Telomeres are repetitive structures, composed of DNA and protein complexes, at chromosome ends that protect the genome by preventing chromosome termini from being recognized as DNA breaks [35,36]. Across multiple cardiovascular-relevant cell types, progressive telomere shortening (from replicative aging and stress) and telomere “uncapping” (loss of shelterin integrity) converge with non-telomeric genomic injury (oxidative lesions, replication stress, strand breaks) to activate a persistent DNA damage response (DDR) and enforce long-term growth arrest accompanied by SASP [36]. In the vasculature, aging is associated with a measurable rise in both general DNA damage and telomere dysfunction, with particularly strong effects in ECs and in atheroprone regions [36,37].

Mitochondria are the central hub of aerobic energy metabolism, and their dysfunction, together with sustained oxidative stress, has emerged as a convergent driver of cellular senescence in different cell fractions of the cardiovascular system [36,51,52]. Across these cell types, a common sequence is frequently observed: metabolic or environmental stress perturb mitochondrial dynamics and bioenergetics, elevates mitochondrial reactive oxygen species (ROS). It also triggers persistent redox-sensitive stress signaling, often coupled to DDR and inflammatory amplification, culminating in stable growth arrest and acquisition of a senescence-associated phenotype [36,51,52].

Autophagy is a natural mechanism that provides measures of neutralizing and removing damaged or degenerated intracellular organelles. It helps maintain the high functionality of different tissues and provides alternative energy sources under unfavorable environmental conditions [68,69]. Defects in autophagy lead to the accumulation of dysfunctional organelles that may act as sources of ROS or impair physiological mechanisms that maintain cellular homeostasis, therefore accelerating the aging process [68,69].

The endoplasmic reticulum (ER) is a membrane network that coordinates biosynthesis of proteins and lipids as well as homeostasis of Ca²⁺ and oxidoreductive balance [82,83,84]. When ER function is chronically challenged by hyperglycemia, oxidized lipids, inflammation or mechanical overload cells activate the unfolded protein response (UPR). The main effector elements of this axis encompass protein kinase R-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor 2 α subunit (eIF2α), activating transcription factor 4 (ATF4), activating transcription factor 6 (ATF6), inositol-requiring enzyme 1α (IRE1α) and spliced X-box binding protein 1 (XBP1s) [82,83,84]. Although the UPR is initially adaptive, sustained ER stress can become maladaptive and amplify oxidative stress, disturb Ca²⁺ handling, impair mitochondria–ER crosstalk and engage DNA-damage. Such alterations may promote stable growth arrest and a pro-inflammatory senescence program across multiple cardiovascular cell types [82,83,84].

Fibroblast senescence can be regarded as a major factor contributing to cardiac fibrosis. They are crucial for supporting myocytes structurally, as well as producing the main components of ECM [94]. Their correct function is thus necessary for cells’ functions and responses. Most importantly, fibroblast activation is crucial for the response to injury—they migrate to the injured region, produce growth factors and inflammatory cytokines, and differentiate from pro-inflammatory to pro-fibrotic phenotype [26,95].

Diseases of the cardiovascular system can cause local fibroblasts to become senescent. The exact mechanism is not yet fully understood; similarly to smooth muscle cells’ senescence, it has been shown to involve a transcription factor, GATA Binding Protein 4 (GATA4) [96]. In mice, the deletion of GATA4 in cardiac fibroblasts was shown to increase senescence. Moreover, the expression of GATA4 has been proven to decrease with aging. The senescence of cardiac fibroblasts can also be triggered by mechanical stressors [97] and oxidative stress. This is mainly in response to DNA damage and the increase in the p53/p21 and p16 accordingly. As was previously explained, SASP factors, secreted by other senescent cells, can also likely trigger the senescence of surrounding fibroblasts.

In mice post-MI, p53-mediated fibroblast senescence is known to be associated with decreased cardiac collagen production [98]. Senescent cells, which are likely fibroblast-derived, were also proven to accumulate in the heart after an MI episode. This may explain the altered uptake of mediators and the decrease in regenerative fibrosis after MI [26].

