How Cell Aging and Oxidative Stress Are Linked to Heart Disease

Cellular senescence is a stable program of growth arrest accompanied by a persistent SASP. Senescence is a conserved cellular response to DNA damage [19], telomere dysfunction [20], oncogenic activation [21], proteostasis collapse [22], and oxidative stress [23]. In response to these cellular stresses in diverse tissues, the canonical DNA damage response (DDR) activates ataxia-telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) proteins, which phosphorylate checkpoint kinases 1 and 2 (CHK1/CHK2) and promote tumor protein P53 (p53) stabilization with the induction of cyclin-dependent kinase inhibitor 1A (p21/CDKN1A) [24,25,26]. In addition, stress- and chromatin-mediated pathways promote cyclin-dependent kinase inhibitor 2A (p16/CDKN2A) and the retinoblastoma protein (RB)-dependent suppression of E2 promoter-binding factor (E2F)-driven transcription [27,28]. At the cell-cycle checkpoint levels, the p53/p21 and p16/RB enhance cell-cycle arrest through inhibition of cyclin-dependent kinases 2, 4, and 6 (CDK2/4/6), maintaining RB in a hypophosphorylated state and preventing transition to S-phase [29,30,31]. The predominance of p16/RB is associated with stable G1 arrest, whereas p53/p21 supports G1 or G2 arrest, depending on stress type, intensity, and cell state [32,33,34]. Downstream of CDK suppression, the dimerization partner (DP), RB-like (RBL1/p107, RBL2/p130), E2F, and MuvB (DREAM) complex assembles to silence a broad mitotic gene program and acts as a key effector of arrest, independent of canonical E2F regulation [35,36,37]. RB-linked circuitry further cooperates with anaphase-promoting complex/cyclosome (APC/C) and APC/C co-activator CDC20 homolog 1 (CDH1) to restrain mitotic cyclins, establishing a second layer that prevents cell-cycle re-entry [38,39,40,41]. The balance between the p53/p21 and the p16/RB axes modulates cell-fate decisions toward apoptosis, adaptive quiescence, or a stable senescent state. Resistance to apoptosis is a characteristic of senescence. Apoptosis is maintained by B-cell lymphoma-2 (BCL-2) family prosurvival proteins and reprogrammed stress-response signaling [42,43,44]. Senescence is generally stable but not irreversible. Under specific conditions, including mammalian target of rapamycin complex 1 (mTORC1) inhibition with rapamycin [45], Janus kinase 1 and 2 (JAK1/2) blockade [46], bromodomain and extraterminal (BET)-bromodomain-containing protein 4 (BRD4) inhibition [47], p38-mitogen-activated protein kinase (MAPK) to MAPK-activated protein kinase 2 (MK2) pathway inhibition [27], or blockade of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway [48], secretory metabolites [49,50] are reduced without loss of cell-cycle arrest.

Telomere dysfunction is a canonical trigger of senescent arrest [20]. Replication-driven telomere shortening exposes chromosome ends and triggers persistent DNA-damage signaling at telomeric foci that resemble one-ended double-strand breaks [20,51]. Telomere-associated DNA damage foci are structurally stable lesions that evade efficient repair and sustain checkpoint signaling [52]. Senescent cells accumulate DNA segments with chromatin alterations, reinforcing senescence (DNA-SCARS) marked by γH2AX and 53BP1 [53]. DNA-SCARS exhibit minimal recruitment of late repair factors, indicating attenuated homologous recombination and increased reliance on end joining [52,53]. Replication stress and R-loop stabilization lead to replication-fork collapse and the formation of persistent DNA damage foci [52]. In addition to telomere dysfunction, oncogene activation triggers replication stress and nucleotide imbalance, which activate the DNA-damage response and establish senescent arrest [54]. Loss of tumor suppressor function promotes senescent arrest via dysregulated growth-factor signaling and metabolic reprogramming [55,56,57]. Phosphatidylinositol 3-kinases (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) signaling promotes p53/p21-mediated senescent arrest, reflecting diverse upstream regulation [58]. Mitogenic hyperactivation elevates nucleotide demand and promotes transcription–replication conflicts, sustaining checkpoint signaling despite limited detectable double-stranded breaks [59,60,61].

