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Cellular senescence

Cellular senescence is a stress-induced, essentially irreversible form of cell-cycle arrest that prevents the proliferation of damaged or aged cells, serving as a protective mechanism against tumorigenesis while also contributing to tissue aging and dysfunction through the secretion of bioactive molecules known as the senescence-associated secretory phenotype (SASP).^[1] This process was first described in 1961 by Leonard Hayflick and Paul Moorhead, who observed that normal human diploid fibroblasts in culture undergo a finite number of divisions, termed the Hayflick limit, before entering a state of replicative senescence due to telomere shortening.^[2] Over subsequent decades, research expanded the concept beyond replicative limits to include various triggers such as persistent DNA damage, oncogenic activation, oxidative stress, and therapeutic agents like chemotherapy, all of which activate tumor suppressor pathways involving proteins like p53 and p16^INK4a to enforce the arrest.^[3] At the molecular level, senescent cells exhibit distinct hallmarks beyond proliferation cessation, including chromatin remodeling, metabolic alterations, and resistance to apoptosis, which allow them to persist in tissues for extended periods.^[4] The SASP, a defining feature, comprises a heterogeneous array of secreted factors—including interleukins (e.g., IL-6, IL-8), chemokines, growth factors (e.g., VEGF), and matrix-degrading enzymes—that propagate senescence in neighboring cells via paracrine signaling and modulate the tissue microenvironment.^[5] These secretions can elicit beneficial effects, such as reinforcing tumor suppression by alerting immune cells to eliminate precancerous lesions or aiding in wound healing and embryonic development by clearing damaged cells.^[6] However, chronic SASP accumulation drives detrimental outcomes, including sterile inflammation, fibrosis, and stem cell exhaustion, which are implicated in age-related pathologies like atherosclerosis, osteoarthritis, and neurodegeneration.^[7] Physiologically, cellular senescence plays dual roles across the lifespan: it acts as a safeguard during development and tissue repair but becomes maladaptive with aging as senescent cells evade immune clearance and accumulate, exacerbating organismal decline. Emerging evidence as of November 2025 identifies a subset of T helper cells that actively eliminate senescent cells, potentially mitigating aging effects.^[8]^[9] In cancer, senescence initially suppresses tumor growth—famously demonstrated by oncogene-induced senescence (OIS) in response to RAS activation—but paradoxically, SASP factors can foster a tumor-permissive niche by promoting angiogenesis, immune evasion, and metastasis in surrounding cells.^[10] Emerging evidence also highlights context-dependent reversibility, challenging the traditional view of permanence; for instance, transient SASP inhibition or epigenetic modulation can restore proliferative capacity in some senescent states, opening avenues for therapeutic intervention.^[6] Therapeutically, targeting senescent cells has gained traction as a strategy to mitigate aging and disease, with senolytics—drugs like dasatinib and quercetin that selectively induce apoptosis in senescent cells—showing promise in preclinical models of frailty, pulmonary fibrosis, and Alzheimer's disease by reducing SASP burden and improving tissue function.^[11] Clinical trials are underway to evaluate these approaches, underscoring cellular senescence as a pivotal target in geroscience, though challenges remain in achieving specificity to avoid disrupting beneficial senescence programs.^[1]

Introduction

Definition and Types

Cellular senescence is a stable and generally irreversible form of cell cycle arrest that prevents the proliferation of damaged or aged cells while maintaining their metabolic viability.^[4] This state is induced by various endogenous and exogenous stresses, including DNA damage, telomere dysfunction, and oncogenic signaling, and is characterized by distinct morphological changes such as enlarged cell size, flattened cytoplasm, and the expression of senescence-associated β-galactosidase (SA-β-gal).^[12] Unlike transient responses, senescent cells remain alive but cease to divide, distinguishing this process as a protective mechanism against tumorigenesis.^[13] The primary types of cellular senescence include replicative senescence, oncogene-induced senescence (OIS), therapy-induced senescence (TIS), and stress-induced premature senescence (SIPS). Replicative senescence arises from progressive telomere shortening during repeated cell divisions, ultimately leading to a critical limit on proliferation as first observed in human fibroblasts.^[12] OIS is triggered by hyperproliferative signals from activated oncogenes, such as RAS, acting as a safeguard against malignant transformation.^[4] TIS occurs in response to genotoxic therapies like chemotherapy or radiation, which cause DNA damage and enforce arrest in potentially cancerous cells.^[13] SIPS encompasses premature arrest due to acute stresses, including oxidative damage, epigenetic alterations, or other non-telomeric insults that mimic aging processes.^[13] Senescent cells differ fundamentally from quiescent cells, which undergo a reversible G0 arrest that can be exited upon mitogenic stimulation, whereas senescence enforces a permanent halt unresponsive to growth factors.^[12] In contrast to apoptosis, a programmed cell death pathway involving caspase activation and cellular dismantling, senescence preserves cell viability and often involves the secretion of pro-inflammatory factors known as the senescence-associated secretory phenotype (SASP).^[4] Evolutionarily, cellular senescence serves as a conserved tumor-suppressive mechanism across eukaryotes, limiting the propagation of mutations that could lead to cancer by arresting at-risk cells.^[12]

Historical Background

The concept of cellular senescence emerged from early observations in cell culture experiments. In 1961, Leonard Hayflick and Paul Moorhead demonstrated that normal human diploid fibroblasts, derived from embryonic lung tissue, undergo a finite number of population doublings—approximately 50—before entering a state of irreversible growth arrest, now known as the Hayflick limit.^[14] This finding challenged the prevailing view that normal cells could divide indefinitely in vitro and laid the groundwork for understanding replicative limits in somatic cells.^[15] Theoretical and experimental advances in the 1970s and 1980s linked this replicative arrest to telomere biology. In 1971, Alexey Olovnikov proposed the "marginotomy" hypothesis, positing that incomplete replication of linear DNA ends leads to progressive shortening of chromosome termini, eventually triggering cellular senescence.^[16] This idea was experimentally supported in the 1980s through work by Elizabeth Blackburn and Jack Szostak, who identified conserved telomeric DNA sequences that protect chromosome ends and demonstrated their role in maintaining linear plasmids in yeast, providing the first evidence of a telomere maintenance mechanism.^[17] The 1990s marked a shift toward recognizing senescence as a tumor-suppressive mechanism beyond replication. In 1997, Manuel Serrano and colleagues discovered oncogene-induced senescence, showing that ectopic expression of oncogenic Ras in primary human and rodent fibroblasts provokes a permanent G1 arrest resembling replicative senescence, mediated by p53 and p16INK4a pathways.^[18] In the 2000s, research elucidated senescence's broader implications for aging and tissue homeostasis. Judith Campisi's group identified the senescence-associated secretory phenotype (SASP) in the late 2000s, revealing that senescent cells secrete proinflammatory cytokines, growth factors, and proteases that can promote chronic inflammation and tumor progression in surrounding tissues.^[19] Concurrently, studies highlighted p16INK4a as a key biomarker of senescence in vivo, with its expression increasing in aged tissues and correlating with age-related proliferative defects in stem cells.^[20] Recent developments through 2025 have integrated senescence with epigenetic and single-cell analyses. In 2016, epigenetic clock models based on DNA methylation patterns were applied to senescent cells, demonstrating accelerated epigenetic aging in response to replicative stress and linking it to organismal aging.^[21] Advances in single-cell RNA sequencing during the 2020s have uncovered significant heterogeneity among senescent populations, revealing diverse transcriptional states in fibroblasts and other cell types that influence SASP variability and therapeutic targeting.^[22]