Direct reprogramming of ischemia-activated fibroblasts seems like a potential therapeutic target [99]. Reprogramming fibroblasts into cardiomyocyte-like cells is currently based on three transcription factors—GATA4, Myocyte Enhancer Factor 2 (MEF2) and T-Box Transcription Factor 5 (TBX5) [100]—collectively known as GATA4, MEF2C, TBX5 (GMT). The clinical potential of direct reprogramming is yet to be shown; nonetheless, great hopes are currently associated with it. To be useful, the GMT gene sequence must be shortened. The way to do so was previously shown by Honda et al. [100], who also suggested and showcased the effectiveness of the deletion of effector domains in MEF2C and GATA4. Recently, it has been suggested that the reprogramming may further be stimulated by epigenetic factors such as the histone reader PHF7 [101]. Most importantly, PHF7 has been shown to improve survival, function, and fibrosis up to 16 weeks after infarction in a murine model. This is likely due to its ability to increase chromatin accessibility [102]. The use of epigenetic factors has the chance to overcome the previous obstacles associated with the use of GMT.

MI triggers a coordinated sequence of inflammatory clearance, scar deposition, and structural remodeling; cellular senescence is increasingly recognized as a key regulator of these stages. After ischemic injury, cardiomyocytes, cardiac fibroblasts, and vascular cells express markers of stress-induced senescence (e.g., p16INK4, p21, SA-β-gal) and produce SASP factors that recruit immune cells and modulate fibroblast behavior [111].

In the early post-MI period, senescence may be adaptive: by restraining excessive fibroblast proliferation, it limits fibrosis, and SASP-derived growth factors (e.g., from the Vascular Endothelial Growth Factor [VEGF] family) may transiently support angiogenesis in the border zone, improving perfusion of salvaged myocardium [111]. However, mounting evidence highlights the darker side of persistent post-MI senescence: long-lived senescent fibroblasts and endothelial cells maintain a pro-inflammatory, matrix-degrading SASP (e.g., IL-1β, TNF-α, MCP-1, MMPs) that sustains maladaptive remodeling—chamber dilation, scar thinning, and progressive contractile dysfunction [107,111]. Senescent cardiomyocytes show mitochondrial dysfunction, disrupted calcium regulation, and reduced contractility; their presence correlates with impaired functional recovery and development of heart failure phenotypes [107,111].

Animal studies demonstrate that pathological persistence of senescent cells in the heart is associated with worse outcomes after ischemic injury, although it remains unclear which cell populations contribute most to these deleterious effects [108]. In preclinical MI models, senolytic approaches have been tested: pharmacologic elimination of senescent cells (e.g., B-Cell Lymphoma 2 (BCL-2) inhibitors such as navitoclax, or dasatinib + quercetin combinations) reduced inflammation and fibrosis and improved cardiac function when administered after the reparative phase. Yet, the timing of drug administration is critical, and adverse effects (e.g., thrombocytopenia with navitoclax) complicate clinical translation [109]. Some studies report mixed or even harmful effects of senolytics when applied without temporal control, emphasizing the need for deeper mechanistic clarity before human trials in post-MI settings [108,109,110].

When properly induced and cleared, senescent cells perform protective and regenerative roles in the cardiovascular system. Key mechanisms include: (1) restricting excessive proliferation of damaged cells (tumor suppressive/antifibrotic checkpoint), (2) secreting SASP factors that support repair, coordinate immune recruitment, and remodel ECM, and (3) transiently enhancing angiogenesis via paracrine secretion of VEGF and related factors by senescent endothelial or perivascular cells. In the context of acute ischemia or mechanical injury, these functions support formation of structurally competent scar tissue and limit maladaptive hypertrophy [108,117].

Additionally, SASP components can actively polarize infiltrating immune cells toward pro-resolving phenotypes (e.g., M2 macrophages) and secrete mediators that dampen excessive inflammation at later phases. An emerging view portrays transient senescence as a biological “brake”, coordinating arrest of proliferation and the shift from inflammatory clearance to reparative remodeling. This suggests that wholesale elimination of senescence signals may be detrimental in acute cardiovascular injury unless alternative repair pathways are secured [117,118].

Chronic accumulation of senescent cells in the vasculature and myocardium is a major contributor to age-related cardiovascular pathology. In vessels, senescent endothelial cells exhibit impaired NO production, increased expression of adhesion molecules and procoagulant factors, and a SASP that promotes leukocyte recruitment and local inflammation—early events in atherogenesis and arterial stiffening [119,120]. Senescent vascular smooth muscle cells lose contractile phenotype markers and secrete ECM-remodeling enzymes, destabilizing atherosclerotic plaques and increasing rupture risk [119,120].

