrest in airway and alveolar epithelial cells.^332^^,^^351^ Consequently, epithelial barrier integrity becomes compromised, increasing susceptibility to pathogen invasion. Ciliary senescence impairs mucociliary clearance, thus promoting chronic bronchitis. Additionally, SASP-mediated release of pro-inflammatory mediators, including IL-1β, IL-6, and TNF-α, recruits neutrophils and macrophages, perpetuating airway inflammation and alveolar destruction.^352^

*Endothelial * Pulmonary endothelial cell senescence plays a critical role in orchestrating COPD-associated vascular pathology. A previous study demonstrated that endothelial cells from patients with COPD exhibit increased senescence and SASP activity, thereby promoting vascular inflammation, atherogenesis, and thrombosis.^346^ Telomere attrition and epigenetic dysregulation contribute to microvascular endothelial senescence, exacerbating disease progression.^353^ These changes primarily involve downregulation of SIRT1 deacetylase and sustained activation of the p53/p21 pathway, which drive endothelial-to-mesenchymal transition (EndMT). The resulting progressive peribronchiolar microvascular rarefaction constitutes a fundamental pathological substrate for pulmonary hypertension and systemic manifestations of COPD.^354^

Fibroblasts: Senescent fibroblasts disrupt collagen homeostasis through increased expression of MMP-2 and MMP-9, coupled with reduced expression of tissue inhibitor of metalloproteinases 1 (TIMP-1), thus accelerating degradation of alveolar wall elastic fibers and promoting emphysematous changes.^355^ COPD patient-derived fibroblasts exhibit enhanced senescent characteristics. Proteomic analysis identified a distinct SASP expression profile in these fibroblasts. 124 identified SASP proteins were secreted at higher levels by fibroblasts from patients with COPD compared with matched controls, which may partially explain pathological features of COPD, such as chronic inflammation.^356^ Importantly, senescent fibroblasts show impaired responsiveness to regenerative growth factors, substantially compromising alveolar epithelial repair. These processes share a unifying mechanism in which a persistent DNA damage response induces irreversible cell-cycle arrest, whereas SASP factors exert paracrine suppression of neighboring stem cell function.^357^ Collectively, these mechanisms lead to irreversible disruption of lung tissue architecture.

Accelerated telomere shortening

Telomeres are repetitive nucleotide sequences (TTAGGG) located at the ends of chromosomes, functioning as protective caps that prevent the loss of essential DNA and chromosome fusion during cell division. During continuous cellular replication, telomeres progressively shorten, ultimately leading to cellular senescence or apoptosis. This effect can be partially offset by telomerase, which allows a limited number of additional divisions. In patients with COPD, telomere shortening occurs at an accelerated rate, whereas telomerase activity is reduced. Intriguingly, smokers without lung disease exhibit preserved telomere length. This suggests that the accelerated telomere attrition typically associated with smoking is being counteracted, possibly through the modulation of regulatory mechanisms like telomerase activity.^358^ Murine models have demonstrated that knockout of telomerase components (TERT/TERC) induces alveolar epithelial senescence, pulmonary inflammation (characterized by elevated IL-1, IL-6, CXCL8, and CCL2), and smoke-exacerbated emphysema.^359^ Telomere shortening also activates p21-mediated senescence and promotes the release of pro-inflammatory mediators, indicating that telomere erosion facilitates cellular senescence and genotoxic stress, thereby increasing the risk of COPD onset and progression.^360^ However, recent Mendelian randomization analyses have evaluated the causal relationship between telomere length and respiratory diseases (COPD and IPF) using UK Biobank data. Meta-analysis of two-sample Mendelian randomization results found no evidence supporting a causal role for telomere length in COPD. Cellular senescence is hypothesized to be a major driving force in both IPF and COPD; telomere shortening may contribute more directly to IPF, suggesting divergent pathogenic mechanisms between the two diseases.^361^ This discrepancy highlights the need for further investigation into telomere-related mechanisms of senescence in COPD.