SASP is initiated by nuclear factor-kappa B (NF-κB), p38 MAPK signaling, and CCAAT/enhancer-binding protein beta (C/EBPβ), subsequently requiring chromatin-dependent gene expression involving bromodomain-containing protein 4 (BRD4) and EP300 [47,62]. The core secretory module encompasses interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1), alongside matrix metalloproteinases (MMPs) and associated regulatory factors [63,64,65]. However, the precise composition of the SASP is highly heterogeneous and depends on the cell type and the specific senescence-inducing stimulus. For instance, senescent fibroblasts tend to secrete extracellular matrix (ECM)-remodeling enzymes, whereas senescent cardiomyocytes often release specific growth factors and matricellular proteins. Cell enlargement and cytoskeletal remodeling facilitate the nuclear translocation of GATA4 and NF-κB. The autophagic control of GATA4 connects lysosome function to secretory intensity [50]. Translational and post-transcriptional control acts through mTORC1, the p38-to-MK2 pathway, and AU-rich element-binding proteins that determine messenger RNA (mRNA) stability [4,66]. Notch signaling mediates secondary senescence via juxtacrine signaling [49,67]. Early IL-1-primed SASP is distinct from a later chromatin-licensed SASP [66]. Cells shift between an inflammatory- and TGF-β-dominant state as conditions change [49]. MK2-dependent phosphorylation of RNA-binding proteins stabilizes AU-rich SASP transcripts, maintaining secretion despite upstream variability [68].

Large-scale epigenetic remodeling stabilizes senescence through heterochromatin redistribution and altered enhancer activity at inflammatory genes. Senescence-associated heterochromatin foci (SAHFs) are compact nuclear domains enriched in repressive chromatin marks, such as histone H3 lysine 9 trimethylation (H3K9me3), and architectural proteins, such as heterochromatin protein 1 (HP1) and macroH2A [69,70,71]. SAHF formation depends on cell type and trigger and is prominent in oncogene-induced senescence. Loss of nuclear lamina integrity promotes micronuclei formation and the release of chromatin fragments into the cytosol [72]. Reduced lamin-B1 (LMNB1), together with loss of high-mobility group box 2 (HMGB2), accompanies nuclear reorganization and reduces chromatin boundaries around inflammatory genes [73,74]. Cytosolic DNA activates cGAS-STING signaling. The resulting signaling induces type I interferon (IFN) and NF-κB signaling that sustains the secretory phenotype and promotes immune cell infiltration [75]. The reactivation of retroelements generates double-stranded RNA that activates innate RNA sensors such as retinoic acid inducible gene-I (RIG-I), melanoma differentiation-associated gene-5 (MDA-5), and Toll-like receptor-3 (TLR-3). The activation of these sensors enhances IFN and stabilizes SASP [76,77,78]. DNA methylation and chromatin accessibility change in partly conserved patterns quantified by DNA methylation clocks [79]. Together, these chromatin and nucleic acid-sensing pathways sustain the persistence of cellular senescence and its paracrine effect.