In addition to plaque destabilization, senescent VSMCs actively contribute to medial vascular calcification (MVC), a key determinant of arterial stiffness. Senescence is associated with phenotypic switching of VSMCs from a contractile to an osteogenic-like state, driven in part by senescence-associated inflammatory and osteoinductive signaling, and characterized by upregulation of bone-related transcription factors and deposition of calcium–phosphate minerals, primarily hydroxyapatite, within the tunica media. Progressive mineral accumulation disrupts the organization and mechanical properties of elastin and collagen fibers, leading to loss of arterial compliance.

Increased arterial stiffness elevates systolic blood pressure and cardiac afterload, thereby promoting hypertension and exacerbating conditions such as heart failure, particularly heart failure with preserved ejection fraction. Moreover, stiffened arteries impair normal pulsatile hemodynamics and limit the buffering capacity of large vessels, further increasing peripheral vascular resistance. Mechanistically, calcification-associated damage to the elastic lamina compromises the ability of the vessel wall to accommodate cyclic strain, ultimately contributing to global vascular dysfunction and age-related cardiovascular disease progression [112].

In the cardiac muscle, prolonged SASP induces paracrine deterioration: persistent inflammatory cytokines and MMPs degrade ECM, favor fibrotic replacement, and impair mechanical coupling. Mitochondrial dysfunction and elevated ROS in senescent cardiomyocytes exacerbate energetic deficits, disrupt calcium cycling, and drive further senescence in a vicious feedback loop [113,120].

Importantly, the ability of the immune system to clear senescent cells declines with age (immunosenescence), permitting their numerical and functional expansion. This correlates with hypertension, heart failure with preserved ejection fraction (HFpEF), and worse outcomes after ischemic episodes [113,120]. Epidemiologic and experimental evidence link senescent cell burden both to disease initiation (e.g., atherosclerosis) and progression (e.g., chronic heart failure), making senescence a tempting but complex therapeutic target [113].

Maintaining the balance between beneficial and harmful effects of senescence requires tight spatiotemporal control over its induction, SASP composition, and immune-mediated clearance. Multiple regulatory layers contribute to this equilibrium: external triggers (DNA damage, telomere shortening, oxidative stress), intracellular effectors (p53–p21 and p16–Rb axes), and extracellular modulators (immune cells and local niche factors that decide whether to amplify or resolve SASP). Crucially, distinct senescence programs may yield different SASP profiles—implying that not all senescent cells are functionally equivalent. This heterogeneity opens the possibility for selective modulation (senomorphic strategies) that suppress harmful SASP elements while preserving reparative signals [114,118].

Atherosclerosis, which leads to conditions such as ischemic heart disease (IHD), peripheral artery disease (PAD), or ischemic stroke [115], is the major cause of death globally [116]. The disease is a result of inflammation and lipid build-up, leading to narrowing of the arterial lumen [121]. Pathophysiology of atherosclerosis involves numerous mechanisms and is continuously researched [122]. Considering that the disease is strongly age-related, cellular senescence is one of the factors contributing to its development [123]. Multiple ways in which cellular senescence contributes to atherosclerosis have been identified. One of them, stemming from the accumulation of senescent cells, is called “inflammaging”, which manifests as constant low-grade inflammation [124]. The pro-inflammatory SASP associated with cellular senescence is responsible for generating pro-inflammatory particles, including interleukins (such as Interleukin-1 alpha [IL-1α], IL-1β, IL-6, IL-8, Interleukin-18 [IL-18], C-C motif chemokine ligand 2 [CCL-2]), metalloproteinases, and TNF-α, leading to persistent inflammation linked to atherogenesis [125]. Another senescence–related contributor to atherosclerosis is foam macrophages. A study by Childs et al. has shown that the senescent intimal foam cells affect not only plaque formation, but also maturation and contribute to the plaque’s instability. Moreover, in the research expression of proatherogenic factors such as MMP3, MMP12, matrix metalloproteinase 3 (MMP13), MCP1, Vascular Cell Adhesion Molecule 1 (VCAM1), and mentioned earlier IL1-α and TNF-α have been found on senescent cells [126]. In addition, the senescence of endothelial cells, immune cells, and vascular smooth muscle cells significantly affects the pathogenesis of atherosclerosis [127].