Oxidative stress

Oxidative stress is a key driving force behind accelerated aging and cellular senescence. CS contains numerous toxic chemicals, including oxygen-derived metabolites or ROS. Excessive ROS accumulation damages proteins, lipids, and DNA, thereby promoting cellular senescence.^362^ Elevated levels of oxidative stress markers—such as hydrogen peroxide, nitric oxide, lipid peroxides, and nitrogen oxides—have been detected in the airways, alveoli, and blood of patients with COPD.^363^ Increased oxidative stress results from the high oxidant burden in tobacco smoke, as well as the sustained activation of inflammatory cells (e.g., neutrophils and macrophages). Persistent activation of these cells perpetuates oxidative stress even after smoking cessation, potentially explaining the continued decline in lung function among ex-smokers.^364^ Mitochondrial dysfunction further amplifies oxidative stress, exacerbating the cascade of events that drive COPD progression. The involvement of ROS in senescence is closely linked to disrupted mitochondrial function and impaired adaptive antioxidant defenses.^365^^,^^366^ In murine models, chronic CS exposure disrupts mitochondrial complexes and dynamics, inducing mitophagy. Dysregulated mitochondrial function and structure are associated with smoke-induced lung injury and the phenotypic development of chronic lung diseases such as COPD and emphysema.^367^

Immune senescence

Respiratory infections are another critical factor in the onset and exacerbation of COPD. Impaired mucociliary clearance and age-related declines in both innate and adaptive immunity—including reduced activity of alveolar macrophages, dendritic cells, and neutrophils—enhance susceptibility to pulmonary infections. Evidence of senescence has been observed in alveolar macrophages, peripheral blood B-cell subpopulations, and NK cells in COPD patients.368, 369, 370 Chronic antigenic stimulation, such as lifelong exposure to CS, together with oxidative stress and excess production of oxygen free radicals, promotes secretion of pro-inflammatory cytokines. This shift produces an imbalance between inflammatory and anti-inflammatory mechanisms, a hallmark of immunosenescence, or aging of the immune system.^7^

Stem cell exhaustion

Stem cell exhaustion is a hallmark of aging and a key mechanism underlying emphysema and impaired lung repair. Senescence of AEC2s, airway club cells, and pulmonary endothelial progenitor cells has been implicated in COPD, supported by evidence from both patients and preclinical animal models.^371^^,^^372^ In vitro experiments have shown that cigarette smoke extract (CSE) induces dysfunction in endothelial progenitor cells and increases the expression of senescence-associated markers.^373^ Stem cell self-renewal, proliferation, and differentiation are regulated by stem cell niche signals during homeostasis and tissue repair. Fibroblasts play an essential supportive role in the lung stem cell niche. Fibroblasts derived from COPD patients, including those with severe exacerbating COPD (SEO—COPD), exhibit elevated levels of cellular senescence, DNA damage, and oxidative stress.^374^ Compared with fibroblasts from healthy individuals, fibroblasts from COPD lungs demonstrate altered and impaired gene expression profiles in response to CSE stimulation^375^ and display a conserved senescent response that varies according to injury type. These expression profiles and senescent responses then compromise the function of isolated alveolar epithelial progenitor cells.^357^^,^^376^ Collectively, these findings underscore the critical role of stem cell depletion and niche dysfunction in COPD pathogenesis.

Epigenetic aging

The link between accelerated epigenetic aging and COPD has received increasing attention. DNA methylation has emerged as a novel biomarker of biological aging. One study evaluated baseline epigenetic age acceleration, measured by DNA methylation, in relation to COPD incidence and lung function. Among 770 participants, 131 developed incident COPD over a period of 7 years. The analysis revealed a significant association between baseline accelerated epigenetic aging and COPD occurrence. Initial measurements of epigenetic age acceleration and subsequent changes over time may both represent risk factors for COPD and impaired lung function.^377^ Another study examined the relationship between mortality and epigenetic measures of biological and telomeric age in 327 patients with COPD. The findings indicated that epigenetic blood biomarkers of cellular and replicative senescence can enhance clinical assessment, particularly when seeking to identify patients with higher mortality risk.^378^ DNA hypomethylation-mediated upregulation of GADD45B promotes airway inflammation and epithelial cell senescence in COPD. Mechanistic analyses have shown that p38 phosphorylation directly mediates GADD45B-driven inflammation, whereas GADD45B interacts with Fos proto-oncogene (FOS) to induce cellular senescence independently of p38 phosphorylation.^379^ Genome-wide DNA methylation analysis of lung tissue from COPD patients suggests that DNA methylation contributes to individual susceptibility to COPD. Moreover, smoking induces DNA methylation at loci distinct from those affected by genetic variation; such alterations may persist even after smoking cessation.^380^