Organelle quality control provides a mechanistic basis for canonical markers of cellular senescence [80]. Lysosomal enlargement with increased senescence-associated beta-galactosidase activity (SA-β-gal) and lipofuscin accumulation is characteristic of senescence [81,82]. Autophagic flux is bidirectionally linked with cellular senescence [83]. Impairment of autophagy promotes the accumulation of damaged proteins and organelles, whereas induction of autophagy attenuates the SASP [84]. Endoplasmic reticulum (ER) stress and the integrated stress response modulate translation via the phosphorylation of eukaryotic initiation factor-2 alpha (eIF2α) and reprogram amino acid and lipid metabolism with a state of cell-cycle arrest [85,86]. There is no single definitive marker. Diagnostic marker combinations integrating SA-β-gal with p16 or p21, loss of LMNB1, telomere-associated damage foci, heterochromatin features, and SASP profiling are best implemented using a single-cell or spatial assay to reduce classification errors [2,87]. To circumvent the inherent limitations of invasive tissue sampling, contemporary research has pivoted toward non-invasive detection modalities to enhance clinical applicability. Liquid biopsy strategies, encompassing the quantification of senescence-associated extracellular vesicles (SA-EVs) and circulating analytes such as growth differentiation factor 15 (GDF15), constitute a scalable paradigm for longitudinal patient surveillance. Concurrently, advancements in molecular imaging, particularly positron emission tomography (PET) utilizing radiotracers specific to senescence-associated enzymes, facilitate the in vivo spatiotemporal quantification of cardiac senescence accumulation [88,89,90,91]. An overview of the senescence-associated cell-cycle arrest pathway is shown in Figure 1.

Reactive oxygen species (ROS) are oxygen (O₂)-containing molecules with high chemical reactivity. Most cellular oxygen is fully reduced to water via mitochondrial electron transport (mETC), and only a small cellular oxygen is diverted to ROS through electron leakage [92]. During oxidative phosphorylation, complexes I and III generate superoxide (O₂•⁻), which is converted by superoxide dismutase 1 and 2 (SOD1/2) into hydrogen peroxide (H₂O₂) [93,94]. In the presence of ferrous iron, H₂O₂ participates in Fenton chemistry, producing hydroxyl radical (HO•), an extremely reactive species that damages lipids, proteins, and nucleic acids [95]. Lipid peroxidation is a chain reaction that initiates as HO• removes a bis-allylic hydrogen from a polyunsaturated fatty acid (PUFA) to form a carbon-centered radical (R•) [96]. Molecular O₂ produces a lipid peroxyl radical (ROO•), which propagates the reaction and gives rise to lipid hydroperoxides (ROOH) [97]. Glutathione peroxidase-4 (GPx4) reduces ROOH to the corresponding alcohol (ROH) using glutathione, thereby limiting membrane damage and cytotoxicity [98]. NADPH oxidase 2 (NOX2) serves as a major non-mitochondrial source of ROS in innate immune cells. Upon microbial stimulation, NOX2 transfers electrons from NADPH to O₂, generating O₂•⁻ within the phagosomal lumen or extracellular space [99]. SODs subsequently convert the resulting O₂•⁻ flux into H₂O₂, at which point myeloperoxidase then reacts with chloride to generate hypochlorous acid (HOCl) [100]. Oxidants are essential for pathogen killing, but excessive production injures host tissues. Other enzymes, including DUOX1/2, xanthine oxidase, cytochrome P450s, monoamine oxidases, and nitric oxide synthases (NOSs), produce ROS or reactive nitrogen species (RNS) in distinct subcellular locations [101,102]. O₂•⁻ reacts rapidly with nitric oxide (NO) to form peroxynitrite (ONOO⁻) [103]. To limit oxidative stress, cells rely on enzyme-based and small-molecule antioxidant defenses. Core enzymes include SOD, catalase, glutathione peroxidases (GPxs), glutathione reductase (GR), peroxiredoxins (Prxs), and the thioredoxin (Trx) system [104,105]. Non-enzymatic antioxidants include reduced glutathione (GSH), ascorbate, tocopherols, urate, and carotenoids, while metal-binding proteins such as transferrin, ferritin, ceruloplasmin, and albumin restrict iron and copper availability and thereby suppress Fenton reactions [105,106]. At the transcriptional level, Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway is a major regulator of the antioxidant defense system. Under normal conditions, Keap1 with cullin 3 (Cul3) targets NRF2 for proteasomal degradation, whereas oxidative stress stabilizes NRF2, promotes nuclear translocation, and activates antioxidant response element programs that upregulate heme oxygenase 1 (HMOX1), NAD(P)H:quinone oxidoreductase 1 (NQO1), SOD and Gpxs, ferritin, Trx, and related detoxifying systems [107,108,109].

