Heterogeneity of Cellular Senescence, Senotyping, and Targeting by Senolytics and Senomorphics in Lung Diseases

The DDR constitutes a central mechanism in the induction of cellular senescence [2,3,10]. Critically shortened telomeres are perceived as persistent, irreparable DNA lesions, thereby initiating a robust DDR that enforces a stable and durable growth arrest [9,10,27]. This cascade converges on key tumor suppressor pathways, most notably the activation of p53, which subsequently induces the expression of the cyclin-dependent kinase inhibitor p21^Cip1/Waf1 [2,3,4,64]. p21^Cip1/Waf1 inhibits CDK2 activity, leading to hypo-phosphorylation of the RB protein and resulting in irreversible cell cycle exit [2,15,64]. In parallel, DDR signaling induces significant chromatin remodeling, including the formation of senescence-associated heterochromatin foci (SAHF) and DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS), both of which contribute to the long-term maintenance of the senescent state [1,2,3,64]. Importantly, DDR activation is not limited to telomere attrition. Other stressors, such as oncogene activation which induces replication stress and exposure to genotoxic agents, can similarly initiate DDR-driven senescence [2,3,6,15,64,65].

Mitochondrial dysfunction-mediated ROS generation is a well-established driver of cellular senescence in the lung [1,2,3], and one of the primary triggers of stress-induced premature senescence (SIPS) in chronic lung diseases, including COPD and IPF. The lungs are continually exposed to environmental stressors such as cigarette smoke and airborne pollutants, which induce substantial oxidative stress [38,66]. Elevated ROS levels cause oxidative DNA damage, which in turn activates canonical senescence pathways in various lung cell types [67,68].

In COPD, for instance, senescent small airway fibroblasts exhibit pronounced mitochondrial dysfunction, along with transcriptional signatures indicative of oxidative stress and impaired mitochondrial bioenergetics [69]. Beyond ROS-mediated mechanisms, senescence can also be initiated through a distinct, non-canonical pathway including termed MiDAS. This form of senescence is not dependent on DNA damage or high ROS levels but is instead driven by metabolic perturbations such as altered NAD⁺/NADH ratios and activation of AMPK [55,70,71]. MiDAS has been implicated in age-related lung diseases characterized by progressive mitochondrial decline, contributing to fibrogenic signaling and epithelial instability, particularly within AT2 cells [55,70,71]. Together, both ROS-dependent and ROS-independent mitochondrial pathways represent critical mechanisms underlying the accumulation of senescent cells in lung pathobiology.

Epigenetic alterations play a central role in the initiation and maintenance of the senescent state in lung cells and are considered integral to the "hallmarks of aging" [8,65,72]. One of the defining features of senescent cells is extensive chromatin reorganization, including the formation of senescence-associated hetero-chromatin foci (SAHF) which silence proliferation-promoting genes), and the emergence of DNA-SCARS [1,2,3,64], thus reinforcing senescence DNA-SCARS. These structural changes are accompanied by global modifications of histones and the downregulation of key nuclear lamina components, such as Lamin B1, which collectively stabilize the senescent cell cycle arrest [1,2,3,64].

Recent findings have highlighted that specific molecular events such as the degradation of histone deacetylase 4 (HDAC4) can initiate an enhancer-based epigenetic program driven by AP-1 and p300, contributing directly to the senescent phenotype [64]. Other HDACs1-3 may also participate in a similar senescence phenotype via their reduction in a co-repressor complex [73]. In the context of lung disease, epigenetic dysregulation emerges as a prominent and pathogenic feature. In COPD, for instance, accelerated lung aging is associated with distinct alterations in DNA methylation and epigenetic clocks such as DNAmGrimAge have been strongly correlated with disease risk and severity [71]. Moreover, epigenetic biomarkers of aging have shown strong associations with lung function decline in elderly populations [74,75]. Dysregulation of key epigenetic regulators, such as the NAD⁺-dependent histone deacetylase Sirtuin 1(SIRT1), is also observed in immune cells from COPD patients and has been linked to persistent inflammation and impaired resolution [76]. These findings emphasize that epigenetic mechanisms in the lung not only serve as markers of biological aging, but also act as active drivers of cellular senescence, offering attractive targets for therapeutic intervention in age-associated pulmonary diseases [77]. Yet the area of epigenetic regulation of senescence remains greatly underexplored with little understanding of the chromatin organization and transcriptional regulation in various cell types, an area that warrants further research.

Senescence is not a single endpoint but exists in diverse states, shaped by the initiating stress, cell type, and tissue context. The replicative state arises from telomere erosion [78,79], whereas stress-induced premature senescence is triggered by DNA damage, oncogenic signaling, oxidative stress, or mitochondrial dysfunction [20,23,80,81]. A distinct p16^INK4a-mediated state is frequently observed in aging tissues and stem-cell niches, where elevated p16 drives a stable growth arrest independent of telomere length, contributing strongly to organismal aging [18,82,83,84]. Another developmental state occurs transiently during embryogenesis and remodeling [21,85], while acute states aid tissue repair and chronic states promote persistent inflammation and fibrosis [41,86,87,88,89,90,91]. Tracking these states is challenging, as no single marker universally defines senescence. To address this, senotyping frameworks classify cells by initiating stimuli, transcriptomic signatures, and functional outputs. For example, replicative senescence can be tracked by telomere attrition and persistent p^53/p21 activity [92,93,94], whereas SASP-based senotyping distinguishes SASP-high inflammatory fibroblasts from SASP-low or metabolic states [36,95]. Other categories include mitochondrial-dysfunction–associated senescence (MiDAS) and DNA-damage dominant states defined by multi-omics profiling [20,80]. Yet, many cells remain unclassified or hybrid, reflecting program plasticity [96,97,98,99]. Additionally, senescent cells may transition between stable states with active SASP and deep states marked by chromatin remodeling and metabolic decline [9,73,100,101,102]. These states may be dependent on the specific hallmarks of aging, cellular proliferation state, immune-senescence state, epigenetic state, and secretory state. Collectively, senescence emerges as a continuum of states, where senotyping provides a framework to resolve heterogeneity and link senotypes to functional outcomes.

Transient cellular senescence plays an important role in normal physiological processes. During embryonic development, programmed senescence contributes to tissue patterning and morphogenesis [1,104]. In the context of acute tissue injury, senescent cells support wound healing and limit fibrotic remodeling by secreting reparative factors such as PDGF-AA (Platelet-Derived Growth Factor-AA) and MMPs, which promote tissue repair and recruit immune cells for the clearance of damaged or apoptotic cells [2,6,8,105]. Arguably, the most well-established beneficial function of senescence is tumor suppression. This occurs through both cell-autonomous mechanisms, via stable cell cycle arrest, and non-cell-autonomous mechanisms, through SASP-mediated immune surveillance that facilitates the clearance of potentially malignant cells [1,2,6,106].