Deficiency of anti-senescence systems

Impaired senescent cell clearance^381^ and diminished levels of anti-aging mediators^382^ indicate a deficiency of anti-senescence systems in COPD. Sirtuins, a family of highly conserved NAD^+^-dependent enzymes, play critical roles in stress resistance, genome stability, and energy metabolism. Seven sirtuin proteins have been identified in mammals; SIRT1 and SIRT6 are most strongly associated with lifespan extension. Reduced expression of SIRT1 has been reported in macrophages of smokers and COPD patients. SIRT1 also regulates NF-κB-dependent pro-inflammatory mediators in the lungs of these individuals. Similarly, decreased SIRT6 expression has been observed in airway epithelial cells of COPD patients exposed to tobacco smoke, leading to cell senescence and impaired autophagy.^383^ Other anti-aging molecules, including growth differentiation factor 11 (GDF11), Klotho, and senescence marker protein 30 (SMP30), have been implicated in COPD pathogenesis. The collapse of this anti-senescence system creates a permissive environment for accelerated aging phenotypes.

Therapeutic strategies targeting aging mechanisms in COPD

The development of novel therapies targeting aging-related cellular and molecular alterations has emerged as a cutting-edge area in COPD treatment. Senescent cells accumulating in COPD lung tissues secrete a complex mixture of factors knowns as SASP, which include numerous pro-inflammatory factors (e.g., IL-6, IL-8), matrix metalloproteinases (MMPs), and tissue-remodeling factors that perpetuate chronic lung inflammation, tissue destruction, and emphysema formation. Senolytics—agents designed to eliminate these senescent cells, such as the combination of dasatinib and quercetin—as well as SASP inhibitors that attenuate the detrimental effects of the SASP (e.g., via targeting the p38 MAPK or JAK/STAT pathways), have significantly ameliorated emphysema and inflammation in preclinical models.^384^^,^^385^ Furthermore, stem cell aging and functional impairment represent another critical target for intervention. Aging and the COPD microenvironment compromise the regenerative and repair capacities of endogenous lung stem/progenitor cells.^357^^,^^386^ Promising strategies include exploring MSC transplantation, modulating niche signaling pathways (such as Wnt and Notch), and employing cytokine-based therapies like exosome administration, all aimed at enhancing lung tissue regeneration and repair.^386^^,^^387^ In addition, modulation of nutrient-sensing pathways—such as inhibiting mTOR activity with rapamycin analogs, or activating AMPK and SIRT1 pathways—mimics caloric restriction and has demonstrated potential in delaying pulmonary aging phenotypes in animal studies.^388^^,^^389^

Although these aging-targeted therapeutic strategies have yielded encouraging results in basic research, their clinical translation still faces considerable challenges. A deeper understanding of the specific mechanisms driving aging in COPD is required. It will also be necessary to optimize drug delivery systems to improve lung targeting and minimize systemic side effects, as well as to verify long-term safety and efficacy in large-scale, rigorously designed clinical trials. Targeting aging represents a pivotal new paradigm for disease-modifying therapy in COPD, one that holds promise for moving beyond conventional symptom control toward truly altering the disease trajectory.

Aging and lung cancer

The incidence of lung cancer sharply increases in adulthood^17^ and peaks between 85 and 90 years of age.^390^ Lung cancer has the lowest 5-year survival rate among major cancers and causes approximately 25 % of all cancer-related deaths.^391^ Non-small-cell lung cancer (NSCLC) represents about 80 % of cases,^392^ whereas 15–20 % are classified as small-cell lung cancer (SCLC).^393^ NSCLC itself comprises multiple histologies—notably lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC)—that differ in lineage, genotype, and therapeutic behavior.^394^ These epidemiologic and pathological features frame aging not merely as background context but as the dominant risk factor.

Aging is the prodominant risk factor for lung cancer, acting through convergent intrinsic and extrinsic programs.^16^ Intracellular aging-related mechanisms that contribute to lung cancer include telomere attrition, epigenetic alterations, genomic instability, loss of proteostasis, macroautophagy dysregulation, deregulated nutrient sensing, and mitochondrial dysfunction. Extracellular factors include dysbiosis, chronic inflammation, stem cell failure, and impaired intercellular communication.^395^^,^^396^ For instance, telomeres sit at the nexus of aging and cancer as both gatekeepers and enablers. They cap chromosome ends and progressively erode with cell division and stress; when critically short, they trigger a DNA-damage response that enforces replicative senescence or apoptosis—an anti-tumor barrier integral to the aging framework.^292^ Yet if checkpoint pathways are compromised, dysfunctional telomeres precipitate “telomere crisis”, seeding breakage-fusion-bridge (BFB) cycles and other catastrophic rearrangements that fuel genomic instability and clonal evolution.^397^ Malignant clones that survive crisis typically reacquire telomere maintenance, most commonly by reactivating telomerase (e.g., via telomerase reverse transcriptase [TERT] promoter-driven programs) or by engaging alternative lengthening of telomeres (ALT), thereby securing replicative immortality, which is called cancerous transformation.^398^ These processes are interconnected across multiple biological levels (e.g., systemic circuits, organ systems, supracellular networks, cells, organelles, and molecules) producing context-dependent effects that play vital roles in tumorigenesis.^18^^,^^399^ Clarification of the mechanisms that govern these interactions could inform targeted therapies for aging-related biology and lung cancer pathogenesis.