Oxidative stress has been implicated as a primary trigger of cellular senescence. Excess ROS leads to DNA damage and a sustained DDR, which activates p53/p21 and p16/RB [110,111]. In parallel, redox-sensitive transcription factors, such as NF-κB and C/EBPβ, are activated and amplify SASP [62,112,113]. However, it is not yet clear whether the antioxidant defense program represents a nonspecific response to increased oxidant or a ROS-dependent response. Nevertheless, cellular senescence is accompanied by the upregulation of antioxidant defense genes [18,114,115]. Moreover, mitochondria in the senescent cells typically exhibit decreased mitochondrial respiratory capacity and membrane potential (ΔΨm), accompanied by increased ROS production [113,116]. Excess dynamin-related protein 1 (DRP1) activity with decreased mitofusins 1 and 2 (MFN1/2) and optic atrophy protein (OPA1) leads to cristae destabilization, elevated ROS, and reduced respiratory capacity [117,118,119]. Senescence-associated mitochondrial dysfunction (SAMD) is characterized by primary organelle injury with oxidized nicotinamide adenine dinucleotide (NAD⁺) depletion and reduced sirtuin (SIRT) activity, accompanied by reprogrammed SASP [18,120,121]. SAMD can be driven by persistent DDR through pathways including p38 MAPK, TGF-β, and Nf-κB signaling, leading to mitochondrial fragmentation, loss of ΔΨm, and impaired complex I and II respiration [27,112,122]. In addition, the dysregulated opening of the mitochondrial permeability transition pore (mPTP) has been implicated as a key effector that links mitochondrial calcium (Ca²⁺) overload and oxidative stress to SAMD. In the cardiac system, maladaptive mPTP opening promotes loss of ΔΨm, ATP depletion, and cardiomyocyte death in models of ischemia–reperfusion injury and chronic remodeling, suggesting that mPTP activity may provide an opportunity to selectively target senescent cardiac cells [123,124,125,126].

Early mitochondrial injury triggers mitochondrial DNA (mtDNA) efflux into the cytosol, activating cGAS-STING and NLRP3 inflammasome, leading to increased SASP and ROS production. Mitophagy reduction, such as PTEN-induced kinase 1 (PINK1)/Parkin, impairs the clearance of damaged mitochondria, while chronic activation of poly ADP ribose polymerase (PARP) in response to DNA damage depletes NAD⁺ and further compromises respiratory reserve capacity [127,128,129,130]. NAD homeostasis is additionally eroded by ecto- and endo-enzymes such as CD38, and by reduced salvage through Nicotinamide adenine dinucleotide (NAMPT), linking damage signaling to sirtuin-dependent chromatin regulation [131]. Beyond mitophagy, selective autophagy of the endoplasmic reticulum, lysosomes, and peroxisomes, together with TFEB and TFE3-driven lysosome biogenesis, shapes organelle quality and influences whether senescence remains stable or transitions toward degeneration [132,133]. A mitochondrial stress-biased program, often termed MiDAS, can produce p21-high and p16-variable arrest with a distinct secretory signature, demonstrating that not all senescence is DDR-centric [120].