Induction Mechanisms

Replicative Senescence

Replicative senescence represents the progressive loss of a cell's proliferative capacity due to the inherent limitations of DNA replication at chromosome ends. In normal somatic cells, this process is primarily driven by the gradual attrition of telomeres, which act as protective caps preventing chromosomal instability. As cells divide repeatedly, telomeres shorten until they reach a critical length that elicits a persistent DNA damage response, ultimately enforcing a stable cell cycle arrest.^[23] Human telomeres consist of repetitive TTAGGG nucleotide sequences arrayed in tandem at the ends of linear chromosomes, forming nucleoprotein complexes that shield against end-to-end fusions and degradation. During each round of DNA replication, the end-replication problem—arising from the inability of DNA polymerase to fully synthesize the lagging strand—results in the loss of approximately 50-100 base pairs from these telomeric repeats. This progressive shortening occurs in the absence of compensatory mechanisms, limiting the number of population doublings a cell population can achieve.00629-1.pdf)^[24] When telomeres erode to a critical length, typically resulting in an average of about 7 kb with the shortest reaching 1-2 kb, they lose their protective function, leading to the formation of telomere dysfunction-induced foci (TIFs). TIFs are cytological markers where telomere ends colocalize with DNA damage response factors, such as γ-H2AX and 53BP1, mimicking double-strand breaks and activating checkpoints that halt proliferation. This uncapping triggers a DNA damage response, often involving p53 pathway activation, to induce senescence.^[23]^[25]^[26] Telomerase, a ribonucleoprotein enzyme that adds TTAGGG repeats to telomere ends using its RNA template, is notably absent or expressed at undetectable levels in most differentiated somatic cells. This lack of telomerase activity enforces the replicative limit by permitting unchecked telomere erosion over successive divisions. In contrast, telomerase is active in stem cells, germ cells, and most cancer cells, allowing indefinite proliferation.80001-5) The Hayflick limit, which describes the finite number of divisions (typically 40-60 for human fibroblasts) before senescence, can be contextualized by the relationship between initial telomere length, the critical threshold, and the shortening rate per division: approximate population doublings ≈ (initial telomere length - critical length) / shortening rate per division. This framework underscores how variations in starting telomere length influence replicative lifespan.^[27] Seminal evidence supporting the causal role of telomere shortening in replicative senescence comes from experiments demonstrating that ectopic overexpression of the telomerase catalytic subunit (hTERT) in primary human fibroblasts stabilizes telomere length and extends their proliferative lifespan by over 20 population doublings without altering karyotype or inducing tumorigenicity. These telomerase-expressing cells bypassed senescence markers, such as β-galactosidase activity, confirming telomeres as the primary molecular clock.^[28]

Oncogene-Induced Senescence

Oncogene-induced senescence (OIS) represents a critical tumor-suppressive mechanism wherein hyperproliferative signals from activated oncogenes trigger a stable cell cycle arrest in primary cells, preventing malignant transformation. This process is initiated when oncogenes such as RAS or MYC drive excessive cell proliferation, leading to replication stress characterized by hyper-replication of DNA. The resulting stalled replication forks and under-replicated DNA regions activate a DNA damage response (DDR), culminating in premature senescence independent of telomere shortening. Unlike quiescence, which is a reversible growth arrest, OIS enforces an irreversible halt through epigenetic modifications that silence proliferation-associated genes.^[29] The molecular cascade begins with oncogenic signaling, exemplified by constitutively active H-RAS^{V12}, which upregulates cyclin D1 and E2F transcription factors to promote entry into S phase and accelerate cell cycling. This hyperproliferative state overwhelms replication machinery, causing DNA hyper-replication and accumulation of DNA double-strand breaks, primarily at fragile sites, as detected by γ-H2AX foci. Feedback loops mitigate this deregulation; for instance, promyelocytic leukemia (PML) nuclear bodies recruit Rb/E2F complexes, sequestering E2F1 and repressing its transcriptional activity to enforce G1 arrest. Similarly, MYC overexpression induces replication stress via deregulation of nucleotide metabolism and redox homeostasis, activating DDR pathways that converge on p53 and Rb effectors to stabilize senescence.^[29]^[30] Seminal experiments in 1997 demonstrated OIS upon retroviral expression of oncogenic H-RAS^{V12} in primary human fibroblasts (e.g., IMR-90) and rodent cells, where transduced cells adopted a flattened, enlarged morphology by day 6 post-infection, ceased DNA synthesis (near 0% BrdU incorporation), and exhibited senescence-associated β-galactosidase activity in up to 60% of cells by the same time point. This arrest was permanent, associated with elevated p53, p21^{CIP1}, and p16^{INK4a} levels (10- to 20-fold increases), and required intact p53 and Rb pathways, as their inactivation allowed proliferation. OIS thus manifests as a subtype of premature senescence, bypassing the need for cumulative cell divisions or telomere erosion seen in replicative senescence, and serves as an early barrier to tumorigenesis in vivo.^[31]^[31] The irreversibility of OIS distinguishes it from transient quiescence, as it involves stable epigenetic silencing of E2F target genes through senescence-associated heterochromatin foci (SAHF). These structures, marked by trimethylation of histone H3 at lysine 9 (H3K9me3) and recruitment of heterochromatin protein 1 (HP1), compact proliferation-promoting loci, preventing re-entry into the cell cycle even upon oncogene withdrawal. In lymphoma models, this chromatin remodeling enforces senescence as an initial restraint on MYC/RAS-driven lymphomagenesis, with escape requiring additional mutations that disrupt these epigenetic locks.