However, aging has a dual effect on the development of lung cancer. On one hand, the aging of cancer cells helps to inhibit the growth of tumors, while cancer cells usually evolve the ability to resist aging. On the other hand, as aging progresses, there will be more mutations, secreted phenotypes, etc., which promote the growth of cancer cells through various pathways (Fig. 6).Fig. 6Schematic 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.Fig 6

Aging-related pathogenesis of lung cancer

Lung cancer-related cellular senescence

Fibroblasts: Senescent fibroblasts act as powerful architects of a pro-tumor lung microenvironment. By adopting a cancer-associated fibroblasts (CAF)-like state, they release a SASP rich in cytokines, chemokines, growth factors and matrix-remodeling enzymes (e.g., IL-6/IL-8, CXCL12, vascular endothelial growth factor A [VEGFA], MMPs, collagen type I alpha 1 chain [COL1A1]), which reshape the tumor microenvironment (TME) to favor immune evasion, angiogenesis, invasion and EMT. This SASP-driven reprogramming is a well-established mechanism by which senescent stromal cells enhance the aggressiveness of nearby (pre)cancerous cells.^400^ In lung cancer specifically, CAFs (and senescent fibroblasts that acquire CAF properties) drive metastasis by activating IL-6/STAT3 signaling in tumor cells; dampening STAT3 signaling in senescent fibroblasts reverses their pro-invasive effects on A549/H1299 cells.^401^ Mechanistically, MMP-1—often coupled with TGF-β1—is sufficient to induce fibroblast senescence and, in turn, to promote tumor growth in lung large-cell carcinoma models; this response depends on protease-activated receptor-1 (PAR-1) signaling and oxidative stress.^402^ Consistent with this axis, senescent lung fibroblasts can export exosomal MMP-1 that engages PAR-1 on NSCLC cells to activate PI3K–AKT–mTOR and accelerate proliferation and clonogenicity.^403^ Overall, senescent fibroblasts both seed and sustain tumor-supportive ecosystems in the lung through SASP-mediated IL-6/STAT3 programs and MMP-1–PAR-1 crosstalk, linking stromal aging to lung-cancer initiation, progression and metastatic fitness.

*Lung cancer * Senescense also exists in lung cancer cells, which involves three (1) replicative senescence, triggered by progressive telomere shortening during successive replication cycles, which acts to prevent DNA replication errors^404^; (2) oncogene-induced senescence, initiated by genetic alterations and aberrant oncogenic signaling^405^; and (3) stress-induced senescence, a form of premature senescence activated by external stressors such as DNA damage, mitochondrial dysfunction, and elevated ROS.^406^^,^^407^ Senescent cells display flattened and enlarged morphology, elevated SA- β-gal activity, frequent alterations in macromolecules (p53, p21, p16, p-γH2AX, and p-Rb),408, 409, 410 irreversible G1 arrest,^411^ and a hypersecretory phenotype.^412^ Because senescent cells cannot proliferate, whereas cancer is characterized by uncontrolled proliferation, cancer cells develop anti-aging progress through both oncogenic and tumor-suppressive signaling networks.^413^ In KRAS^G12D^ lung models, premalignant adenomas are rich in senescent cells, but progression to malignancy is accompanied by loss of the p53-senescence brake, a hallmark of “senescence escape”.^414^ Mechanistically, KRAS signaling can stabilize nuclear BECLIN-1 via the deubiquitinase ubiquitin-specific protease 5 (USP5), which in turn enhances MDM2-mediated p53 degradation, thereby overriding p53-dependent senescence and promoting tumorigenesis. Genetic or pharmacologic disruption of this USP5-BECLIN-1 axis restores senescence and suppresses KRAS-driven lung tumor growth. Similarly, FBXO22 is a p53-induced F-box adaptor that forms an SCF (FBXO22)-lysine demethylase 4A (KDM4A) complex to ubiquitylate methylated p53 during late senescence and targets the pro-metastatic factor BTB and CNC homology 1 protein (BACH1) for degradation. Therefore, FBXO22 loss in lung cancer cells both perturbs p53-senescence feedback and more directly stabilizes BACH1 to promote LUAD metastasis.^415^