During ischemia, mETC activity is inhibited, and succinate accumulates [145]. During reperfusion, oxidation of succinate triggers reverse electron transport (RET) at complex I and causes increased mitochondrial ROS (mtROS) [146]. Subsequently, cytosolic and mitochondrial Ca²⁺ overload, opening of mPTP, loss of ΔΨm, and ATP depletion occur, thereby increasing cardiac injury [141,147]. Nevertheless, both the identification of mPTP and the proposed distinction that transient opening is physiological and sustained opening is pathological remain controversial [142]. Previous studies have reported that cardiomyocytes, endothelial cells, and fibroblasts at the infarct border zone exhibit increased p16 and p21 expression accompanied by SASP accumulation [148,149,150,151]. Importantly, these cell types exhibit distinct SASP profiles that differentially impact post-ischemic remodeling. Senescent cardiomyocytes are a primary source of CCN1 (cyr61) and pro-fibrotic factors such as TGF-β, which drive replacement fibrosis. In contrast, senescent cardiac fibroblast and endothelial cells predominantly secrete pro-inflammatory cytokines (e.g., IL-6 and IL-1β) and MMPs, which perpetuate inflammation and degrade the extracellular matrix. Consistent with the relative resistance of senescent cells to apoptosis, experimental models indicate that senescent cardiomyocytes and non-myocytes are not efficiently eliminated during I/R, resulting in persistence and accumulation within the peri-infarct region. Genetic and pharmacological senolytic strategies that increase apoptotic susceptibility in senescent cells, such as BCL-2 family inhibition with navitoclax or combined dasatinib and quercetin, reduce senescent cell accumulation, attenuate adverse remodeling, and improve post-infarction cardiac function in aged mice, indicating that senescent cells survive the initial ischemic insult and contribute to chronic injury [152,153]. However, whether these signatures are causal drivers or downstream consequences of injury remains unclear and appears to depend on the experimental model and the assay used [154]. Recent studies indicated that lipid peroxidation-dependent ferroptosis contributes to I/R injury [155,156]. In addition, mtDNA release with the activation of the cGAS/STING pathway can exacerbate inflammation after reperfusion [157,158]. I/R-induced senescent cardiomyocyte has been linked to hypertrophy, inflammation, and fibrosis via SASP mediators, although some studies report that senescence induction in fibroblasts limits fibrosis and promote repair, suggesting dependence on cell type, timing, and experimental conditions [154,159,160]. Clinical trials of broad antioxidant supplementation have not shown consistent benefits, and low-level ROS may mediate preconditioning, indicating the importance of dose and timing [161,162,163,164,165]. More targeted strategies administered at reperfusion appear promising [166,167]. In experimental models, the administration of malonate at reperfusion to inhibit succinate oxidation attenuates injury and adverse remodeling [146,165]. In contrast, acute inhibition of monocarboxylate transporter 1 (MCT1) to prevent succinate efflux has been reported to increase mtROS and exacerbate injury [168]. These findings emphasize the importance of the RET and succinate timing axis. Overall, I/R injury may be mitigated by approaches that attenuate the early increase in ROS driven by RET, prevent the sustained opening of mPTP, restore mitochondrial quality control, and preserve NAD⁺ metabolism. The modulation of ferroptosis and the cGAS/STING pathway should be guided by the prevailing phenotype. Success is likely to depend on biomarker-guided phenotyping using measures such as succinate and oxidized phospholipids, mitochondrial damage-associated molecular patterns derived from mtDNA, lipid peroxidation markers, and cellular senescence markers, together with precise therapeutic timing.