In contrast, the chronic accumulation of senescent cells particularly with aging or in the context of unresolved tissue stress has deleterious effects [1,8,103]. This accumulation is exacerbated by immunosenescence, the age-associated decline in immune surveillance capacity, which impairs the effective clearance of senescent cells [1,4]. The resulting persistent SASP induces a chronic, low-grade inflammatory state known as "inflammaging," a hallmark of aging and numerous age-related disorders [1,8]. This unresolved pro-inflammatory milieu disrupts tissue architecture, promotes paracrine senescence in neighboring cells, depletes tissue-resident stem cell populations, and fosters a microenvironment conducive to tumorigenesis. Consequently, senescence contributes to the pathophysiology of a broad spectrum of diseases, including cancer, type 2 diabetes, cardiovascular disease, IPF, liver fibrosis, osteoarthritis, neurodegenerative disorders such as Alzheimer's disease, and clinical frailty [1,2,6,8,65,103,104,107,108,109,110]. Understanding the dynamic balance between the beneficial and harmful effects of senescence across tissue types and temporal contexts is critical for designing effective, context-specific therapeutic interventions [2].

COPD is a progressive lung disorder predominantly associated with underlying inflammation, alveolar destruction, and aging. Clinically, COPD encompasses phenotypes such as chronic bronchitis and emphysema, with small airway disease being a central pathological feature. The disease is characterized by airflow limitation, and extensive structural remodeling of the airways and lung parenchyma. Accumulating evidence demonstrates increased cellular senescence in key lung cell populations including type II alveolar epithelial cells, endothelial cells, and fibroblasts in emphysematous lungs [29,129]. A meta-analysis involving 6,378 individuals further supported this association, revealing a significant correlation between shortened leukocyte telomere length and increased COPD risk [130] (Figure 2).

Given that cigarette smoke is the primary etiologic factor in COPD, several in vitro studies have investigated its role in epithelial senescence. These studies report upregulation of senescence-associated markers including p21^Cip1/Waf1, p53, SA-β-Gal, CXCL5, CXCL8, VEGF, and the DNA damage marker Gamma-Histone H2A Variant X (γH2A.X) [119,131]. Early evidence showed the role of p21^Cip1/Waf1 [132] and later p16^Ink4a [13] in regulation of cellular senescence in COPD. However, the role of p16^Ink4a remains debated. While murine models show increased p16^Ink4a expression in COPD, prior work by Sundar et al. (2018) showed that genetic ablation of p16^Ink4a alone did not protect against smoke-induced senescence [13]. Subsequent studies, however, suggest that p16^Ink4a contributes to the regulation of smoke-mediated senescence responses [82,133]. Additionally, Woldhuis et al. (2020) demonstrated elevated p16^Ink4a expression in COPD-derived fibroblasts, which inversely correlated with decorin expression, linking accelerated senescence with ECM dysregulation [46].

Senescence propagation may also occur through extracellular vehicles (EVs) carrying senescence-promoting microRNAs. In a recent study, EVs from COPD patients were shown to carry miR-34a, which induced senescence in healthy small airway epithelial cells (SAECs) by downregulating SIRT1 and upregulating p21^Cip1/Waf1, suggesting a mechanism for both local disease exacerbation and systemic comorbidities [134]. Recombinant human CC16 (rhCC16) has demonstrated senescence-reducing effects in lung epithelial cells and COPD mouse models by downregulating senescence markers, such as β-galactosidase, p16^Ink4a, p21^Cip1/Waf1, and ROS. These effects are mediated via activation of the AMPK/SIRT1-PGC-1α signaling pathway, thereby restoring mitochondrial function and offering promise as a senescence-modulating therapy [135].

A clinical trial supplementing COPD patient with nicotinamide riboside (NR) a precursor of NAD⁺ reported reduced airway inflammation (IL-8), increased systemic NAD⁺ levels, and improvements in genomic integrity and epigenetic aging, highlighting its therapeutic potential in targeting cellular senescence [136]. Yao et al. showed SIRT1 via FOXO3 mediated pathways attenuate lung cellular senescence in COPD/emphysema [137]. SIRT1 is reduced in lungs of patients with COPD [138]. Bioinformatics studies using machine learning and weighted gene co-expression network analysis (WGCNA) have identified four key genes EP300, mTOR, NFE2L1, and TXN as molecular links between COPD and aging. A diagnostic model based on these genes, developed using artificial neural networks, showed high predictive accuracy for COPD [139]. A six-month physical activity intervention in COPD patients reduced the proportion of senescent T-lymphocytes, improved their proliferative capacity, and reduced their ability to induce fibroblast senescence, thereby improving immune function [140].

Cellular senescence also appears to link COPD and cancer pathogenesis. A 2018 study showed that exposure of human bronchial epithelial cells (HBECs) to serum from COPD patients led to increased markers of senescence- SA-β-Gal, γH2A.X, p21^Cip1/Waf1, and ROS. The conditioned medium from these cells contained elevated CXCL5, CXCL8/IL-8, and VEGF, which promoted adhesion, proliferation, and migration of hypersecretory cells. These findings suggest that COPD-associated senescence may create a pro-tumorigenic microenvironment, independent of smoking status [119].

A pilot study revealed that induced sputum cells in COPD patients exhibit higher biological aging than peripheral blood leukocytes, as measured by DNA methylation age (DNAmAge) and age acceleration (AgeAcc). While telomere length did not show strong correlation, lung function (FEV₁%) and use of inhaled corticosteroids were associated with reduced biological aging in leukocytes suggesting a clinical relevance for site-specific aging markers [141]. While the concept of targeting senescence in COPD is compelling, it remains an emerging field requiring further validation. COPD is a highly heterogeneous disease, with variability in clinical manifestations depending on the location of injury, type of insult, patient age, sex, and comorbid conditions. Although senescence is a critical component of accelerated lung aging, it is not the sole driver of COPD pathogenesis. Importantly, senescence also serves physiological roles in tissue repair and immune regulation. Therefore, indiscriminate elimination of senescent cells may lead to adverse effects. A more nuanced approach focused on identifying and targeting pathogenic senescent cell subtypes that contribute to irreversible tissue damage, immune dysfunction, and stem cell depletion is essential for developing effective senescence-directed therapies in COPD.

Senescent lung fibroblasts are increasingly recognized as a contributor to the pathogenesis of IPF, a progressive and irreversible interstitial lung disease marked by excessive ECM deposition and alveolar remodeling [142]. While telomere shortening and replicative stress have long been implicated in promoting fibroblast senescence in IPF, emerging evidence highlights the additional roles of oxidative stress, mitochondrial dysfunction, and chronic inflammation in driving this phenotype [143]. Multiple studies have investigated biomarkers of fibroblast senescence in IPF. Sanders and colleagues found that elevated plasma levels of Growth Differentiation Factor 15 (GDF15), IL-6, CRP, and TNFRII are associated with an increased risk of interstitial lung abnormalities (ILA), a precursor state to pulmonary fibrosis [144]. Primary lung fibroblasts derived from IPF patients exhibit increased expression of canonical senescence markers including SA-β-gal, p53, p16^Ink4a, and p21^Cip1/Waf1, alongside a robust SASP [95,145].