Immunocyte: In the aging lung, senescent immune cells cooperate to shape a tumor-permissive microenvironment. Aging-associated chronic inflammation polarizes macrophages toward an M2 phenotype, an immunosuppressive state through IL-10 — JAK/STAT3 signaling, weakening antigen presentation and cytotoxic T-cell surveillance.^416^^,^^417^ Senescent tumor cells further induce CD73 on tumor-associated macrophages (TAMs) (via IL-6/JAK–STAT3), elevating extracellular adenosine. Furthermore, the CD39/CD73 pathway suppresses T-cell function. Blocking CD73 restores CD8⁺ antitumor immunity in senescent TMEs.^418^ Analyses of clinical specimens and lung cancer databases consistently demonstrate a positive association between TAM CD73 expression and tumor cell senescence. In KRAS-driven lung tumors, senescent macrophages accumulate early; depleting macrophages or clearing senescent cells reduces tumor burden and prolongs survival, highlighting senescent TAMs as actionable targets. Mechanistic exploration indicates that the removal of senescent macrophages reduces tumor growth by converting an immunosuppressive TME—characterized by high Treg levels and reduced CD4^+^ and CD8^+^ T cell infiltration—into an immunostimulatory TME with decreased Treg levels and increased CD4^+^ and CD8^+^ T cell activity.^419^ Tumor-derived GM-CSF activates JAK/STAT in neutrophils, upregulating Bcl-xL and extending the survival of tumor-associated neutrophils (TANs) that fuel lung tumor growth.^420^ Targeting Bcl-xL with the selective BH3 mimetic A-1331852 prunes these aging, tumor-promoting TANs without systemic neutropenia, lowering TAN abundance and slowing progression in vivo. Beyond survival, TANs reinforce metastatic competence and immune evasion, often engaging STAT3-linked programs that cross-talk with macrophage pathways in the same niche.^421^

Genomic instability

Aging leads to the accumulation of somatic mutations, possibly due to prolonged exposure to endogenous oxidative stress and impaired DNA repair associated with cellular senescence,^422^ even in the absence of smoking. Mutations in the epidermal growth factor receptor (EGFR) occur more frequently in never-smokers with lung cancer than in smokers, suggesting non-tobacco-related etiologies, such as age-associated molecular alterations.^423^ For instance, collagen aging in lung cancer cells induces resistance to the cytotoxic and apoptotic effects of EGFR-targeted therapies by significantly upregulating EGFR expression.^424^ When telomeres get too short, cells enter a telomere crisis. Tumors that survive usually restart telomere upkeep by switching on TERT. TERT amplification was reported in 13 % and 14 % of LUAD and LSCC cases, respectively.^425^ In addition, a high proportion of individuals with lung cancer have liver kinase B1 (LKB1) mutation, which are associated with poor prognosis and an inadequate response to treatment.^426^ Changes in LKB1 weaken control of telomerase and blunt the senescence programs of lung cancer cells, easing the path to further DNA damage and tumor evolution.^427^ Together, these observations outline an age-shaped, non-tobacco route to lung endogenous oxidative stress with erosion of DNA repair raises somatic mutational load.

Epigenetic alterations

In the development of lung cancer, cellular senescence in respiratory epithelial cells serves as a critical link connecting early epigenetic alterations to later malignant progression. This process is initiated by epigenetic dysregulation, encompassing changes in histone modifications and widespread transcriptomic shifts. These senescent cells create a pro-inflammatory and pro-proliferative local microenvironment. This environment not only lowers the threshold for oncogenic pathway activation but also provides a “permissive background” for the clonal expansion of cells with driver mutations, such as EGFR, thereby directly promoting lung carcinogenesis.^428^ At the molecular level, dysregulation of the microRNA network is a key mechanism governing the balance between cellular senescence and tumorigenic behavior.^429^ For instance, in NSCLC, 3′-untranslated region (UTR) shortening of the CDK16 gene allows it to escape suppression by miR-485-5p. Restoring miR-485-5p expression or directly knocking down CDK16 has been shown to induce senescence in lung cancer cells, exerting tumor-suppressive effects.^430^ In contrast, miR-34a can suppress NSCLC progression by inducing senescence and apoptosis at the G1–S checkpoint.^431^ Furthermore, therapeutic interventions themselves can induce adverse outcomes via senescence. Evidence indicates that chemotherapeutic agents like cisplatin can trigger a senescent state in some cancer cells. These therapy-induced senescent cells subsequently activate glucose-regulated protein 78 (GRP78)/Akt-dependent signaling, upregulating various stem cell markers (including Nanog, CD133, and CD44).^430^ This process ultimately fosters a stem-like phenotype and chemoresistance, complicating treatment.