Heart failure with preserved ejection fraction is a heterogeneous syndrome prevalent among older adults with obesity, type 2 diabetes, and hypertension [169,170]. Systemic inflammation and coronary microvascular dysfunction are frequent. Endothelial oxidative stress attenuates NO/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) signaling, which reduces titin phosphorylation, increases passive myocardial stiffness, and impairs diastolic relaxation [171,172]. Disruptions to redox and signaling pathways occur within a cellular environment characterized by senescence across multiple cardiac cell types [173,174]. In the coronary microvasculature, endothelial cells exhibit increased p16 and p21, loss of LMNB1, telomere-associated DNA damage foci, and SASP enriched in IL-1β, IL-6, TGF-β, and matrix metalloproteinases (MMPs) [173,175]. Consequently, SASP factors promote microvascular rarefaction, endothelial-to-mesenchymal transition (EndMT), and interstitial remodeling [176,177]. In addition, senescent cardiac fibroblasts promote collagen deposition and cross-linking, whereas cardiomyocytes exhibit mitochondrial dysfunction, impaired mitophagy, reduced NAD⁺ and sirtuin activity, and metabolic inflexibility [178,179,180,181]. Consequently, senescence pathways interact with redox imbalance and reduced NO/cGMP/PKG signaling to enhance diastolic dysfunction [182,183]. Despite the established preliminary model, robust experimental validation for the proposed interaction has yet to be provided. Clinically, senescence signatures are heterogeneous and depend on the analytic method, tissue accessibility, and biomarker specificity [2,184]. Currently, available circulating markers remain nonspecific, while the relative contribution of vascular and extracardiac drivers remains controversial, and the causal relationship between microvascular senescence and clinical HFpEF phenotypes has not been definitively established [185,186,187]. Clinical trials that directly augmented the NO/cGMP/PKG pathway have yielded neutral or mixed results, likely reflecting heterogeneity in pathway predominance by patient phenotype, intervention timing, and comorbid state [188,189,190]. By contrast, interventions that attenuate metabolic, inflammatory, and oxidative stress have shown benefit. Sodium–glucose cotransporter-2 (SGLT-2) inhibitors reduce HF in preserved or mildly reduced ejection fraction, and glucagon-like peptide-1 (GLP-1) receptor agonists improve symptoms, physical function, and weight in obese phenotypes [191,192,193,194]. Senescence-targeted therapies, including senolytics and senostatics, remain experimental, with human efficacy and safety still uncertain. Taken together, HFpEF reflects an interplay among microvascular endothelial senescence with oxidative stress, reduced NO/cGMP/PKG signaling, impaired mitochondrial quality control, and metabolic dysfunction. Given that dominant mechanisms are not uniform across patients, treatment should be phenotype-based. Weight reduction combined with SGLT-2 inhibitors or GLP-1 receptor agonists is appropriate in obese metabolic–inflammatory phenotypes. Approaches that enhance microvascular function and NO production are reasonable in cases characterized by predominant fibrosis. Biomarker panels and imaging of microvascular function will be essential for precise phenotyping and therapy.

Dilated cardiomyopathy involves chronic oxidative stress, defective organelle quality control, and the accumulation of senescence markers in cardiomyocytes and cardiac fibroblasts [195,196,197]. Mitochondrial dysfunction, with impaired mitophagy, lysosomal deacidification, and reduced TFEB signaling, disrupts ATP homeostasis and increases ROS [198,199,200]. Proteostasis failure driven by loss-of-function variants in titin and mutations in lamin A/C (LMNA), BCL2-associated athanogene 3 (BAG3), and desmin (DES) produces proteotoxic and ER stress with depleted cellular NAD⁺ [201,202,203,204,205]. Nuclear envelope instability and micronuclei formation lead to cytosolic DNA release and an activated cGAS/STING pathway, sustaining inflammatory signaling and SASP, which promotes adverse remodeling, systolic dysfunction, and an arrhythmogenic substrate [75,206]. Nevertheless, senescence markers are not consistently detected in detailed cardiomyopathy patients; concurrently, antioxidant supplementation has failed to yield consistent benefits in clinical trials [2,207]. NOX isoforms may fulfill conflicting roles across varying physiological contexts, evidenced by reports of both detrimental and adaptive signaling [208,209,210,211]. The penetrance of titin-truncating variants remains unresolved, with competing attributions to haploinsufficiency, poison-peptide mechanism, and additional second hits such as viral myocarditis, pressure overload, and metabolic stress [212,213]. Although senolytic and autophagy-enhancing approaches have shown promise in preclinical studies, efficacy and safety in human dilated cardiomyopathy have not yet been demonstrated [214,215]. Overall, dilated cardiomyopathy reflects an interplay between redox imbalance, failures in organelle quality control, and stress-responsive transcriptional programs. Therapeutic development should emphasize phenotype-guided approaches that target mitochondrial function and mitophagy, stabilize proteostasis, modulate cGAS/STING signaling, and support NAD⁺ metabolism, together with guideline-directed neurohormonal blockade.