Stress-Induced Senescence

Stress-induced premature senescence (SIPS) arises from various exogenous and endogenous stressors that accumulate cellular damage, distinct from telomere attrition or oncogenic activation. Key triggers include oxidative stress generated by reactive oxygen species (ROS) from mitochondrial dysfunction, which overwhelms antioxidant defenses and leads to macromolecular damage.^[32] Genotoxic agents such as ultraviolet (UV) radiation and chemotherapeutic drugs like doxorubicin also induce senescence by causing direct DNA lesions.^[33] Additionally, epigenetic alterations, such as aberrant DNA methylation or histone modifications triggered by chronic stress, contribute to chromatin instability and enforce cell cycle arrest.^[34] Severe mitogenic signals, including hyperactivation of pathways like MEK/MAPK, can similarly provoke senescence through excessive proliferative pressure and associated damage.^[35] At the molecular level, these stresses often converge on the DNA damage response (DDR) pathway. Persistent double-strand breaks (DSBs) activate ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3-related (ATR) kinases, which phosphorylate histone H2AX to form γ-H2AX foci, marking sites of irreparable damage and sustaining a pro-senescence signal.^[36] This persistent DDR prevents repair and amplifies arrest signals. Beyond telomeric regions, stress induces non-telomeric chromatin alterations, including loss of heterochromatin marks like H3K9me3, leading to global genome instability and reinforcement of the senescent state.^[37] Experimental evidence underscores these mechanisms. In 2004, treatment of human fibroblasts with hydrogen peroxide (H₂O₂) was shown to induce a senescent phenotype characterized by irreversible growth arrest and β-galactosidase activity, mimicking oxidative damage in aging.^[38] Similarly, doxorubicin therapy in cancer cells triggers senescence via DSB accumulation, contributing to treatment outcomes but also potential relapse risks.^[39] A threshold model explains induction: even a small number of persistent unrepaired DSBs, as few as one or two per cell, can favor senescence over successful repair, apoptosis, or continued proliferation.^[40]

Other Triggers

Cellular senescence can also be triggered by cellular hypertrophy, where enlarged cell size in tissues such as the liver, muscle, or heart disrupts normal homeostasis and activates senescence pathways. In cardiomyocytes, for instance, hypertrophy associated with dilated cardiomyopathy leads to increased cell size, which correlates with elevated markers of senescence like p16^INK4a and β-galactosidase activity, as observed in studies from the 2010s examining heart failure models. This process involves dysregulation of the Hippo signaling pathway, where overgrowth signals via YAP/TAZ effectors promote a pro-senescence state, and dilution of cytoplasmic components due to volume expansion impairs proteostasis and metabolic balance, ultimately enforcing cell cycle arrest.^[41]^[42] Metabolic stress represents another trigger, encompassing conditions like nutrient deprivation or chronic high glucose exposure that dysregulate energy sensing and induce senescence through mTOR pathway hyperactivation. Under nutrient scarcity, such as glucose deprivation, mTORC1 inhibition typically promotes survival adaptations, but paradoxical hyperactivation in response to metabolic imbalance—often seen in diabetes—drives cellular senescence by enhancing protein synthesis while suppressing autophagy, leading to accumulation of damaged organelles. High glucose levels, in particular, trigger mTORC1 hyperactivity in a glutamine-dependent manner, suppressing mTORC2 and promoting senescent phenotypes in endothelial and renal cells.^[43]^[44] Mechanical cues from the extracellular matrix (ECM) stiffness can further induce senescence, particularly in fibrotic conditions where rigid matrices signal through integrins to activate mechanotransduction pathways. In fibrosis, increased ECM stiffness—due to excessive collagen deposition and cross-linking—engages integrin-mediated focal adhesion kinase (FAK) signaling, which upregulates YAP/TAZ activity and promotes p53-dependent senescence in fibroblasts and epithelial cells. This mechanosensitive response contributes to pathological tissue remodeling, as demonstrated in lung and liver fibrosis models where substrate stiffness mimicking diseased states elevates senescence-associated β-galactosidase and SASP factors.^[45]^[46]^[47] Emerging research highlights additional triggers such as viral infections and protein aggregation, which impose chronic stress leading to senescence in specific contexts. HIV infection, for example, accelerates cellular senescence in immune cells and tissues through persistent viral proteins like Tat, which upregulate senescence biomarkers via TLR7 and mitochondrial dysfunction, contributing to premature aging in infected individuals. Similarly, in neurodegeneration, protein aggregates like tau in Alzheimer's disease induce senescence in neurons and glia by activating DNA damage responses and inflammasome pathways, exacerbating tissue decline. Recent 2020s studies also implicate the gut microbiome in modulating senescence, where dysbiosis alters metabolite production—such as phenylacetylglutamine—that promotes mitochondrial dysfunction and senescent phenotypes in distant organs like the endothelium and brain.^[48]^[49]^[50]

Molecular Signaling Pathways

p53-Dependent Pathways

Cellular senescence is critically mediated by the tumor suppressor protein p53, which acts as a key sensor of cellular stress, particularly DNA damage, to enforce irreversible cell cycle arrest. Upon detection of DNA double-strand breaks or other genotoxic insults, kinases such as ATM and ATR phosphorylate p53 at multiple sites, including serine 15 and serine 20, stabilizing the protein by disrupting its interaction with the E3 ubiquitin ligase MDM2.^[51] This prevents MDM2-mediated ubiquitination and proteasomal degradation of p53, allowing its accumulation in the nucleus where it functions as a transcription factor.^[52] In the context of senescence, this stabilization shifts p53 from a transient response to a sustained activation state, distinguishing it from apoptosis or reversible arrest.^[53] Activated p53 transcriptionally upregulates several downstream effectors that collectively enforce G1 phase arrest and reinforce senescence. The cyclin-dependent kinase inhibitor p21 (encoded by CDKN1A) is a primary target, binding to and inhibiting the CDK2/cyclin E complex to prevent phosphorylation of the retinoblastoma protein (Rb) and block E2F-dependent progression into S phase.^[54] Additionally, p53 induces plasminogen activator inhibitor-1 (PAI-1, encoded by SERPINE1), which supports the senescent phenotype by modulating extracellular matrix remodeling and reinforcing arrest, and promyelocytic leukemia protein (PML), which forms nuclear bodies that further stabilize p53 through post-translational modifications.^[54] These effectors ensure a robust, multilayered barrier to proliferation, with p21 playing a central role in the initial arrest while PAI-1 and PML contribute to long-term maintenance.^[3] p53 also promotes epigenetic modifications that lock in the senescent state, including the deposition of histone H3 lysine 9 trimethylation (H3K9me3), a repressive heterochromatin mark, at promoters of E2F-responsive genes such as cyclins and DNA replication factors. This heterochromatin formation, often observed in senescence-associated heterochromatin foci (SAHFs), silences proliferation-associated loci and is dependent on sustained p53 activity, which indirectly recruits histone methyltransferases like SUV39H1 via p21-mediated Rb hypophosphorylation.^[3] Evidence for p53's essential role comes from seminal mouse models: p53 knockout mice, generated in the early 1990s, exhibit normal development but dramatically increased susceptibility to spontaneous tumors due to bypassed senescence checkpoints, highlighting p53's tumor-suppressive function through this pathway. More recent single-cell RNA sequencing studies from the 2010s onward have revealed heterogeneity in p53 activation across senescent populations, with variable p21 expression correlating to arrest stability and underscoring p53's dynamic regulation in vivo.^[22] A reinforcing feedback loop exists between p53 and the senescence-associated secretory phenotype (SASP), where p53 suppresses pro-inflammatory SASP components like IL-6 while SASP factors such as COX-2-derived prostaglandins enhance p53 stability, amplifying the arrest in a paracrine manner.^[53] This crosstalk ensures senescence persistence but can also propagate senescence in neighboring cells, contributing to tissue-level effects.^[54]