Disabled autophagy

Autophagy, an essential intracellular catabolic process, plays a context-dependent dual role in cancer, functioning as both a tumor suppressor in early stages and a tumor promoter in established malignancies.^432^^,^^433^ Prior to tumor formation, autophagy acts primarily as a protective mechanism by maintaining genomic stability and cellular homeostasis. It clears damaged proteins and organelles—such as dysfunctional mitochondria—under conditions of metabolic stress, thereby reducing oxidative damage and preventing the accumulation of mutations that could initiate tumorigenesis. This homeostatic function is critical in pre-malignant cells, where loss of autophagic activity has been linked to increased cancer susceptibility. For instance, deletion of autophagy-related genes like Beclin1 elevates the risk of cancers such as ovarian, prostate, and breast cancer.^434^ Additionally, autophagy can induce senescence or apoptosis in genetically compromised cells, further limiting the expansion of potential tumor-initiating clones.

However, once tumors are established, autophagy is frequently co-opted to support survival and growth. Cancer cells leverage autophagy to mitigate metabolic stress, resist therapy, and sustain proliferative signaling. For example, in lung adenocarcinoma (LUAD), caveolin-1 (Cav-1) upregulation promotes vasculogenic mimicry by enhancing autophagic activity and glycolytic reprogramming, thereby accelerating progression.^435^ Similarly, under hypoxic conditions or chemotherapy exposure (e.g., cisplatin), lung cancer cells activate autophagy to evade therapy-induced senescence or apoptosis—a pro-survival adaptation that can be reversed using autophagy inhibitors like hydroxychloroquine.^411^ The PI3K–Akt–mTOR pathway, often dysregulated in aging and cancer, further modulates downregulation of PTEN inhibits autophagy, sensitizing cells to agent-induced death.^403^ The interplay between autophagy and oncogenic signaling also involves selective autophagic degradation of key regulators. In colorectal cancer, transmembrane protein TM9SF1 promotes the autophagic degradation of vimentin—a protein involved in metastasis—via the TRIM21-Tollip pathway, thereby inhibiting invasion. This illustrates that autophagy can exert either anti- or pro-tumor effects based on the specific cargo degraded and the stage of disease.^436^ In summary, autophagy serves a tumor-suppressive function pre-tumorigenesis by preserving cellular integrity and preventing malignant transformation. In contrast, in advanced cancers, it often supports tumor adaptation and resistance. Understanding this duality is essential for designing autophagy-targeting therapies.

Chronic inflammation

The vicious cycle linking aging-associated chronic inflammation to lung cancer initiation and progression is primarily driven by the SASP.^396^^,^^437^ This cycle begins when cells experiencing irreversible damage enter senescence and cease proliferating. However, these cells remain metabolically active and secrete a plethora of SASP factors—including IL-6, IL-8, IL-1α/β, TGF-β, various MMPs, and ECM components—which collectively establish a state of persistent chronic inflammation within the TME. Single-cell analyses of lung cancer tissues further confirm an increased abundance of senescent cells compared to normal lungs.^438^ This SASP-driven chronic inflammation remodels the TME to favor tumor development through multiple mechanisms. A pivotal mechanism linking immune aging to cancer is the finding that hematopoietic aging promotes cancer by fueling IL-1α-driven emergency myelopoiesis, leading to the accumulation of myeloid-derived suppressor cells in the tumor microenvironment that facilitate tumor progression.^439^ This surge promotes a destructive inflammatory response that reduces the number and function of anti-tumor immune cells, such as dendritic cells, effector T cells, and natural killer (NK) cells, thereby creating opportunities for cancer immune escape.^439^ Concurrently, metabolic and stromal reprogramming occurs. For instance, senescent cells in the tumor stroma can reprogram the metabolism of lung cancer cells, while SASP-associated ECM-modifying proteins alter the tissue architecture, stimulating cancer stemness and invasiveness. Despite its initial role as a tumor-suppressive mechanism, the long-term persistence of senescent cells and sustained SASP signaling ultimately shifts the microenvironment from suppressing to promoting cancer. This paradox underscores the therapeutic potential of targeting this axis. Research demonstrates that intervening to block the IL-1α/β signaling pathway with the IL-1 receptor antagonist anakinra can disrupt this pro-tumorigenic crosstalk, delay tumor progression, and improve survival in aged mice models, highlighting a promising strategy for age-related lung cancer prevention and treatment.^439^