Cardiac hypertrophy is an initially adaptive response to hemodynamic or metabolic load but often progresses to maladaptive remodeling with fibrosis, microvascular rarefaction, and diastolic or systolic dysfunction [216]. Recent studies indicate that senescence-oxidative stress crosstalk is central to driving progression from adaptive hypertrophy to pathological remodeling [18,217]. Mechanical and metabolic stress increase mtROS and activate redox-sensitive transcriptional programs such as NF-κB, activating protein-1 (AP-1), and hypoxia-inducible factor-1 alpha (HIF-1α), together with mechanotransduction pathways including integrin–focal adhesion kinase (FAK) and yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) [218,219,220,221]. Taz acts with the TEA domain (TEAD) to convert mechanical load into pro-hypertrophic and pro-fibrotic gene expression [222]. Perturbed Ca²⁺ handling at mitochondria–ER contact sites promotes mitochondrial permeability transition, loss of ΔΨm, and energetic inefficiency [223]. Single-cell and spatial profiling reveal heterogeneous senescent states across endothelial cells, fibroblasts, and cardiomyocytes [224]. Distinct SASP profiles among these cell populations dictate a specific therapeutic target. For example, senescent cardiomyocytes secrete endothelin-1(EDN-1) and GDF15, which act in an autocrine/paracrine manner to promote hypertrophy and fibrosis, whereas senescent fibroblasts exhibit a strongly inflammatory SASP (IL-6 and CCL2) that recruits immune cells. Endothelial p16 and p21 expression with SASP enriched in adhesion molecules (ICAM-1 and VCAM-1) and TGF-β promote EndMT and microvascular rarefaction [175,225]. Fibroblast populations range from proinflammatory, matrix-secreting cells to quiescent, matrifibrocyte-like states, suggesting time- and cell-type-specific contributions of senescence to remodeling [226,227]. Cytosolic mtDNA and micronuclei activate cGAS/STING and inflammasome pathways, thereby linking organelle injury to sterile inflammation and fibrotic progression [228,229]. However, several crucial mechanistic aspects have yet to be fully elucidated. Physiologically, low levels of ROS mediate adaptive signaling, complicating antioxidant strategies [230]. The consequences of YAP/TAZ signaling depend on the cellular state and timing—early after load, transient YAP/TAZ activation is protective—whereas sustained activation drives fibrotic remodeling [222,231,232]. In addition, whether senescence in cardiomyocytes or fibroblasts precedes remodeling or activates downstream consequences remains unknown, and the direction of the effect likely varies with the model, timing, and measurement endpoints [233]. Therapeutic strategies for hypertrophic remodeling should emphasize unloading and stiffness reduction, together with the selective modulation of mechanotransduction pathways [234,235]. The strategy comprises augmentation of cGMP/protein kinase G (PKG) signaling to increase titin compliance, targeting integrin–FAK and YAP/TAZ to suppress prohypertrophic/profibrotic programs, anti-fibrotic strategies that limit fibroblast activation and extracellular-matrix cross-linking, improvement in microvascular function, and isoform-specific load-dependent modulation of NOX activity [236,237,238]. Responses should be evaluated using remodeling-specific endpoints, such as left ventricular mass, extracellular volume fraction, and myocardial strain, to guide biomarker-informed, stage-specific interventions [239]. An overview of cardiac disease is shown in Figure 2.