Rb-Dependent Pathways

The retinoblastoma protein (Rb), a key tumor suppressor, enforces permanent cell cycle exit in cellular senescence primarily through the Rb-dependent pathway, which blocks progression from G1 to S phase. In this mechanism, the cyclin-dependent kinase inhibitor p16^{INK4A}, encoded by the CDKN2A gene, binds to and inhibits cyclin-dependent kinases 4 and 6 (CDK4/6), preventing their association with cyclin D. This inhibition maintains Rb in its hypophosphorylated state, allowing Rb to remain bound to E2F transcription factors and thereby repressing the expression of genes required for DNA synthesis and cell proliferation, such as those involved in the G1/S transition.^[3]^[55] The resulting blockade is a hallmark of senescence, distinct from reversible quiescence, as hypophosphorylated Rb actively silences proliferative targets in a stable manner.^[56] Upregulation of p16^{INK4A} is a critical step in activating this pathway and occurs in response to various senescence-inducing stresses, including replicative exhaustion and oncogenic signaling. Stress signals, such as persistent DNA damage or mitogenic cues, activate the p38 mitogen-activated protein kinase (MAPK) pathway, which directly enhances p16^{INK4A} transcription and protein levels, thereby amplifying the inhibitory effect on CDK4/6. Additionally, epigenetic modifications, including demethylation of the CDKN2A promoter and chromatin remodeling at the INK4/ARF locus, contribute to sustained p16^{INK4A} expression during senescence onset.^[57]^[58] Beyond cell cycle repression, Rb promotes senescence through additional functions, including the silencing of proliferation-associated genes like cyclin A via direct interaction with E2F-responsive promoters. In senescent cells, hypophosphorylated Rb recruits histone deacetylases and other chromatin-modifying complexes to E2F target loci, inducing heterochromatin formation and long-term transcriptional repression, which reinforces the irreversible arrest. This chromatin remodeling is essential for maintaining the senescent state, as Rb loss disrupts these epigenetic marks and allows partial reactivation of proliferative genes.^[59]^[60] For instance, Rb-mediated heterochromatin at E2F sites, such as senescence-associated heterochromatin foci (SAHF), exemplifies how Rb integrates cell cycle control with stable epigenetic silencing.^[61] Experimental evidence underscores the necessity of the p16^{INK4A}-Rb axis for senescence induction. In human fibroblasts, combined disruption of p16^{INK4A} and Rb function prevents replicative senescence, allowing continued proliferation despite telomere shortening or stress, as demonstrated in early 2000s studies showing bypass of growth arrest in Rb-deficient cells. Similarly, p16^{INK4A} knockout in murine models impairs oncogene-induced senescence in fibroblasts, highlighting the pathway's role across species. In humans, p16^{INK4A} expression positively correlates with chronological aging, accumulating in tissues like T-cells and fibroblasts as a biomarker of senescent burden, linking the Rb pathway to age-related functional decline.^[62]^[63] The Rb-dependent pathway exhibits crosstalk with parallel senescence mechanisms, such as the p53-p21 axis, where hypophosphorylated Rb can stabilize p53 by binding and sequestering MDM2, its negative regulator, thereby enhancing p53-dependent transcription in certain stress contexts. This interaction allows coordinated activation of both pathways during oncogene-induced senescence, though Rb primarily enforces the cell cycle exit independently of p53 in many scenarios.^[64]

Additional Pathways

Beyond the core p53 and Rb pathways, the NF-κB signaling pathway serves as a key modulator of cellular senescence, particularly in response to persistent DNA damage or oncogenic stress. Activation of NF-κB occurs through an autocrine loop involving interleukin-1α (IL-1α), where cell surface-bound IL-1α triggers NF-κB nuclear translocation, promoting the transcription of pro-inflammatory genes and enhancing senescent cell survival while driving the senescence-associated secretory phenotype (SASP).^[65] This mechanism was elucidated in studies from the late 2000s, demonstrating that IL-1α depletion in senescent cells reduces NF-κB activity and disrupts the maintenance of the senescent state.^[65] Consequently, NF-κB reinforces senescence by integrating damage signals with inflammatory responses, independent of direct cell cycle arrest effectors. The PI3K/AKT/mTOR pathway also contributes to senescence induction and maintenance, often through hyperactivation by growth factors or loss of PTEN tumor suppressor function. This hyperactivation phosphorylates and inhibits FoxO transcription factors, leading to metabolic reprogramming that favors senescence, including increased glycolysis and reduced oxidative phosphorylation.^[66] Research from the 2010s highlighted how sustained PI3K/AKT signaling in oncogene-transformed cells triggers mTOR-dependent senescence, where mTOR kinase activity suppresses feedback mechanisms that would otherwise promote proliferation.^[66] In metabolic contexts, this pathway links nutrient sensing to senescent arrest, ensuring cells enter a state of permanent quiescence amid aberrant growth signals.^[67] Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) plays a supportive role in sustaining the metabolic profile of senescent cells by regulating fatty acid oxidation (FAO). PPARβ/δ activation upregulates genes involved in β-oxidation, such as those encoding carnitine palmitoyltransferase-1 (CPT1) and acyl-CoA oxidase (ACOX1), which help maintain energy homeostasis in the altered lipid environment of senescence.^[68] Epigenetic modifiers further enforce senescent arrest through chromatin remodeling. Histone deacetylase (HDAC) inhibitors, such as trichostatin A, induce senescence by increasing histone acetylation at promoters of cell cycle inhibitors like p21, leading to transcriptional activation and irreversible growth arrest.^[69] Similarly, the polycomb repressive complex 2 (PRC2) component EZH2 methylates histone H3 at lysine 27 (H3K27me3), repressing proliferation-associated genes; however, EZH2 downregulation in response to DNA damage triggers senescence by derepressing these loci without altering global H3K27me3 levels.^[70] These modifications create a stable epigenetic landscape that locks cells in senescence, distinct from transient epigenetic changes in quiescence. Recent advances as of 2025 have identified additional pathways modulating senescence. For instance, the TFEB-HKDC1 axis promotes mitophagy and lysosomal repair, thereby inhibiting senescence in various cell types.^[71] Similarly, the IL-4-STAT6 signaling pathway upregulates DNA repair genes to delay senescence in macrophages.^[71] These pathways integrate into broader networks that reinforce senescence. For instance, persistent mTORC1 activation in senescent cells inhibits autophagy by phosphorylating ULK1 and repressing lysosome biogenesis, leading to accumulation of damaged organelles and perpetuating the senescent state.^[72] This crosstalk with NF-κB and PI3K/AKT pathways forms feedback loops, where mTORC1-driven metabolic shifts amplify inflammatory signaling and epigenetic silencing, ensuring robust maintenance of senescence across diverse stressors.^[73]