Altered cellular communication

Growing evidence underscores that aging critically disrupts pulmonary immunosurveillance, fundamentally altering intercellular communication within the lung microenvironment to foster carcinogenesis.^440^^,^^441^ This age-dependent immune dysfunction, or immunosenescence, is mainly driven by the SASP, which floods the tissue landscape with factors like CCL2, CCL5, CXCL1, CXCL10, IL-6, and TNF-α. These signals recruit and activate various immune cells. However, in aging, this process becomes maladaptive, leading to a pro-inflammatory state that paradoxically supports tumorigenesis. The functional decline of cytotoxic lymphocytes is a cornerstone of this process. Although the natural killer group 2, member D (NKG2D) and MHC class I polypeptide-related sequence A/B (MICA/B), upregulated on NK cells and senescent cells respectively, can initially mediate SASP-induced cytolysis, its efficacy wanes with age.^442^ Critically, the function of CD8+ cytotoxic T lymphocytes, the primary effectors of tumor cell elimination, is severely compromised in the elderly.^443^ This is not only due to cell-intrinsic senescence but is also modulated by other immune populations. For instance, T regulatory cells (Tregs) accumulate with age and exhibit enhanced suppressive activity, further quenching effective anti-tumor responses.^443^ Moreover, a recent study identified a unique subset of CD39^+^ CD73^+^ CD8^+^ T cells (DP8 cells) that accumulates with age. These cells are recruited to tumors via the CXCL16-CXCR6 axis and suppress anti-tumor CD4+ T cells in an adenosine-dependent manner, actively promoting cancer progression.^444^

Beyond soluble SASP factors, other modes of intercellular communication are implicated. For example, NSCLC-derived exosomes can carry specific microRNAs (e.g., elevated miR-3200-3p induced by vascular endothelial growth factor receptor 2 [VEGFR2] suppression) that promote Treg senescence via the ROS/DDB1- and CUL4-associated factor 1 (DCAF1)/glutathione S-transferase Pi 1 (GSTP1) pathway, creating a complex feedback loop that can surprisingly suppress tumor growth in some contexts.^445^ Furthermore, the loss of specific protective T cell populations with age is a key mechanism. Research has shown that CD103^+^ tissue-resident memory T cells (TRM), which are crucial for eliminating oxidative-stress-damaged alveolar epithelial cells, decline significantly in aged lungs. This loss of local immunosurveillance permits the outgrowth of premalignant lesions.^446^ The net result of these age-related changes is a profoundly immunosuppressive TME. Therefore, the interplay between immunosenescence and dysregulated intercellular communication creates a permissive niche for lung cancer initiation and progression, highlighting the urgent need for therapeutic strategies designed specifically for the aged immune landscape.

Therapeutic strategies targeting aging mechanisms in lung cancer

Cellular senescence exerts a dual role in lung cancer initially, it acts as a tumor-suppressive mechanism by halting the proliferation of damaged cells; however, the persistent presence of senescent cells and their SASP ultimately foster a tumor-promoting microenvironment. This duality underpins several emerging therapeutic strategies aimed at inducing or eliminating senescence, modulating the SASP, or harnessing the immune system to target senescent cells.

A key approach is pro-senescence therapy, which aims to trigger irreversible cell-cycle arrest in cancer cells. Multiple molecular pathways have been identified as viable targets for inducing senescence in lung cancer. Interferon regulatory factor 8 (IRF8) suppresses lung tumor growth by inhibiting Akt signaling and promoting the accumulation of the cell-cycle inhibitor P27.^447^ LKB1, a tumor suppressor frequently inactivated in NSCLC, inhibits LUAD progression by suppressing telomerase activity and promoting histone lactylation-induced senescence.^405^ Telomerase inhibitors such as thymoquinone and meso-Tetra(N-methyl-4-pyridyl)porphine (TMPyP4) bind to G-quadruplex structures in telomeric DNA, inducing G1-phase cell-cycle arrest and senescence.^448^ Knockdown of nuclear protein 1 (NUPR1), achieved via short hairpin RNA (shRNA) or inhibited by the antipsychotic drug trifluoperazine, promotes premature senescence, impairs autophagy, and suppresses LUAD growth in vivo.^449^ Furthermore, inhibition of focal adhesion kinase (FAK) triggers senescence in NSCLC cells through its downstream effector enhancer of zeste homolog 2 (EZH2), suggesting the FAK–EZH2 axis as a promising therapeutic target.^450^