Recent studies have implicated STAT3 activation in driving early senescence and IPF progression, suggesting that modulation of STAT3 signaling could mitigate fibroblast dysfunction [142]. Senescent fibroblasts in IPF also exhibit increased expression of anti-apoptotic Bcl-2 family proteins (Bcl-W, Bcl-2, Bcl-XL) and decreased expression of pro-apoptotic factors (Bak, Bax), conferring resistance to cell death [146,147]. Additionally, age-associated upregulation of PAI-1 has been observed in murine lung fibroblasts. PAI-1 promotes fibrotic remodeling via a vitronectin-independent pathway mediated through its interaction with SorLA (sortilin-related receptor 1), which is upregulated in both mouse models and human IPF tissue [148,149]. Targeting the PAI-1–SorLA axis may thus represent a novel therapeutic approach in IPF.

At the tissue level, senescent IPF fibroblasts display expanded SASP profiles, including pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), profibrotic growth factors (TGF-β, Connective Tissue Growth Factor (CTGF), Platelet-Derived Growth Factor (PDGF), chemokines (MCP-1, CXCL1), and matrix-degrading enzymes (MMP-2, MMP-9, MMP-12), which collectively foster a self-reinforcing fibrotic niche [95,150]. Notably, CTGF has been shown to induce fibroblast senescence via ROS accumulation and p53-mediated induction of p16^Ink4a [151]. Proteomic analyses further support a senescence-associated chromatin remodeling phenotype, including the accumulation of Nuclear Factor Kappa B (NF-κB) subunit p65 on chromatin in senescent fibroblasts [101].

Advances in single-cell transcriptomics have revealed substantial heterogeneity within the fibroblast compartment in IPF lungs. Studies by Tsukui et al. (2020) and Habermann et al. (2020) identified diverse fibroblast subtypes, including homeostatic fibroblasts, pathogenic myofibroblasts, and peribronchial fibroblasts [152,153]. However, it remains unclear which of these subpopulations are most prone to senescence and responsible for sustaining a chronic SASP. Integrating high-resolution single-cell RNA sequencing with spatial transcriptomics and senescence marker profiling may enable precise mapping of senescent fibroblast niches and clarify their interactions with neighboring senescent epithelial cells [152,154,155].

Additionally, applying RNA velocity and lineage tracing techniques may help determine whether activated fibroblast subtypes transition into a senescent state and whether this state is reversible under therapeutic pressure. These tools could illuminate the plasticity of fibroblast senescence in IPF and inform the development of subpopulation-specific senolytic therapies and targeted delivery systems. Taken together, senescent fibroblasts play a central role in shaping the profibrotic microenvironment of the IPF lung. Understanding the heterogeneity, plasticity, and molecular underpinnings of fibroblast senescence remains essential for designing precision interventions aimed at halting or reversing fibrotic progression (Figure 1). It is paramount to mention however that most of the existing literature focuses on studying the mechanism of senescence in lung fibroblasts in relation to IPF. But future work should focus on the crosstalk of senescent fibroblasts with neighboring cell milieu and the transitional cell states within a fibrotic versus a non-fibrotic tissue.

In the context of lung cancer particularly non-small cell lung cancer (NSCLC) and its predominant adenocarcinoma subtype cellular senescence exhibits a distinctly paradoxical or "dual" role. In early carcinogenesis, cellular senescence functions as a potent tumor-suppressive mechanism, interfering with the proliferation of cells with oncogenic alterations through stable/persistent cell cycle arrest and immune-mediated clearance. However, in advanced or established tumors, senescent cells—especially those that persist—can adopt a pro-tumorigenic phenotype via SASP. This chronic SASP output promotes inflammation, tumor progression, immune evasion, metastatic spread, and resistance to therapy [156]. For tumor progression, cancer cells must bypass this senescence barrier, frequently through the acquisition of loss-of-function mutations in p53 or p16^Ink4a [157].

OIS represents a critical tumor-suppressive barrier that acts to prevent malignant transformation at the earliest stages of carcinogenesis. In lung adenocarcinoma, activation of oncogenes such as KRAS or BRAF elicits a potent senescence response characterized by stable cell cycle arrest, effectively halting the proliferation of transformed cells [15]. This protective mechanism, often referred to as the "friend" role of senescence, helps to confine lesions to a pre-malignant or early malignant state. However, for tumor progression to occur, cancer cells must bypass this senescence barrier, frequently through the acquisition of loss-of-function mutations in tumor suppressors such as p53 or p16^Ink4a [157].

Paradoxically, once senescent cells persist particularly in the setting of TIS they often adopt a "foe" role in cancer progression. Senescent cells develop a robust SASP, which is a complex cocktail of pro-inflammatory cytokines (e.g., IL-6, IL-8), chemokines, growth factors, and proteases that remodel the tumor microenvironment (TME) [6]. This remodeling can promote epithelial–mesenchymal transition (EMT), angiogenesis, and invasion, thereby enhancing tumor aggressiveness [158,159].

Recent studies have demonstrated that senescent lung fibroblasts such as those found in IPF, a known risk factor for lung cancer, secrete exosomes enriched in matrix metalloproteinase-1 (MMP-1). These exosomes are readily internalized by NSCLC cells, where they activate the PI3K–AKT–mTOR pathway, stimulating cellular proliferation and clonogenicity [160]. The persistence of senescent cells following chemotherapy is therefore increasingly linked to adverse clinical outcomes, including tumor relapse and metastasis [161].

SASP also exerts profound effects on the immune landscape of the TME. While initially capable of recruiting immune cells for senescent cell clearance, a chronic SASP may shift the microenvironment toward immunosuppression. This phenomenon has been exemplified in KRAS-driven lung cancer models, where senescent macrophages have been identified as a major pro-tumorigenic population [162]. These macrophages, which are also found in aged lungs and pre-malignant human lung lesions, exhibit a unique SASP (specific to tumor cells) that promotes tumor progression. Notably, senolytic clearance of these cells using agents such as ABT-737 was shown to reduce tumor burden, enhance anti-tumor immunity, and extend survival in murine models [162].

These findings show the context-dependent duality of senescence in lung cancer. While senescence can initially restrain malignant transformation, its persistence especially in the TME facilitates tumor evolution and immune evasion. Critically, these effects are mediated by specific, targetable senescent cell populations, reinforcing the therapeutic potential of senolytics and SASP modulators in lung cancer treatment.

The role of cellular senescence in ALI and ARDS has emerged as a critical area of investigation, particularly in the wake of the COVID-19 pandemic. In contrast to chronic lung diseases where senescence is well established as a pathogenic driver the function of senescence in acute injury is more context-dependent and paradoxical. It often exhibits characteristics of a "double-edged sword", exerting both protective and deleterious effects depending on the timing, duration, and cellular context of its activation [87,124,163].

In response to acute insults such as viral infection or severe inflammation, the lung initiates a transient senescence response that serves as an early protective mechanism [164]. This form of acute senescence acts to arrest the proliferation of damaged or infected cells, thereby limiting the spread of pathogens and preserving tissue integrity. Unlike apoptosis, this temporary growth arrest allows for cellular survival and immune-mediated clearance, preventing further tissue disruption [87].