Hypertension, which significantly contributes to premature mortality worldwide [128], is an age-related disease [129]. Age-related changes in vessels that contribute to high blood pressure include hypercontractility, remodelling, stiffening, and inflammation. Moreover, cellular senescence is a common finding in patients affected by hypertension [130]. Senescence of endothelial cells leads to endothelial dysfunction, closely related to the development of hypertension [131]. In rats, the detrimental effects of endothelial cells’ senescence were prevented by targeting mitochondria with the antioxidant MitoQ. MitoQ administration was shown to reduce systolic blood pressure highlighting the role of ROS production in hypertension [132]. In a 2023 study, Clayton et al. demonstrated that cellular senescence is a mediator in endothelial dysfunction, and senolytic therapy shows a restorative effect. In addition, the study links senescence to alterations in aortic wall stiffness as well as collagen deposition, elastin degradation, and enhanced presence of AGEs (advanced glycation end products) [133]. Aortic stiffness has been linked to a higher risk of hypertension [134].

Another senescence-related contributors to hypertension include eNOS dysfunction, vascular redox imbalance, and increased levels of ROS [135]. Research by Long et al. revealed that a decrease in expression of the natriuretic peptide receptor A (NPRA) gene is associated with endothelial senescence and hypertension. Age-related down-regulation of NPRA leads to disruption in ANP-mediated signaling-NPRA/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) axis, which is crucial to maintain blood pressure [136]. It is also worth noting that cellular senescence is not only the cause of hypertension, but might result from it [137].

Senescent cells, such as endothelial cells, VSMCs, cardiac progenitor cells (CPCs), cardiomyocytes, myofibroblasts, and immune cells, are involved in the development of chronic heart failure [138]. Cardiac progenitor cells have the ability to differentiate into vascular cells or myocytes in case of heart damage [139]. In 2019, Lewis-McDougall et al. demonstrated on a mouse model that senescent CPCs have impaired differentiation, growth ability, and regeneration capacity [140], which influences fibrotic remodeling and myocardial hypertrophy, contributing to chronic heart failure [138]. Moreover, these cells present SASP [140]. In a study by Bian et al., high expression of CDKN1A, heat shock protein family A member 1B (HSPA1B) in senescent cardiomyocytes was strongly associated with increased risk of heart failure. CDKN1A is speculated to modulate numerous mechanisms leading to heart failure [141]. The results of another study, conducted on mice, indicate that senescent cardiomyocytes induce myocardial remodeling after a heart attack, contributing to the development of heart failure. As aforementioned, excessive mitochondrial ROS production seen in heart failure further promotes premature senescence through DNA-damage in the genome or the telomeres [142]. Indeed, transplantation of exogenous mitochondria derived from mesenchymal stem cells was shown to alleviate MI-induced endothelial senescence further highlighting the role of mitochondrial dysfunction in the process [143]. Another mitochondrial process driving myocardial remodeling is the accumulation of toxic byproducts. Spreading senescence to other kinds of cells, as an earlier proposed mechanism leading to remodeling, has also been confirmed [142]. Similarly, remodeling in the heart was shown to further disrupt the functioning of cardiac mitochondria [144]. The role of SASP in fibrosis and scar formation has been highlighted as well [108].

Inflammaging, a state of chronic low-grade inflammation with high levels of pro-inflammatory particles, predisposes to cardiovascular diseases and might be an underlying mechanism in the pathology of those diseases as well [145]. There are several mechanisms of inflammaging involved in the pathogenesis of cardiovascular diseases. One of them is the replacement of C-C chemokine receptor type 2 (CCR2-) macrophages, which participate in reducing inflammation following myocardial damage, with pro-inflammatory CCR2+ macrophages. This process may cause constant inflammation in the myocardial tissue [146]. Another mechanism is mitochondrial dysfunction, which leads to the accumulation of ROS, causing oxidative stress in the vascular endothelium. Aging enhances this phenomenon via the sirtuin 2-mitochondria-oxidative damage axis [147]. This results in dysfunction of the endothelium, which contributes to the initiation and progression of atherosclerosis [148]. Moreover, inflammation has a crucial influence on the pathogenesis of acute and chronic heart failure due to, inter alia, an increase in oxidative stress, cardiac remodeling, and inflammatory response in other organs, which also affects the heart [149].