Characteristics of Senescent Cells

Morphological and Functional Changes

Senescent cells undergo profound morphological alterations, becoming enlarged and flattened with an expanded cytoplasm that often appears granular and vacuolated.^[74] These changes were first observed in human diploid fibroblasts approaching the end of their replicative lifespan, where cells in late passages exhibited a flattened shape and increased cytoplasmic volume compared to proliferating counterparts.^[74] Electron microscopy studies from the 1970s further revealed the presence of autophagic vacuoles and lysosomal structures within the cytoplasm of these senescent cells, contributing to their irregular, irregular morphology.^[75] A key biomarker for detecting senescent cells is senescence-associated β-galactosidase (SA-β-gal) activity, detectable at pH 6.0 through a histochemical assay.^[76] This enzyme activity reflects lysosomal hypertrophy, a functional hallmark where senescent cells accumulate enlarged lysosomes, potentially due to impaired degradation pathways.^[76] At the nuclear level, senescent cells form senescence-associated heterochromatin foci (SAHF), compact chromatin domains enriched in repressive histone marks like H3K9me3 and HP1 proteins, which help maintain the proliferative arrest.00183-2) Functionally, senescent cells exhibit a metabolic reprogramming toward increased glycolysis, even in the presence of oxygen, accompanied by reduced oxidative phosphorylation and elevated lactate production.30228-5) This shift supports the heightened biosynthetic demands of the senescent state, including protein synthesis for structural changes, while also contributing to redox balance through the pentose phosphate pathway.^[77] Additional biomarkers include the loss of nuclear lamin B1, which disrupts nuclear architecture and correlates with senescence entry, and persistent γ-H2AX foci indicating unresolved DNA damage. These can be quantified via immunofluorescence or western blotting, while upregulated cell cycle inhibitors like p16^INK4a and p21^CIP1 are commonly assessed by qPCR for transcript levels or immunohistochemistry for protein expression.^[3] Proteomic analyses in the 2020s have identified approximately 100 proteins upregulated in senescent cells, including those involved in lysosomal function, extracellular matrix remodeling, and stress response, underscoring the multifaceted proteome alterations.^[78] For instance, mass spectrometry of senescent human mammary epithelial cells revealed robust changes in lysosomal and metabolic proteins, validating these shifts at a systems level.^[78] Senescent cells also display enhanced resistance to apoptosis, mediated by upregulation of anti-apoptotic Bcl-2 family members such as Bcl-2, Bcl-W, and Bcl-xL, which inhibit mitochondrial outer membrane permeabilization.^[79] This persistence allows senescent cells to accumulate in tissues, influencing surrounding microenvironments beyond their intrinsic changes.

Senescence-Associated Secretory Phenotype (SASP)

The senescence-associated secretory phenotype (SASP) is a hallmark feature of senescent cells, characterized by the robust and sustained secretion of a proinflammatory secretome that influences the surrounding tissue microenvironment. This secretome comprises a diverse array of bioactive molecules, including cytokines such as interleukin-6 (IL-6) and IL-8, chemokines like CXCL1 (also known as GRO-α), growth factors including vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs) such as MMP-3 and MMP-10, and damage-associated molecular patterns (DAMPs) like high-mobility group box 1 (HMGB1). These components were first systematically profiled in human fibroblasts and epithelial cells induced to senesce by genotoxic stress, revealing approximately 40 distinct factors associated with inflammation, tissue remodeling, and immune modulation.^[19] The regulation of SASP involves both transcriptional and post-transcriptional mechanisms. At the transcriptional level, nuclear factor kappa B (NF-κB) and CCAAT/enhancer-binding protein beta (C/EBPβ) act as key drivers, cooperatively inducing the expression of proinflammatory SASP factors like IL-6 and IL-8 in response to persistent DNA damage signaling. Post-transcriptionally, p38 mitogen-activated protein kinase (MAPK) enhances SASP production by stabilizing mRNAs and boosting NF-κB activity, independent of DNA damage response pathways. This regulated secretion typically develops over 4–7 days following senescence induction and can persist for weeks to months, contributing to the long-term impact of senescent cells.^[3] SASP exhibits significant heterogeneity influenced by the type of senescence-inducing stress. For example, oncogene-induced SASP often includes prosurvival factors that reinforce the senescent arrest in an autocrine manner, whereas stress-induced SASP (e.g., from genotoxic or oxidative damage) emphasizes paracrine signaling to propagate senescence or modulate nearby cells. Advances in single-cell RNA sequencing (scRNA-seq) during the 2020s have highlighted this context-specific diversity, identifying distinct SASP subtypes across cell types and inducers, such as enriched inflammatory profiles in therapy-induced senescence versus metabolic regulators in replicative senescence.30892-8) Functionally, SASP reinforces the senescent phenotype through autocrine loops that maintain cell cycle arrest and DNA damage resistance, while its paracrine effects can propagate senescence to neighboring cells. However, prolonged SASP activity from uncleared senescent cells fosters chronic low-grade inflammation by continuously releasing proinflammatory mediators, exacerbating tissue dysfunction over time.^[19]31121-3)