A clear illustration of this process is observed in the context of severe COVID-19, where SARS-CoV-2 infection has been shown to induce a pronounced senescent phenotype in AT2 epithelial cells. These infected senescent cells exhibit elevated expression of key markers such as p16^Ink4a and the DNA damage marker γ-H2AX, indicating the activation of a canonical senescence program [126]. In the setting of ALI and LARDS (COPD, IPF, Asthma, etc.) the SASP plays a dual role in immunomodulation. Initially, the secretion of pro-inflammatory cytokines and chemokines facilitates a beneficial immune response, aiding in the recruitment of immune cells to eliminate pathogens, clear apoptotic or damaged cells, and remove senescent cells once their protective role is fulfilled [87]. This acute inflammatory signaling is prominently observed in severe COVID-19, where senescent AT2 epithelial cells exhibit markedly elevated expression of SASP cytokines such as IL-1β and IL-6. These factors contribute directly to the hyperinflammatory state that characterizes severe disease [87].

However, when senescent cells are not efficiently cleared, this initially protective SASP can become pathogenic. Persistent SASP signaling can promote chronic inflammation, impair tissue repair, and exacerbate lung damage. This failure of clearance is particularly pronounced in the context of immunosenescence, a state of age-associated immune dysfunction which limits the immune system's capacity to resolve inflammation and remove senescent cells [87]. Thus, the context, duration, and immune competence of the host are critical determinants of whether the SASP functions as a beneficial or deleterious mediator in ALI and LARDS.

When the acute senescence program fails to resolve appropriately, it transitions from a protective mechanism into a pathogenic driver of chronic lung damage. This unresolved senescent state contributes to delayed resolution, fibrotic remodeling, and long-term impairment of pulmonary function [164]. The persistent secretion of SASP factors from an accumulating burden of senescent cells perpetuates a chronic inflammatory milieu, which affects with normal tissue regeneration and promotes the deposition of extracellular matrix, ultimately leading to fibrosis which can occur in long COVID-19 [87].

The accumulation of senescent alveolar epithelial cells significantly compromises the host's capacity to recover, diminishing epithelial integrity and regenerative potential in ALI [165].

This chronic, unresolved senescent state characterized by persistent SASP signaling, immune dysfunction, and a loss of reparative capacity is increasingly recognized as a central mechanism underlying the post-acute sequelae observed in survivors of ARDS and severe COVID-19 [126]. These findings emphasize the need for therapeutic strategies aimed at modulating senescence resolution, restoring immune surveillance, and preserving epithelial regeneration in the aftermath of acute lung injury.

Cellular senescence is a critical pathological feature in cystic fibrosis (CF), a genetic disease marked by chronic neutrophilic inflammation, mucus accumulation, and progressive lung tissue damage [166,167]. While CF was traditionally considered a pediatric disorder, advancements in treatment have significantly extended patient lifespan, uncovering hallmarks of premature lung aging in this population [166]. The CF airway epithelium exhibits a distinct senescence-associated signature, with elevated expression of canonical senescence markers including p16^Ink4a, γH2A.X, and phospho-Chk2, when compared to non-CF controls. Notably, this senescent phenotype is spatially and cell-type-specific. Recent single-cell RNA sequencing revealed that basal and secretory epithelial cells within CF airways show the highest expression of senescence markers [168]. Intriguingly, even in the absence of inflammatory stimuli, CFTR-deficient bronchial epithelial cells exhibit a senescent-like phenotype characterized by elevated p21^Cip1/Waf1 levels and reduced proliferative capacity, suggesting that CFTR dysfunction itself acts as a cell-intrinsic senescence. Among the extrinsic inducers of senescence in CF, neutrophil elastase (NE) is particularly important. NE, abundantly released into the CF airway due to sustained neutrophil infiltration, has been shown to induce cellular senescence in airway epithelial cells via p16^Ink4a mediated CDK4 inhibition [169,170]. This establishes a self-reinforcing loop, as senescent cells develop a SASP that exacerbates inflammation by recruiting additional immune cells, thus amplifying tissue damage and further promoting senescence [170,171]. Additionally, neutrophils isolated from bronchoalveolar lavage fluid of CF patients have been shown to express p21^Cip1/Waf1, which may prolong their survival and contribute to persistent inflammation [167].

Emerging studies have begun to elucidate novel pathways that sustain senescence in CF beyond CFTR loss. The FGFR-MAPK-p38 axis has been implicated in promoting senescence in CF bronchial epithelium. Pharmacologic inhibition of FGFR4 significantly reduced senescence marker expression and improved mucociliary clearance in preclinical models, indicating this pathway's therapeutic potential [168]. These findings suggest that although CFTR dysfunction initiates disease, secondary senescence may be maintained by CFTR-independent mechanisms, possibly explaining persistent inflammation in CF patients treated with highly effective modulator therapies [168]. Altogether, the accumulation of senescent cells in CF lungs not only accelerates structural damage but also contributes to chronic inflammation and impaired repair. As such, targeting cellular senescence represents a promising therapeutic avenue to mitigate disease progression, especially in the aging CF population [171].

Pulmonary Arterial hypertension (PAH) is a progressive and proliferative vascular disorder in which cellular senescence is increasingly recognized as a central pathological mechanism [172,173]. The accumulation of senescent cells, particularly pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs), contributes to the vascular remodeling that characterizes PH pathogenesis [174].

In both human idiopathic pulmonary hypertension, PH (Idiopathic Pulmonary Arterial Hypertension) and animal models, elevated expression of senescence markers such as p16^Ink4a, p21^Cip1/Waf1, and γH2AX has been consistently reported in vascular tissues [172,175]. Notably, hypoxia-induced senescence in PASMCs leads to paracrine secretion of IL-6, promoting the proliferation of neighboring PASMCs via the mTOR/S6K1 signaling axis [176].

In addition to paracrine signaling, juxtacrine interactions between senescent endothelial cells (ECs) and PASMCs have been shown to drive disease progression. Specifically, senescent ECs upregulate Notch ligands (e.g., Jagged-1 (JAG1), Delta-Like 4(DLL4), which activate Notch signaling in adjacent PASMCs. This mechanism was confirmed in EC-specific progeroid mouse models, where pharmacological inhibition of Notch signaling attenuated disease severity [177]. Transcriptomic analyses have further identified YWHAZ as a central hub gene in hypoxic PAECs and PH models; its silencing promotes autophagy, suggesting a potential strategy to facilitate senescent cell clearance [178,179]. Other pathways and molecules, such as SIRT1, mTOR, miRNA 21, epigenetic modifications, and mitophagy may be involved in cellular senescence of lung endothelial cells. This may also be associated with co-morbidity of IPF/COPD with PAH.

Senescence also appears to demarcate the irreversibility of PH progression. In a congenital heart disease-associated PH (PAH-CHD) rat model, the transition from reversible to irreversible pathology was marked by a shift toward a senescent vascular phenotype, with increased expression of p16^Ink4a, p21^Cip1/Waf1, MMP2, and IL-6. Remarkably, senolytic therapy with ABT263 reversed advanced PH in this model, supporting a causal role for senescent cell accumulation in disease progression [180]. This pro-fibrotic and pro-remodeling function of senescence is echoed in findings that frataxin deficiency, a known inducer of mitochondrial dysfunction, promotes endothelial senescence and PH, which is also amenable to senolytic intervention [173].