While inducing senescence halts tumor cell proliferation, the subsequent accumulation of senescent cells and persistent SASP may promote chronic inflammation, immunosuppression, and tumor progression. To address this, senotherapeutic strategies have been developed, including senolytics to selectively eliminate senescent cells and senomorphics to attenuate the detrimental effects of SASP.^412^ Senolytic agents such as fisetin senescent cells and preclinical studies demonstrate that combining fisetin with chemotherapy (e.g., cyclophosphamide) yields a synergistic effect, significantly enhancing tumor reduction in lung cancer models compared to either agent alone.^451^

An alternative strategy involves mobilizing the immune system to recognize and clear senescent cells. Chemotherapy-induced senescent tumor cells may display immunogenic surface markers such as urokinase-type plasminogen activator receptor (uPAR), which can be targeted with chimeric antigen receptor (CAR) T cells; in preclinical LUAD models, combining senescence-inducing drugs with uPAR-targeted CAR T cells significantly prolonged survival.^452^ Other investigational approaches include employing hydrogen inhalation to reverse immune senescence, as observed in a clinical trial of advanced NSCLC patients (NCT03818347).^453^

Aging and lung cancer share several key biological mechanisms—including cellular senescence, dysregulated autophagy, and impaired immunosurveillance—which collectively influence cancer progression and treatment response. Future drug development should focus on optimizing senolytics and senomorphics, and designing combination therapies that exploit the dual nature of senescence while minimizing stromal damage and SASP-related side effects. Further preclinical studies and clinical trials will be essential to translate these senescence-targeting strategies into safe and effective treatments for lung cancer.

Conclusions and future directions

As global life expectancy continues to increase, the prevalence of age-related diseases is rising among older adults. Identifying reliable biomarkers of aging and defining disease phenotypes in the context of disease heterogeneity remain critical priorities for future research. Given the complex interplay between lung disease and aging, future investigations should focus on elucidating the underlying mechanisms and developing interventions tailored to the unique vulnerabilities of older individuals. Studies that integrate cellular and molecular analyses of lung aging with multi-omics data may provide novel insights into how aging shapes the onset, progression, and prognosis of lung disease. In the future, three major challenges must be (1) regulating SASP to overcome senescence evasion and resistance to senolytic drugs^454^^,^^455^; (2) identifying and overcoming potential barriers to the clinical translation of senescence-based therapies; and (3) addressing the ethical and societal implications of such approaches, considering that aging is a universal natural process rather than a disease. Accordingly, there is a need for deeper analyses of senescent cell biology, including assessment of the differential impacts of senescence on distinct lung cell types, along with explorations of the efficacy and adverse effects of antisenescence therapies.

Funding

This study was supported by the National Natural Science Foundation of China (Nos. 82130001, 82272243, 82330002, 82225001, 82430002, 82270039, 82270052, 82241012, 82120108001, 82170065, 82170069, 82370063, 82470063, 82030001, 82573498); the Shanghai Municipal Science and Technology Major Project (No. ZD2021CY001); the National Key Research and Development Program of China (Nos. 2024YFC3044400, 2022YFE0131500, 2024YFA1108500, 2021YFC2500704); the Research & Development Program of Guangzhou National Laboratory (Nos. GZNL2024A02003, GZNL2023A02013); the Construction of a Multi-Disciplinary Treatment System for Severe Pneumonia (No. W2020-013); the Shanghai 3-Year Action Plan to Strengthen the Construction of Public Health System (No. GWVI-11.1-18); the Science and Technology Commission of Shanghai Municipality (No. 22Y11900800); and the Shanghai Municipal Key Clinical Specialty (No. shslczdzk02201).

CRediT authorship contribution statement

Yanan Zhou: Writing – original draft. Gaoying Chen: Writing – original draft. Xiang Li: Writing – original draft. Xiaohe Li: Writing – original draft. Zeqiang Lin: Writing – original draft. Li Liu: Writing – original draft. Dan Pu: Writing – original draft. Jiyuan Chen: Writing – original draft. Yuqin Chen: Writing – original draft. Ziying Lin: Writing – original draft. Zili Zhang: Writing – original draft. Lingling Zhu: Writing – original draft. Wenju Lu: Writing – review & editing. Wen Ning: Writing – review & editing. Jian Wang: Writing – review & editing. Songmin Ying: Writing – review & editing. Jing Zhang: Writing – review & editing. Qinghua Zhou: Writing – review & editing. Yuanlin Song: Writing – review & editing, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.