Congenital heart disease (CHD) represents a complex pathophysiological paradigm in which chronic hypoxia and hemodynamic overload accelerate biological aging through distinct molecular mechanisms [240,241]. Unlike HF in adults, the myocardium in CHD is exposed to sustained cyanosis and pressure loading from early development, leading to maladaptive metabolic reprogramming driven by hypoxia-inducible factor-1α (HIF-1α) [242,243]. While initially adaptive, chronic HIF-1α stabilization alters mitochondrial biogenetics and upregulates NOX2 and NOX4, thereby establishing a persistent source of mitochondrial and cytosolic ROS [244,245]. Under these conditions, NRF2 signaling is insufficient to yield an adequate antioxidant response, resulting in chronic redox dysfunction and exacerbated oxidative injury [246,247]. Cumulative oxidative stress directly compromises genomic stability. ROS-induced DNA double-stranded breaks activate the ATM/ATR-p53-p21 axis, initiating cell-cycle arrest, while concurrent oxidative damage to telomeres suppresses telomerase reverse transcriptase (TERT) activity, thereby accelerating telomere shortening in cardiomyocytes and vascular endothelial cells [248,249]. Crucially, the transition from damage accumulation to a stable senescent state is consolidated by p16 upregulation, which correlates with ventricular dysfunction severity in patients with CHD. Senescent cells adopt SASP characterized by NF-κB-dependent secretion of IL-6, TGF-β, and MMPs, which drives EndMT and myocardial fibrosis [250]. Furthermore, perioperative I/R injury and mechanical stress from cardiopulmonary bypass invoke marked increases in mtROS and the release of mtDNA, which may trigger the cGAS/STING pathway and link metabolic stress to sterile inflammation [157,214,251]. Thus, CHD constitutes a trajectory of "accelerated cardiovascular aging" driven by the convergence of hypoxic signaling, NRF2 dysfunction, and p53/p16-mediated senescence.

Notwithstanding the robust preclinical evidence elucidating the therapeutic potential of the senescence-oxidative stress axis, clinical translation remains in its early stages [252]. Contemporary clinical investigations are primarily stratified into two distinct approaches: the repurposing of established pharmacotherapies with pleiotropic senomorphic properties and the evaluation of novel senolytic or mitochondria-targeted agents [17,139]. The most substantial clinical advancement has been realized with sodium-glucose cotransporter-2 (SGLT-2) inhibitors such as Empagliflozin and Dapagliflozin. Although initially developed as antidiabetic agents, landmark cardiovascular outcome trials have substantiated efficacy in reducing HF hospitalization and mortality across all ejection fraction ranges [192,253]. Mechanistically, these agents have been demonstrated to attenuate oxidative stress, ameliorate mitochondrial energetics, and suppress cellular senescence pathways in cardiomyocytes and endothelial cells, thereby effectively functioning as putative "senomorphics" in clinical practice [254,255]. Concurrently, Metformin is under active investigation for the potential to alleviate age-related cardiovascular decline via AMPK activation and ROS reduction, and the prospective TAME (Targeting Aging with Metformin) trial is anticipated to provide definitive insights [252,256]. Pharmacological strategies targeting the selective elimination of senescent cells, termed senolytics, are currently subject to evaluation in pilot clinical trials. The combination of Dasatinib and Quercetin is being assessed for safety and efficacy in pathologies exhibiting significant mechanistic overlap with adverse cardiac remodeling, including diabetic kidney disease and idiopathic pulmonary fibrosis [257]. Furthermore, the flavonoid Fisetin is under investigation in the AFFIRM-LITE trial to delineate its impact on frailty and systemic inflammation in the geriatric population [258,259]. While these agents exhibit therapeutic promise, clinical application necessitates precise dosing protocols to optimize the therapeutic window while minimizing off-target cytotoxicity. In parallel, interventions designed to directly modulate mitochondrial oxidative stress and antioxidant defense mechanisms have yielded heterogeneous outcomes. Elamipretide (SS-31), a peptide engineered to stabilize cardiolipin and reduce mtROS, has been evaluated in HF cohorts [139,141]. Although broad efficacy endpoints have shown variability, post hoc analyses suggest potential benefits in patient subgroups defined by specific mitochondrial phenotypes. Additionally, NRF2 activators such as bardoxolone methyl have demonstrated the capacity to augment antioxidant response elements in renal pathologies, although the cardiovascular safety profile necessitates vigilant monitoring due to potential fluid retention [260]. Collectively, these translational efforts underscore a paradigm shift toward precision medicine and necessitate the stratification of therapeutic interventions based on individual oxidative or senescent phenotypes.