Paradoxically, recent data suggest that senescence may play a protective or homeostatic role in certain contexts. In contrast to the above findings, genetic (p16^Ink4a-ATTAC model) and pharmacological (ABT263, Forkhead Box O4-Drug Resistance Inhibitor (FOXO4-DRI) clearance of senescent cells in various rodent PH models resulted in worsened hemodynamics and enhanced vascular remodeling [175]. These effects were attributed to the loss of senescent pulmonary endothelial cells (P-ECs), which represent a significant portion of the senescent population even in healthy lungs and may serve essential homeostatic and anti-proliferative functions [174,175].

Asthma, especially severe, late-onset, and Th2-low phenotypes, shows airway cellular senescence that intersects with chronic inflammation and remodeling. Repeated epithelial injury from allergens, viral exposures, pollutants, and oxidative stress drives DNA-damage responses, mitochondrial dysfunction, and checkpoint activation (p16/p21), producing a stable growth-arrested state with a pro-inflammatory, matrix-remodeling secretome that amplifies hyperresponsiveness and promotes fixed airflow limitation [111,122,181].

In the epithelium, thymic stromal lymphopoietin (TSLP) has been identified as an upstream trigger of senescence and remodeling. Human asthmatic airway biopsies display increased epithelial p16 and p21 expression together with collagen I and α-SMA, consistent with remodeling. Silencing p16 and p21 or pharmacologic STAT3 inhibition prevents the induction of collagen I and α-SMA in vitro. In allergen-challenged mice, STAT3 inhibition reduces epithelial senescence, diminishes airway remodeling, and alleviates hyperresponsiveness, supporting a causal role for TSLP-driven senescence in asthma pathology [111]. Airway smooth muscle (ASM) senescence is thought to participate by altering calcium handling, sustaining baseline contractile tone, and producing a SASP that stimulates fibroblast activation and ECM turnover. Crosstalk among senescent epithelial cells, ASM, and fibroblasts, enhanced by TSLP signaling, may reinforce hyperresponsiveness and steroid insensitivity [111].

Fibroblasts also display evidence of accelerated senescence. Bronchial fibroblasts isolated from mild asthmatic patients exhibit significantly shorter telomeres than those from healthy controls, with an average reduction from approximately 10.7 kb to 8.9 kb. They also show a markedly higher fraction of SA-β-gal-positive cells. Importantly, telomere length in fibroblasts correlates inversely with airway hyperresponsiveness, as measured by methacholine PC20, suggesting that replicative senescence contributes directly to disease severity [92].

Together, these data highlight biomarker patterns of airway senescence in asthma, including epithelial p16/p21 upregulation with loss of proliferative markers, epithelial and mesenchymal SA-β-gal activity, telomere attrition in bronchial fibroblasts, and induction of collagen I and α-SMA in remodeled tissue. These signatures are closely aligned with clinical features of severe asthma, including frequent exacerbations, poor bronchodilator response, and fixed obstruction, particularly in elderly-onset, obesity-associated, and T2-low endotypes [92,111].

From a therapeutic standpoint, senomorphics that dampen epithelial and mesenchymal senescence signaling, such as inhibitors of the TSLP–STAT3 axis or related inflammatory pathways, could reduce remodeling and restore treatment responsiveness. In preclinical models, STAT3 inhibition has been shown to attenuate both senescence and airway dysfunction. In parallel, airway-targeted senolytics may help selectively eliminate senescent cell populations that sustain remodeling, particularly if applied in short, pulsed regimens layered onto standard asthma therapies and biologics [92,111].

An array of proteins is critically involved in the complex process of cellular senescence in the lungs. These proteins participate in various pathways, including cell cycle regulation, DNA damage response, and the secretion of SASP factors, all of which contribute to lung aging and the pathogenesis of lung age-related diseases (Table 1).

Senotherapeutics encompass two main strategies for targeting cellular senescence: senolysis and senomorphism. Senolytics are compounds designed to selectively induce apoptosis in SnCs, thereby reducing the burden of these cells in tissues [77,202]. This approach contrasts with senomorphics (or senostatics), which aim to suppress the deleterious SASP without necessarily eliminating the cells themselves [77,203]. The rationale behind senolysis is that the removal of SnCs can alleviate their detrimental contributions to aging and age-related diseases, potentially improving tissue function and extending healthspan [77,202] (Figure 3).

The selective action of senolytics relies on exploiting the vulnerabilities inherent in the senescent state. To survive despite accumulating cellular damage and producing a potentially self-toxic SASP, SnCs upregulate a network of pro-survival pathways, collectively termed senescent cell anti-apoptotic pathways (SCAPs) [77,204,205]. These pathways confer resistance to apoptosis. Senolytics function by transiently disabling these specific SCAPs, rendering SnCs susceptible to their pro-apoptotic microenvironment or internal damage signals [77,202].

Bioinformatic analyses of senescent versus non-senescent cells identified several key SCAPs, including pathways involving Ephrins, PI3K/AKT, p53/p21^Cip1/Waf1/Serpins, HIF-1α, and notably, the BCL-2 family of anti-apoptotic proteins [77,202,204]. The dependency on specific SCAPs can vary between different types of SnCs, highlighting the heterogeneity of senescence and suggesting why certain senolytics exhibit cell-type specificity [77,204].

Research into senolytics has identified promising candidates from diverse sources, including natural products, repurposed drugs originally developed for other indications, and novel synthetic molecules specifically designed to target senescence pathways (Table 2).

The first senolytics reported, dasatinib (D) and quercetin (Q), were identified through a hypothesis-driven, bioinformatics-based approach targeting SCAPs [205]. Dasatinib is a tyrosine kinase inhibitor used clinically for leukemia, while quercetin is a natural flavonoid known to interact with PI3K and Bcl-2 family members [77,202,206]. While each compound has senolytic activity against specific cell types (e.g., dasatinib against senescent preadipocytes, quercetin against senescent HUVECs), their combination (D+Q) exhibits broader efficacy, targeting a wider range of SnCs and often showing synergistic effects [77,202]. Preclinical studies demonstrated that D+Q administration can alleviate numerous age-related dysfunctions in mice, including improving cardiovascular function, reducing osteoporosis, mitigating frailty, and improving physical function even when administered late in life [202]. Furthermore, D+Q treatment has shown benefits in models of atherosclerosis, pulmonary fibrosis, hepatic steatosis, neurodegeneration, and metabolic dysfunction associated with diabetes or obesity [77,108,202]. D+Q treatment also protected against cisplatin-induced ovarian injury by removing SnCs [109].

Additional classes with senolytic activity include cardiac glycosides (e.g., ouabain, digoxin) which inhibit Na⁺/K⁺-ATPase [214], and compounds targeting the p53 pathway, such as FOXO4-DRI peptides which disrupt the FOXO4-p53 interaction [215], and inhibitors of MDM2 or USP7 which stabilize p53 [77]. Aspirin has also been reported to have senolytic properties in certain contexts [202].