Physiological Roles

In Development and Tissue Repair

Cellular senescence plays a critical role in embryonic development by contributing to tissue patterning and remodeling. In mammalian embryos, senescence occurs in specific structures such as the endolymphatic sac of the inner ear and the mesonephros, where it facilitates proper organ formation by limiting excessive cell proliferation and promoting structured tissue regression. For instance, in mouse models, senescent cells in the endolymphatic sac help establish the balance between cell proliferation and differentiation necessary for inner ear development, with these cells being cleared after fulfilling their patterning function.01295-6) Similarly, in human placental development, senescence in trophoblast cells supports villous maturation and nutrient exchange, acting as a programmed mechanism to ensure proper placental architecture without leading to pathology. In wound healing, transient senescence enhances tissue repair by coordinating cellular responses. Shortly after injury, fibroblasts in the wound bed undergo senescence, secreting platelet-derived growth factor AA (PDGF-AA) that stimulates keratinocyte proliferation and migration, thereby accelerating re-epithelialization and wound closure. This senescence is temporary, resolving within days as the wound heals, and its absence impairs repair efficiency, as demonstrated in mouse excisional wound models where inhibiting senescence delays closure. Senescence also contributes to tissue remodeling in regenerative processes, such as liver regeneration, where it curbs excessive fibrotic responses. In response to partial hepatectomy in mice, senescent hepatic stellate cells accumulate and limit extracellular matrix deposition, preventing fibrosis and allowing orderly hepatocyte proliferation to restore liver mass. This anti-fibrotic role highlights senescence's function in maintaining tissue homeostasis during repair. Evidence from senescence-deficient mouse models, including those lacking p21, reveals developmental defects such as impaired mesonephros regression and ectodermal ridge abnormalities, underscoring the necessity of senescence for proper embryogenesis and repair.00807-6)^[3] Unlike persistent senescence in other contexts, developmental and repair-associated senescence is transient and efficiently resolved, often through clearance mechanisms that prevent long-term accumulation. This resolution ensures that senescence supports positive outcomes without contributing to chronic issues.^[80]

In Tumor Suppression

Cellular senescence serves as a critical barrier to tumorigenesis by inducing a stable cell cycle arrest in response to oncogenic stress, thereby preventing the proliferation of premalignant cells. Oncogene-induced senescence (OIS), first demonstrated with oncogenic Ras, activates the p53 and Rb tumor suppressor pathways to enforce this arrest, halting the expansion of early lesions. In mouse models, activation of oncogenes like K-Ras in lung epithelial cells triggers senescence in premalignant adenomas, limiting tumor progression until evasion occurs.^[81] Similarly, in human tissues, evidence of senescence enforcement through p53/Rb activation is observed, particularly in premalignant stages.00111-X) Genetic evidence underscores senescence's tumor-suppressive role. Knockout of the Ink4a/Arf locus, which encodes p16^INK4a (an Rb activator) and p14^ARF (a p53 stabilizer), leads to spontaneous development of sarcomas, lymphomas, and other tumors in mice within months of birth, demonstrating that loss of senescence predisposes to malignancy.^[82] In humans, benign nevi contain senescent melanocytes harboring BRAF^V600E mutations, where OIS mediated by p16^INK4a and senescence-associated β-galactosidase activity prevents progression to melanoma.^[83] These examples illustrate how senescence confines oncogenic lesions, with markers like p16^INK4a and SA-β-gal prominently expressed in benign or premalignant tissues but absent in fully malignant tumors.^[81] Cancer cells evade senescence to promote tumorigenesis, often through mutations disrupting p53 or Rb pathways. Inactivating p53 mutations occur in approximately 50% of human cancers, disabling DNA damage-induced senescence and allowing survival of genotoxically stressed cells.^[84] Likewise, p16^INK4a loss via deletion or epigenetic silencing is frequent in cancers such as melanoma and pancreatic adenocarcinoma, bypassing Rb-dependent arrest and enabling unchecked proliferation.^[85] This evasion is evident in the transition from senescent premalignant lesions to invasive carcinomas, where inactivation of senescence effectors like p53 or Ink4a/Arf abolishes the growth arrest.00247-3) The senescence-associated secretory phenotype (SASP) contributes to tumor suppression by recruiting immune cells for "senescence surveillance," where natural killer cells and macrophages eliminate senescent premalignant cells via innate immune recognition.^[86] Therapeutic strategies exploit this by inducing senescence in tumors with chemotherapy or targeted agents, enhancing immune-mediated clearance and improving outcomes in preclinical models.00121-1) However, chronic SASP can paradoxically drive tumor progression by promoting epithelial-mesenchymal transition (EMT) in adjacent nonsenescent cells through proinflammatory cytokines like IL-6 and TGF-β.^[87] Thus, while senescence initially curbs cancer, its evasion or persistence underscores its dual-edged nature in oncogenesis.