Senotherapeutics are small-molecule interventions designed to counteract the adverse effects of cellular senescence. They work by either eliminating senescent cells or modulating their pathological activity. These strategies can be divided into two principal groups: senolytics, which selectively induce apoptosis in senescent cells, and senomorphics, which suppress the pro-inflammatory SASP to reduce tissue damage. Together, these approaches aim to restore cellular balance and delay age-related degeneration.

While aging typically impairs the body’s ability to clear senescent cells, senotherapeutic agents can enhance immune-mediated removal mechanisms to mitigate tissue dysfunction. Senolytics are designed to selectively trigger cell death pathways in senescent cells by targeting antiapoptotic and survival mechanisms such as those mediated by p53 and p21. By reducing the overall “burden” of these cells, senolytics help restore tissue health and may even reverse signs of aging. Many senolytic compounds are repurposed chemotherapeutic agents administered in lower, intermittent doses—examples include dasatinib and navitoclax. Experimental studies have demonstrated that senolytic treatment decreases the number of naturally occurring senescent human cells in vitro, while in aged animal models, it improves physical performance and extends lifespan.

In contrast, senomorphics do not kill the senescent cells but instead modify their behavior to lessen their detrimental systemic impact. These compounds downregulate components of the SASP and act through molecular targets such as Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF–κB), Mechanistic Target of Rapamycin (mTOR), and interleukin-1α. Representative senomorphic agents include rapamycin, everolimus, apigenin, and metformin [172,173].

Cardiovascular aging is driven by cellular senescence (CS)—a state where cells permanently stop dividing but remain metabolically active. This arrest is triggered by various stressors, including oxidative stress, DNA damage, and mitochondrial dysfunction. Senescent cardiovascular cells, such as endothelial, smooth muscle, fibroblast, cardiomyocyte, and immune cells, accumulate in vascular and myocardial tissues. Their presence contributes to the development and progression of cardiovascular diseases like atherosclerosis, valvular disease, arrhythmias, and cardiomyopathies [174]. In cardiovascular diseases, the accumulation of senescent cells (SCs) and their secretome, particularly the SASP, exacerbates existing pathological conditions. SASP exerts potent paracrine and autocrine activities on SCs, displaying both beneficial and harmful effects depending on the cellular context. It is, at least partially, responsible for reshaping the microenvironment of aging tissues, contributing to their structural and functional deterioration and to the process of inflamm-ageing. In the extracellular environment, specific SASP components alter the ECM, leading to dysfunctions typical of senescent cells. These alterations include the upregulation of metalloproteases, which promote matrix degradation, and modifications in the expression of ECM components such as collagen, fibronectin, and proteoglycans. Inflamm-ageing plays a central role in age-related diseases (ARDs), including cardiovascular disturbances. As aging progresses, the combination of inflamm-ageing and immunosenescence establishes an immunosuppressive environment that hinders the effective inflammatory response in older individuals. The persistent activity of SASP further amplifies chronic inflammation, thereby aggravating the impact of cellular senescence on the onset and progression of cardiovascular pathologies.

Senotherapeutic strategies—specifically senolytic agents that target senescent cells and reduce SASP levels—have shown significant benefits. Research indicates that senolytics improve health in conditions like diabetes and cardiovascular disorders, highlighting their potential to reduce the harmful effects of cellular senescence in the heart and vessels [175]. Evidence shows that senescent cells accumulate in aging hearts and within atherosclerotic vascular lesions. Virtually all cardiac cell types—including cardiomyocytes, endothelial cells, fibroblasts, progenitor cells, and immune cells—can undergo senescence during aging or under cardiovascular stress. In cardiomyocytes, which are terminally differentiated, senescence may develop in response to inflammation, oxidative damage, or ischemia–reperfusion injury, resulting in increased expression of Cyclin-dependent kinase inhibitor 1A (p21Cip1), p16Ink4a, and SASP factors that promote fibrosis and hypertrophy. Similarly, endothelial and smooth muscle cells in aged vessels exhibit “senescent features”, such as cell-cycle arrest and a drop in nitric oxide signaling. Inside atherosclerotic plaques, these senescent cells amplify inflammation through SASP signaling, which makes the plaques more likely to rupture. By targeting these specific cells, senotherapeutics could reduce vascular inflammation and slow the progression of atherosclerosis [110,175,176].