Beyond the known classes of senolytics such as tyrosine kinase inhibitors (Dasatinib), flavonoids (Quercetin, Fisetin), and Bcl-2 family inhibitors (Navitoclax), several novel strategies have recently emerged to improve selectivity and efficacy while minimizing off-target effects. For instance, β-galactosidase-activated prodrugs such as Galacto-Navitoclax exploit the elevated SA-β-Gal activity in senescent cells to release cytotoxic payloads selectively, demonstrating enhanced precision in preclinical models [216]. Similarly, PROTAC-based senolytics like ARV825 have been designed to degrade anti-apoptotic or epigenetic survival proteins specifically in senescent cell populations, offering a promising next-generation approach [217,218].

Additionally, MDM2 inhibitors such as Nutlin-3a can reactivate p53 pathways to induce apoptosis in senescent or stressed cells [211]. Selective targeting of other anti-apoptotic proteins is also gaining traction; for example, Mcl-1 inhibitors (e.g., S63845) have shown potential for removing resistant senescent cells, though primarily explored in oncology thus far [219]. Finally, the development of nanoparticle-encapsulated senolytics, including lung-targeted formulations of Quercetin or Dasatinib, represents an innovative strategy to localize senolytic activity, potentially reducing systemic toxicity and improving therapeutic index for lung diseases [220].

Beyond small molecules, innovative approaches are being developed.

While the elimination of SnCs via senolytics has garnered significant attention, an alternative and potentially complementary therapeutic strategy involves modulating the characteristics of SnCs without inducing cell death (Table 3). This approach utilizes agents termed as senomorphics or senostatics. The core principle behind senomorphism is the suppression or alteration of the detrimental aspects of the SASP [1,77,103].

The rationale for developing senomorphics stems from several considerations. Firstly, the SASP itself is recognized as a major driver of the deleterious effects associated with SnC accumulation [1,77]. Targeting the SASP directly offers a way to mitigate these effects. Secondly, SnCs are not uniformly detrimental; they play essential roles in physiological processes such as tumor suppression, embryonic development, and wound healing [8,77]. Senolytic therapies risk ablating these beneficial functions by eliminating SnCs. Senomorphics, on the other hand, might offer a more nuanced intervention by preserving the SnCs while neutralizing their harmful secretion. Thirdly, the heterogeneity of SnCs and their SASP profiles across different tissues, cell types, and inducing stimuli [7,77] presents a challenge for broadly effective senolytics. Senomorphic agents targeting common SASP regulatory pathways might provide a more universally applicable approach. By altering the SnC phenotype rather than inducing cell death, senomorphics aim to achieve a state of "senostasis," reducing the pro-aging impact of senescent cells [202] (Figure 4).

Senomorphic compounds exert their effects primarily by interfering with the signaling pathways and molecular machinery responsible for producing and secreting SASP components. The SASP is remarkably complex, comprising hundreds of distinct factors including pro-inflammatory cytokines (e.g., IL-6, IL-8), chemokines (e.g., MCP-1/CCL2), growth factors, proteases (e.g., matrix metalloproteinases-MMPs), bioactive lipids, extracellular vesicles (EVs), and other molecules [7,63]. The production of this diverse secretome is tightly regulated at multiple levels, transcriptional, post-transcriptional, and translational, providing various points for senomorphic intervention [77]. Among various regulatory mechanisms, following pathways stand out as the principal drivers of inflammatory SASP factors:

Senomorphics offer a distinct therapeutic paradigm for tackling aging and age-related diseases. By focusing on neutralizing the harmful environment created by SnCs rather than eliminating the cells themselves, they may provide a safer long-term strategy, particularly considering the potential beneficial roles of SnCs and the risks associated with broad senolysis [77,202]. This approach could be particularly valuable for chronic conditions where sustained suppression of inflammation and tissue protection is desired. Evidence from preclinical models using agents like rapamycin, metformin, and specific pathway inhibitors (NF-κB, JAK, ATM) suggests that senomorphic interventions can indeed improve health span and alleviate symptoms associated with aging and specific diseases [77]. The recent demonstration of clinical benefit from a topical senomorphic formulation in skin aging further supports this potential [223].

Despite this promise, the development and application of senomorphics face significant hurdles [77]. A primary challenge lies in the complexity and context-dependency of the SASP [7]. Indiscriminate suppression of all SASP factors may be detrimental, as some components might have protective or necessary physiological functions (e.g., immune recruitment, tissue repair signals). Achieving selective modulation of only the pathogenic SASP components requires a much deeper understanding of SASP composition and regulation in different physiological and pathological contexts. Long-term safety is a major concern, especially for agents targeting fundamental pathways like mTOR, NF-κB, or ATM, which have vital roles beyond SASP regulation. Chronic inhibition of SASP could lead to unforeseen adverse effects, including impaired immunity, metabolic disturbances, or potentially increased cancer risk [77]. Developing robust biomarkers to specifically monitor senomorphic activity (i.e., effective SASP suppression) in vivo and in clinical trials is crucial for assessing efficacy and guiding dosing regimens, yet such biomarkers are currently lacking. Furthermore, optimizing drug delivery to ensure adequate and sustained levels of senomorphic agents in target tissues while minimizing systemic exposure remains a significant pharmacokinetic challenge [77]. Finally, the heterogeneity of senescence itself means that the effectiveness of a given senomorphic might vary considerably depending on the specific type of SnCs present and the underlying cause of their senescence. Overcoming these limitations will require continued basic research into SASP biology, careful preclinical safety and efficacy testing, innovative drug design and delivery strategies, and thoughtfully designed clinical trials (Table 4).

Together, these emerging modalities expand the senotherapeutic arsenal and underscore the need for disease-specific delivery systems and rigorous preclinical validation, particularly in fibrotic lung diseases such as IPF.

Effective and targeted delivery remains a challenge for many senotherapeutics, particularly natural products with poor bioavailability or agents with potential off-target toxicities. Nanotechnology offers promising solutions.

The broad involvement of SnCs in numerous pathologies suggests that senolytics could have wide-ranging therapeutic applications, including for osteoarthritis, neurodegenerative diseases (e.g., Alzheimer's disease), metabolic disorders (e.g., type 2 diabetes, obesity-related dysfunction), cardiovascular diseases, IPF, and frailty [77,103,108,202,214].

Given the heterogeneity of SnCs and their SCAPs, combination strategies are being considered. Combining senolytics with different mechanisms or targets (e.g., D+Q) may broaden the spectrum of SnCs eliminated and enhance overall efficacy [77,202]. Additionally, combining senolytics with senomorphics could offer a dual approach, reducing SnC burden while also suppressing the SASP from remaining or newly formed SnCs [77].

A key strategic advantage proposed for senolytics is the potential for intermittent dosing. Since SnCs accumulate relatively slowly, periodic administration ("hit-and-run" approach) might be sufficient to maintain a low SnC burden and achieve therapeutic benefits, while minimizing the potential for side effects associated with continuous drug exposure [108,202]. The long-lasting effects observed with senolytic CAR T cells further support the feasibility of intermittent or even single-dose curative therapies [214].