In Aging and Disease

Cellular senescence contributes to the aging process through the progressive accumulation of senescent cells in various tissues, which promotes chronic low-grade inflammation known as inflammaging primarily via the senescence-associated secretory phenotype (SASP). This accumulation impairs tissue homeostasis and function, as senescent cells resist apoptosis and secrete pro-inflammatory cytokines, chemokines, and matrix-degrading enzymes that disrupt neighboring cells and extracellular matrix integrity. Studies in human tissues demonstrate that senescent cell burden increases with chronological age, varying by tissue type but reaching notable levels in adipose, skin, and vascular tissues by late adulthood, thereby accelerating age-related decline.^[88]^[89]^[90] In age-related diseases, senescent cells play a pathogenic role by exacerbating tissue dysfunction and pathology. In atherosclerosis, senescence of vascular endothelial cells and smooth muscle cells promotes plaque formation, endothelial dysfunction, and arterial stiffening through SASP-mediated inflammation and impaired vasodilation. Similarly, in osteoarthritis, senescent chondrocytes contribute to cartilage degradation by upregulating matrix metalloproteinases and inflammatory factors, leading to joint degeneration. In neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, neuronal and glial cell senescence drives neuroinflammation, amyloid-beta accumulation, and synaptic loss, worsening cognitive decline. These examples illustrate how localized senescence amplifies disease progression across organ systems.^[91]^[92]^[93] Progeroid syndromes, rare genetic disorders mimicking accelerated aging, often involve defects that induce premature cellular senescence, providing insights into senescence's role in aging pathologies. Key examples include: Hutchinson-Gilford progeria syndrome (caused by LMNA mutations, featuring growth retardation, alopecia, scleroderma-like skin changes, and fatal cardiovascular disease); Werner syndrome (WRN helicase deficiency, with bilateral cataracts, type 2 diabetes, osteoporosis, and high cancer risk); Bloom syndrome (BLM mutations, characterized by short stature, photosensitivity, and elevated cancer incidence); Rothmund-Thomson syndrome (RECQL4 defects, involving poikiloderma, skeletal dysplasias, and cataracts); Cockayne syndrome (ERCC6 or ERCC8 mutations, marked by progressive neurodegeneration, cachexia, and photosensitivity); trichothiodystrophy (mutations in DNA repair genes like GTF2H5, presenting with brittle hair, ichthyosis, and intellectual disability); and ataxia-telangiectasia (ATM gene alterations, leading to cerebellar ataxia, telangiectasias, immunodeficiency, and lymphoma predisposition). These syndromes highlight how DNA repair and lamin defects trigger senescence-like phenotypes, resulting in multi-system premature aging.^[94]^[95] Evidence from experimental models and human studies underscores senescence's causal role in aging and disease. In a seminal 2011 study, genetic clearance of p16^INK4a-positive senescent cells in progeroid mice delayed age-related disorders, demonstrating that reducing senescent burden ameliorates aging phenotypes.^[96] Human biopsies from patients with idiopathic pulmonary fibrosis (IPF) reveal elevated p16-positive senescent cells in lung tissue, correlating with disease severity and fibrosis progression. These findings support the notion that senescent cells drive pathology through persistent presence.^[97] The mechanisms underlying senescence's detrimental effects in aging involve impaired immune-mediated clearance, leading to senescent cell persistence and amplified tissue damage. Failed clearance mechanisms, such as reduced natural killer cell activity with age, allow senescent cells to accumulate, exacerbating fibrosis via SASP-induced extracellular matrix remodeling and contributing to stem cell exhaustion by creating hostile microenvironments that impair regeneration. This vicious cycle perpetuates organ dysfunction and frailty in aging.^[98] Recent 2025 research has linked cellular senescence to long COVID-19 symptoms, where therapy-induced or virus-triggered senescence in lung epithelial and endothelial cells contributes to persistent inflammation, fibrosis, and multi-organ sequelae in long-haul patients, suggesting senescence as a mediator of post-viral aging-like syndromes.^[99]

Clearance and Persistence

Immune-Mediated Clearance

The immune system plays a crucial role in recognizing and eliminating senescent cells to preserve tissue homeostasis, primarily through innate effectors like natural killer (NK) cells and macrophages. Senescent cells express surface ligands such as MICA and MICB, which bind to the activating receptor NKG2D on NK cells, facilitating their identification.^[100] Additionally, components of the senescence-associated secretory phenotype (SASP), including cytokines like IL-6, act as chemoattractants to recruit NK cells and macrophages to sites of senescence.^[5] These mechanisms ensure targeted surveillance, though senescent cells can upregulate inhibitory signals like HLA-E to evade detection in certain contexts.^[100] Once recognized, NK cells induce apoptosis in senescent cells through granule exocytosis, releasing perforin to permeabilize the target membrane and granzymes to activate caspase cascades.^[101] Macrophages, particularly the pro-inflammatory M1 subtype, contribute by engulfing senescent cells via phagocytosis, often mediated by "eat-me" signals such as exposed calreticulin on the senescent cell surface, which binds to low-density lipoprotein receptor-related protein 1 (LRP1) on macrophages.^[102] This process is supported by CD4+ T cells, which provide helper functions to amplify the response; for instance, in mouse models of oncogenic stress in the liver, CD4+ T cells were essential for the efficient recruitment and activation of cytotoxic effectors to clear premalignant senescent hepatocytes.^[103] In young organisms, this clearance is highly efficient, with senescent cells exhibiting a half-life of approximately 5 days due to robust immune surveillance.^[104] However, with advancing age, immune exhaustion—characterized by reduced NK cell cytotoxicity and macrophage phagocytic capacity—prolongs this half-life to weeks or longer, allowing senescent cell accumulation.^[104] Evidence from human studies supports the potential of immunotherapy to restore clearance; for example, chimeric antigen receptor (CAR) T cells engineered to target uPAR on senescent cells have shown enhanced elimination in preclinical models relevant to human age-related pathologies, with potential for future clinical translation in conditions like osteoarthritis.^[105] Regulation of this process balances efficacy against risks like autoimmunity, with TGF-β secreted by senescent cells inhibiting excessive NK and T cell activation to limit collateral tissue damage.^[5] This inhibitory feedback, while protective in youth, contributes to impaired clearance in aging by dampening immune responsiveness.

Accumulation and Consequences

The persistence of senescent cells arises from multiple factors that impair their clearance, including age-related immune senescence, which diminishes the efficacy of immune surveillance mechanisms.^[106] Fibrotic remodeling in tissues can physically shield senescent cells from immune detection, while the senescence-associated secretory phenotype (SASP) promotes local immunosuppression by recruiting regulatory T cells and secreting anti-inflammatory factors.^[107] These processes collectively allow senescent cells to evade elimination, leading to their gradual buildup over time. Accumulation of senescent cells disrupts tissue homeostasis, primarily through chronic inflammation and direct interference with neighboring cells. In the stem cell niche, senescent cells secrete factors that inhibit progenitor proliferation and differentiation, resulting in impaired tissue regeneration and functional decline, as observed in aged muscle and hematopoietic tissues.^[2] Paracrine signaling from SASP further propagates senescence to adjacent healthy cells, amplifying the senescent burden in a bystander effect. Systemically, this contributes to frailty by promoting multimorbidity, with elevated senescent cell levels correlating with reduced physical resilience and increased vulnerability to stressors in older adults.^[1] Models estimate that elderly humans harbor a low but functionally significant fraction of senescent cells across tissues, representing less than 1% of total cells in most organs.^[108] Experimental clearance of senescent cells has been shown to reduce associated biomarkers by 30-50% in human tissues, underscoring the potential impact of this burden.^[109] Evidence from human studies highlights these effects; for instance, in extremely obese individuals, senescent preadipocytes accumulate over 30-fold higher in visceral adipose tissue compared to non-obese controls, exacerbating metabolic dysfunction and inflammation.^[110] Longitudinal cohort studies in the 2020s have correlated higher senescent cell burden, measured via circulating biomarkers like p16^{INK4a}, with increased multimorbidity and mortality risk in aging populations.^[111] This accumulation creates vicious feedback cycles, as persistent senescent cells intensify SASP production, further suppressing immune clearance and promoting additional senescence in surrounding tissues.^[112]