Experimental and genetic studies indicate that removing senescent cells can improve cardiac function, reduce fibrosis, and limit atherosclerotic progression in various animal models. Senolytic drugs such as dasatinib, quercetin, and navitoclax have shown beneficial effects on myocardial remodeling, vascular function, and overall survival. However, emerging evidence also reveals potential adverse outcomes. In certain conditions, these treatments may impair tissue repair, destabilize atherosclerotic plaques, or even increase mortality. These observations highlight the need for careful evaluation of senotherapeutic interventions in cardiovascular disease, as their efficacy and safety likely depend on disease stage, senescent cell type, and treatment context [110].

The cardiac glycoside digoxin has recently gained attention for its potential senolytic activity. Traditionally used to treat heart failure and atrial fibrillation, digoxin has been shown to selectively eliminate senescent human cells without harming healthy ones. Furthermore, subsequent studies confirmed its senolytic action across various human cell types through shared survival pathways [177]. An ongoing clinical trial (NCT06240403) is evaluating its effects on adipose tissue homeostasis and endothelial function in patients with heart failure and type 2 diabetes, underscoring its translational potential in cardiovascular aging. Altogether, the convergence of its classical cardiotonic role with emerging senolytic properties positions digoxin as a promising bridge between traditional cardiovascular therapy and geroscience [177].

Among the most extensively investigated senolytic strategies is the combination of dasatinib (D) and quercetin (Q). These two compounds work synergistically to eliminate senescent cells. Dasatinib, a tyrosine-kinase inhibitor used in leukemia therapy, induces apoptosis through inhibition of survival pathways such as Phosphoinositide 3-Kinase (PI3K)/Akt, Janus kinase (JAK)/signal transducer and activator of transcription (STAT), and Mitogen-Activated Protein Kinase (MAPK)/extracellular signal-regulated kinase (ERK). While high doses can cause cardiotoxicity by disrupting mitochondrial function, lower and intermittent doses are effective as a senolytic.

Quercetin is a plant-derived flavonol with antioxidant and anti-inflammatory properties. It works primarily by inhibiting PI3K and modulating signaling through NF-κB, AMPK, and Nuclear factor erythroid 2–related factor 2 (Nrf2). The D + Q combination targets multiple pro-survival networks, thereby reducing senescent-cell burden and improving tissue homeostasis in both aged and disease models.

Preclinical findings show that intermittent D + Q treatment in aged mice restores cardiac function, reduces fibrosis, and increases progenitor-cell activity. In diabetic models, the treatment decreases the release of the SASP, prevents cardiomyocyte senescence, and improves heart structure. Moreover, studies in female mice after myocardial infarction showed improved repair and renewed cardiomyogenic potential following D + Q exposure. Collectively, preclinical findings support the D + Q combination as one of the most promising and widely investigated senolytic interventions with demonstrable benefits for age- and diabetes-related cardiovascular dysfunction [178].

Another notable senolytic agent is navitoclax (ABT-263)—a small-molecule inhibitor that targets the BCL-2 family of pro-survival proteins, specifically BCL-2, BCL-xL, and BCL-w. It acts as a senolytic in certain cell types, effectively reducing the viability of senescent endothelial, lung fibroblast, and murine embryonic fibroblast cells, while sparing non-senescent cells such as preadipocytes. This selectivity reflects cell-type-specific dependence on BCL-2 family proteins, similar to the way cancers respond to navitoclax. Overall, navitoclax eliminates senescent cells by disrupting their survival pathways, thereby extending the catalog of senolytic agents first identified through the dasatinib-quercetin discovery approach [179]. In cardiovascular models, navitoclax has shown significant efficacy. In aged mice or those recovering from a heart attack, it targets senescent cardiomyocytes, reduces the expression of fibrotic proteins, and improves heart structure and diastolic function. When administered after oxygen deprivation (ischemia–reperfusion injury), it limits tissue damage, decreases scar formation, and enhances overall heart performance. In addition, navitoclax has demonstrated potential in limiting vascular restenosis following stent implantation by suppressing excessive smooth-muscle proliferation. Consistently, in atherosclerotic mouse models, navitoclax reduced lesion size and plaque instability markers, suggesting benefits that may extend beyond direct senolytic activity. Although these findings highlight its therapeutic promise in cardiovascular aging and injury, the exact cellular targets and mechanisms underlying its senolytic effects remain to be fully elucidated. This lack of mechanistic specificity contributes to significant hurdles in clinical translation; most notably, navitoclax is hindered by off-target toxicities such as dose-limiting thrombocytopenia, which necessitates careful monitoring and intermittent dosing strategies [180].