Despite significant progress, the development of senolytics faces challenges. The heterogeneity of SnCs necessitates careful selection of senolytic agents based on the specific cell types involved in a particular disease [77,202]. Off-target toxicity remains a concern, as exemplified by navitoclax, underscoring the need for highly selective agents or targeted delivery systems [204]. Furthermore, long-term safety data, particularly concerning potential effects on tissue repair, immune function, and tumorigenesis, are still needed [103,202]. Ongoing research focusing on identifying more specific senolytic targets, developing novel delivery platforms like PROTACs and advanced nanocarriers, refining immunotherapy approaches, and conducting well-designed clinical trials will be crucial for realizing the full therapeutic potential of senolytics in combating age-related diseases [77,202,214].

Senescent epithelial and stromal cells in the lung actively modulate the immune microenvironment by secreting SASP factors that influence both innate and adaptive immune cell function.

Senescence in the lung represents a highly heterogeneous phenomenon, with distinct molecular signatures, functional consequences, and SASP profiles emerging across diverse cell types. Single-cell transcriptomic analyses have demonstrated that lung epithelial cells, endothelial cells, fibroblasts, and immune cells each adopt unique senescence programs, shaped by their specialized functions and stress responses within the tissue microenvironment [53,98,260]. The advent of high-throughput single-cell and single-nucleus RNA sequencing has enabled unprecedented resolution in characterizing these senescent states and identifying novel cell-type-specific markers [52].

For instance, using high-content imaging, Neri et al. examined senescence marker expression in primary human endothelial cells and fibroblasts and identified that G2-arrested senescent cells exhibited higher expression of canonical markers, greater IL-6 secretion, and increased sensitivity to the senolytic ABT263, compared to G1-arrested counterparts [97]. Functionally, senescent alveolar epithelial cells impair barrier integrity and reduce surfactant production, whereas senescent endothelial cells contribute to vascular permeability and leukocyte extravasation through pro-inflammatory SASP activity [55,261,262,263]. Senescent fibroblasts frequently adopt a pro-fibrotic phenotype characterized by secretion of TGF-β, IL-6, and ECM proteins that promote fibrogenesis [264].

Beyond intercellular differences, intra-lineage heterogeneity has also been documented. Single-cell analyses utilizing tools such as SenePy have revealed that even within the same cell type, distinct senescent "states" exist, each defined by variable transcriptional outputs and responses to stress stimuli [53,99]. These differences are influenced by the nature of the senescence-inducing insult whether DNA damage, oxidative stress, or oncogenic activation each eliciting a context-specific senescence program. Proteomic and transcriptomic profiling confirm that the SASP composition is not only cell-type specific but also inducer-dependent, with senescent fibroblasts producing a cytokine and matrix-modifying profile distinct from that of senescent epithelial or endothelial cells [100]. Similarly, senescence states (see above section) of the lung cells based on stimuli, type of cells, and transitory cell phenotypes may play an important role in senotyping of lung cells.

To better navigate this complexity, transcriptional marker panels such as SenMayo have been developed to detect senescent cells across multiple lung cell populations by targeting conserved features of the senescence program. Nonetheless, expression of individual markers, such as CDKN2A or p21^Cip1/Waf1, can still vary substantially based on both cell lineage and senescence trigger [265]. Collectively, these findings emphasize that lung cellular senescence is a non-uniform, context-dependent process that requires precise, cell-type aware identification and interpretation for both mechanistic studies and the development of targeted senotherapeutics.

While cellular senescence has long been regarded as a terminal, irreversible growth arrest, emerging evidence challenges this notion by revealing that certain senescent states can, under specific conditions, be at least partially reversible. This plasticity appears to be influenced by factors including cell type, the nature and severity of the inducing stressor, the duration of senescence, and the metabolic and epigenetic landscape of the cell.

Experimental studies have shown that transient senescence, particularly in response to sublethal DNA damage or oxidative stress, may be reversible. For example, oxidative stress-induced senescence in lung epithelial cells and hepatic stellate cells can be reversed upon removal of the insult or through modulation of the p53/p21^Cip1/Waf1 pathway [93]. Similarly, mesenchymal stem cells exposed to reversible senescence stimuli demonstrate restored proliferative capacity when treated with epigenetic modulators [275].

At the molecular level, senescence reversal is associated with restoration of mitochondrial function, metabolic reprogramming, and epigenetic remodeling. Specifically, replenishment of NAD⁺ levels or improvement in mitochondrial health has been shown to suppress SASP expression and restore proliferative competence in certain senescent cell types [276]. These findings underscore that not all senescent states represent a permanent cell fate, and that therapeutic interventions aimed at modulating or reversing early or context-dependent senescence may hold promise in treating fibrosis, cancer, and age-associated dysfunction.

Changes in the biomechanical properties of the ECM particularly increased stiffness in fibrotic lungs and loss of structural integrity in emphysematous tissue play a critical role in both initiating and reinforcing cellular senescence. In pulmonary fibrosis, excessive deposition of collagen and cross-linked ECM proteins leads to increased tissue stiffness, which exerts abnormal mechanical stress on resident fibroblasts, epithelial cells, and endothelial cells. This mechanical cue is transduced via integrins, focal adhesion kinase (FAK), and the YAP/TAZ signaling axis, culminating in senescence-associated growth arrest and the upregulation of SASP components [279]. Fibroblasts cultured on stiff substrates or isolated from fibrotic lung tissue exhibit a robust senescent phenotype, marked by increased expression of p16^Ink4a, IL-6, TGF-β, and matrix metalloproteinases, thereby further promoting ECM remodeling and fibrosis [280].

In contrast, emphysematous lungs are characterized by progressive ECM degradation particularly the loss of elastin and collagen resulting in weakened alveolar architecture and aberrant cell–ECM interactions. This destabilized mechanical environment induces abnormal cellular stretching, mitochondrial dysfunction, and oxidative stress, collectively driving epithelial cell senescence and impairing regenerative capacity [281]. Importantly, senescent cells within these mechanically altered tissues demonstrate enhanced resistance to apoptosis and maintain persistent SASP activity, establishing a self-perpetuating loop of matrix remodeling, inflammation, and senescence [35].

These findings emphasize that ECM mechanics are not mere consequences of chronic lung pathology, but active determinants of senescence induction and maintenance. Targeting mechanotransduction pathways or ECM remodeling processes offers a promising avenue for senescence-modulating therapies in fibrotic and degenerative lung diseases.

Cellular senescence in the lung is intimately associated with profound metabolic reprogramming that encompasses alterations in glycolysis, lipid metabolism, and mitochondrial bioenergetics. These metabolic shifts not only accompany the senescent phenotype but actively contribute to its initiation, maintenance, and pathological effects.

A prominent metabolic hallmark of senescent cells is a shift toward enhanced glycolysis often described as a "Warburg-like" effect even in the absence of proliferation. In senescent lung fibroblasts and epithelial cells, glycolytic reprogramming supports increased NADPH production and fuels the biosynthetic and pro-inflammatory output of the SASP [282]. In parallel, senescent cells exhibit dysregulated lipid metabolism, characterized by the accumulation of intracellular lipid droplets and upregulation of lipogenic enzymes such as fatty acid synthase. These changes are particularly evident in AT2 epithelial cells and fibroblasts from aged or fibrotic lungs, where altered lipid handling contributes to lipotoxic stress, mitochondrial dysfunction, and fibrotic activation [283,284,285].