Therapeutic Approaches

Senolytic Drugs

Senolytic drugs are pharmacological agents that selectively eliminate senescent cells by inducing apoptosis, targeting their characteristic resistance to programmed cell death. These cells upregulate anti-apoptotic pathways, including those mediated by Bcl-2 family proteins such as Bcl-2, Bcl-xL, and Bcl-w, which senolytics exploit to promote their demise while sparing proliferating cells. This approach relies on the senescent cells' reliance on hyperactivated survival signals, allowing for selective clearance without broad cytotoxicity. Key examples of senolytics include the combination of dasatinib, a Src tyrosine kinase inhibitor, and quercetin, a natural flavonoid polyphenol, first identified in 2015 through a targeted screen for agents that kill human endothelial, mouse embryonic fibroblast, and primary fat cell senescent models. This regimen clears 30-70% of senescent cells in adipose tissue, lung, and other sites in preclinical models, demonstrating potency across multiple cell types. Navitoclax (ABT-263), a small-molecule BH3 mimetic that inhibits Bcl-2, Bcl-xL, and Bcl-w, was discovered as a senolytic in 2016 and effectively reduces senescent cell burden in diverse tissues like bone marrow and lung. Fisetin, another flavonoid, emerged in 2018 as a potent senolytic, selectively inducing apoptosis in senescent but not non-senescent cells in vitro and reducing senescence markers in progeroid and aged mice when administered intermittently. These agents achieve specificity partly through senescent cells' altered SASP, which can sensitize them to apoptosis, though dosing regimens are optimized to minimize effects on healthy cells. Mechanistically, senolytics disrupt the pro-survival network in senescent cells, where pathways like PI3K/AKT and MAPK are chronically active, leading to Bcl-2 family overexpression that these drugs counteract. For instance, dasatinib inhibits kinases upregulated in senescence, while quercetin modulates heat shock proteins and pro-apoptotic factors; together, they synergize to tip the balance toward cell death. Navitoclax directly binds anti-apoptotic proteins, freeing pro-apoptotic effectors like Bax and Bak to permeabilize mitochondria. Fisetin similarly engages multiple pathways, including inhibition of anti-apoptotic Bcl-2 and modulation of senescence-associated β-galactosidase. This targeted vulnerability arises from senescence's irreversible growth arrest, making these cells "addicted" to survival signals absent in healthy cells. Preclinical evidence highlights senolytics' potential to mitigate age-related decline; in naturally aged mice, intermittent dasatinib plus quercetin reduced senescent cell accumulation, improved physical function, and extended median lifespan by 36% (Xu et al., 2018).^[113] In progeroid models, it improved healthspan. In naturally aged mice, fisetin treatment decreased senescence markers in multiple tissues and enhanced lifespan by 10%. Human trials, primarily phase I and II, support translation: in idiopathic pulmonary fibrosis (IPF), dasatinib plus quercetin administered intermittently over 3 weeks (3 days/week) cleared senescent cells in lung tissue and improved physical function, including a median increase of 21.5 meters (~10%) in 6-minute walk distance and 0.12 m/s in gait speed, with good tolerability (Justice et al., 2019).^[114] For osteoporosis, a 2024 phase 2 trial with similar regimens in postmenopausal women showed no overall reduction in bone resorption markers but modest effects in a subgroup with higher baseline levels; larger studies are needed.^[115] UNITY Biotechnology's navitoclax analog UBX1325 advanced to phase 2b for diabetic macular edema, reporting functional improvements in vision as of 2025; their earlier osteoarthritis program did not advance beyond phase 2.^[116]^[117] Challenges persist in clinical application, including off-target effects—navitoclax induces dose-limiting thrombocytopenia by depleting platelets via Bcl-xL inhibition—and variable efficacy across tissues due to delivery barriers like the blood-brain barrier. Intermittent "hit-and-run" dosing mitigates toxicity but requires optimization for tissue-specific senescence burdens, and long-term safety data remain limited despite promising short-term results.

Senomorphic Interventions

Senomorphic interventions refer to pharmacological strategies that modulate the deleterious effects of senescent cells by suppressing their harmful outputs, particularly the senescence-associated secretory phenotype (SASP), without inducing cell death.^[118] These approaches target key signaling pathways involved in SASP production, such as JAK/STAT, NF-κB, and mTOR, thereby mitigating inflammation and tissue dysfunction associated with senescence accumulation.^[1] Unlike senolytics, senomorphic effects are often reversible, allowing senescent cells to persist while restoring their functionality to a more benign state.^[119] A primary mechanism of senomorphic action involves inhibiting SASP secretion through interference with transcriptional regulators. For instance, JAK inhibitors block the IL-6/STAT3 pathway, reducing pro-inflammatory cytokine release from senescent cells.^[120] Similarly, BRD4 inhibitors target epigenetic modifications that drive SASP expression, preventing enhancer remodeling and immune surveillance evasion in senescent cells.^[121] These interventions preserve the tumor-suppressive benefits of senescence while attenuating its pathological consequences.^[122] Prominent examples include metformin, an AMPK activator that suppresses NF-κB-mediated SASP factors, thereby alleviating senescence-induced oxidative stress and mitochondrial dysfunction in aging cells.^[123] Rapamycin, an mTOR inhibitor, exemplifies a classic senomorphic agent by inhibiting the secretory phenotype in senescent fibroblasts and other cell types, with effects observed across multiple preclinical models since the 2010s.^[124] Additionally, anti-IL-6 antibodies directly neutralize key SASP components, reducing inflammation driven by interleukin-6 in senescent microenvironments.^[125] Preclinical evidence demonstrates the efficacy of senomorphics in extending healthspan without senescent cell clearance. In aged mouse models, JAK inhibitors administered for 10 weeks reduced systemic inflammation, enhanced physical function, and alleviated frailty by suppressing SASP.^[120] Rapamycin treatment in mice similarly improved health metrics and extended lifespan by modulating mTOR-dependent SASP secretion, as shown in studies from the mid-2010s onward.^[119] These findings highlight senomorphics' potential in age-related conditions, with reversible modulation allowing for sustained therapeutic benefits. Senomorphic interventions offer advantages over cell-eliminating strategies, including a safer profile for chronic use due to lower toxicity and the ability to combine with immune-enhancing therapies for synergistic effects on senescence persistence.^[126]

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