At the mitochondrial level, senescent lung cells display altered oxidative phosphorylation (OXPHOS), elevated ROS generation, and disrupted mitochondrial dynamics, including increased fission and reduced mitophagy. These mitochondrial defects exacerbate the DNA damage response and reinforce senescence-associated growth arrest [286]. Furthermore, mitochondrial dysfunction amplifies SASP output through NF-κB activation and inflammasome signaling, linking bioenergetic collapse to persistent inflammation [20].

Importantly, interventions that target mitochondrial regulators such as PGC-1α or enhance mitophagy have been shown to attenuate senescence phenotypes and restore epithelial homeostasis in preclinical lung models [287,288]. These findings suggest that the metabolic rewiring of senescent cells is not merely epiphenomenal but represents a core driver of lung aging and disease progression.

Recent studies have elucidated distinct metabolic dependencies in senescent cells, paving the way for the development of metabolic senolytics agents that selectively eliminate senescent cells by exploiting their altered bioenergetic state. Senescent lung cells exhibit a unique metabolic phenotype characterized by enhanced glycolysis, impaired mitochondrial oxidative phosphorylation (OXPHOS), elevated ROS production, and reliance on specific survival pathways [30,286,289,290]. These adaptations render senescent cells particularly vulnerable to therapeutic strategies that disrupt redox homeostasis, NAD⁺ metabolism, or mitochondrial function.

One of the most extensively studied metabolic senolytics is navitoclax (ABT-263), a BCL-2/BCL-xL inhibitor that induces apoptosis preferentially in senescent cells by targeting their heightened mitochondrial priming [211]. Similarly, the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) has demonstrated selective cytotoxicity against senescent cells with elevated glycolytic flux [291]. In preclinical lung models, pharmacologic modulation of mitochondrial health using agents such as metformin or mitophagy enhancers like urolithin A has successfully reduced senescent cell burden and mitigated fibrotic remodeling [292].

Additionally, peptide-based approaches targeting senescence-specific survival pathways have shown promise. For instance, the FOXO4-DRI peptide disrupts the interaction between p53 and FOXO4, a critical axis for senescent cell survival leading to selective apoptosis of senescent cells, including in lung tissues [215]. These findings underscore the therapeutic potential of metabolic senolytics in treating chronic lung diseases such as COPD, IPF, and post-COVID-19 pulmonary fibrosis, conditions where persistent senescent cells perpetuate inflammation and tissue remodeling. Future strategies that combine metabolic senolytics with anti-fibrotic or pro-regenerative therapies may yield synergistic effects, restoring lung homeostasis and improving clinical outcomes.

The concept of personalized medicine in the context of lung senescence seeks to tailor therapeutic strategies according to an individual's senescent cell burden, spatial distribution, and cell type-specific senescence profiles. Senescent cells accumulate heterogeneously across lung compartments including alveolar epithelium, fibroblasts, endothelium, and immune infiltrates with this variation shaped by intrinsic factors such as aging and extrinsic stressors like environmental pollutants, viral infections, and fibrotic remodeling [296]. However, the clinical implementation of senescence profiling remains limited by the absence of validated in vivo biomarkers.

Transcriptomic tools such as SenMayo and SenePy developed from bulk and single-cell RNA sequencing datasets have shown promise in estimating senescent cell signatures from biopsy-derived samples [53,265]. Additional modalities, including machine learning-based histological classifiers, circulating SASP factors, and senescence-associated EVs, are under active investigation as non-invasive surrogates of senescence burden [297].

The integration of these approaches with clinical and molecular disease staging holds potential for stratifying patients into senescence-enriched or senescence-low subgroups. For example, in IPF, profiling patients with elevated senescent fibroblast signatures could guide the selective use of senotherapeutic agents alongside existing antifibrotic therapies [39]. Such personalized approaches may optimize treatment efficacy, minimize off-target toxicity, and enable longitudinal monitoring of therapeutic response.

Senescence in the lung is intricately influenced by environmental exposures, microbiome dynamics, and circadian rhythm regulation, each acting as a modifiable contributor to senescence induction and progression in chronic respiratory diseases.

Environmental pollutants such as cigarette smoke, particulate matter (PM2.5), ozone, and diesel exhaust are well-established inducers of senescence, triggering oxidative stress, DNA damage, and mitochondrial dysfunction in epithelial cells, fibroblasts, and endothelial cells [298,299,300]. For instance, cigarette smoke induces premature senescence through the activation of p16^Ink4a and p21^Cip1/Waf1, alongside a pro-inflammatory SASP that perpetuates tissue injury and inflammation in COPD [40].

The lung microbiome is another key regulator. Dysbiosis marked by reduced microbial diversity and increased abundance of pro-inflammatory mediators can amplify alveolar macrophage activation and epithelial dysfunction, fueling chronic inflammation and promoting senescence via low-grade immune activation [301]. Microbial metabolites such as short-chain fatty acids (SCFAs) and lipopolysaccharides (LPS) may further influence SASP output in a context-dependent manner [302].

Circadian rhythm disruption, common in aging, shift work, or chronic stress, also contributes to lung senescence. Core clock genes (e.g., BMAL1, CLOCK, Nrf2) regulate redox homeostasis, mitochondrial health, and DNA repair. Their dysregulation has been linked to impaired alveolar regeneration and increased susceptibility to fibrotic remodeling via enhanced senescence and inflammatory signaling [303,304,305]. Thus, this highlights the importance of incorporating exposome and chrono-biological context into senescence-related research and therapeutic design.

Although senescence presents a promising therapeutic target in chronic lung diseases, its clinical translation is hindered by several unresolved challenges. A primary obstacle is the lack of reliable, non-invasive biomarkers for senescence in human lungs, limiting patient stratification, therapeutic monitoring, and outcome assessment [1]. Moreover, the cellular heterogeneity of senescence across lung compartments necessitates cell type- and context-specific interventions, as no universal senolytic agent is effective across all senescent cell types [7].

Current senolytic agents such as navitoclax (ABT-263) exhibit significant off-target toxicity, particularly hematologic effects, posing risks for elderly patients and those with comorbidities [306]. These safety concerns have constrained the advancement of senolytics in clinical settings.

Nevertheless, promising advances are underway. Early-phase clinical trials of dasatinib+quercetin (D+Q) have shown improved physical performance and reduced circulating SASP components in IPF patients [307]. Other compounds under development include UBX1325 (a BCL-xL inhibitor) and FOXO4-DRI peptides, which target senescent cells in fibrotic and post-COVID lung injury models. Concurrently, AI-driven histopathological scoring systems and integrative multi-omics approaches are being tested to stratify patients and predict treatment responses [308,309].

Moving forward, success in this field will rely on: Development of lung-specific senescence biomarkers; Optimization of inhalable senolytics for localized delivery; Advanced patient stratification based on molecular senescence subtypes; Long-term safety profiling and regulatory oversight to mitigate off-target risks. In sum, while hurdles persist, the clinical translation of senotherapeutics in lung disease is entering a promising phase-I, driven by molecular precision, computational insight, and a growing appreciation for the complex biology of senescence.