Among naturally derived compounds, fisetin—a flavonoid found in plants, fruits, and vegetables—has recently attracted attention as a senotherapeutic agent for treating age-related chronic diseases. It targets senescent cells that accumulate with aging and disease, which contribute to chronic inflammation and tissue dysfunction through their SASP [181]. Experimental evidence indicates that fisetin confers cardioprotective effects by reducing myocardial infarction–induced injury, lowering IL-6 and TNF-α levels, and improving left ventricular function in animal models. Moreover, it can modulate key signaling pathways, including suppression of receptor for advanced glycation end products (RAGE)/NF-κB activation and enhancement of the insulin-like growth factor 1 receptor (IGF-1R)/PI3K/Akt survival cascade, supporting its potential role in protecting cardiac tissue from ischemic damage [182]. Similarly, the second natural senolytic, curcumin, is a polyphenolic compound derived from turmeric that exhibits significant anti-inflammatory and antioxidant effects. It has been shown to inhibit NF-κB signaling and suppress SASP expression, thereby reducing vascular inflammation, endothelial dysfunction, and smooth-muscle cell proliferation associated with cardiovascular aging [182].

In recent years, researchers have identified pharmacological approaches capable of modulating vascular aging, with SGLT2 inhibitors gaining particular attention. These compounds have been reported to reduce the burden of senescent cells and systemic inflammation, exhibiting senomorphic activity that may confer protective effects in age-associated cardiovascular conditions. Consequently, SGLT2 inhibitors are being explored as potential senotherapeutic agents relevant to both diabetic and non-diabetic cardiovascular disease [183].

Given that the accumulation of senescent cells in the heart and vasculature contributes to structural and functional deterioration with age. Experimental studies show that clearing these cells, either genetically or pharmacologically, improves cardiac performance and reduces fibrosis. SGLT2 inhibitors have emerged as a promising tool in this area due to their ability to restore calcium balance and improve both mitochondrial and endothelial function. In preclinical models, these agents alleviated cardiac remodeling, atherosclerosis progression, and arterial stiffening, suggesting protective effects against cardiovascular aging. Moreover, their use has shown benefits in counteracting drug-induced cardiotoxicity and hypertension-related vascular dysfunction. While several mechanisms have been proposed—including the modulation of oxidative stress, autophagy, and STAT3 signaling—the exact pathways are still being defined. Taken together, SGLT2 inhibitors represent a promising class of pharmacological senotherapeutics with potential to ameliorate both metabolic and age-related cardiovascular decline [183]. While these agents are well-tolerated, their long-term use as senotherapeutics requires further investigation to ensure that chronic modulation of cellular pathways does not interfere with physiological stress responses or tissue regeneration.

Beyond SGLT2 inhibitors, several other agents—including resveratrol, rapamycin, and metformin—have shown promise in slowing cardiovascular decline. These compounds work through senomorphic mechanisms that suppress the SASP and restore tissue balance. For example, resveratrol reduces oxidative stress through its antioxidant and anti-inflammatory effects, while rapamycin blocks the Akt–mTOR pathway to decrease inflammation in heart muscle cells. Likewise, metformin activates AMPK, improving endothelial function and inhibiting profibrotic signaling. Together, these agents represent complementary strategies aimed at suppressing the SASP and restoring cardiovascular homeostasis [184].

Metformin, traditionally used for diabetes, is a cornerstone of senomorphic research. It counteracts cardiovascular aging by reducing vascular inflammation, oxidative stress, and endothelial dysfunction. Through AMPK activation and suppression of SASP-related signaling, it enhances mitochondrial efficiency and improves vascular smooth muscle cell function, thereby supporting cardiovascular protection and longevity. Although not possessing direct senolytic properties, metformin effectively suppresses cellular senescence and SASP activity across tissues affected by age-related cardiovascular deterioration. Its pharmacokinetic behavior depends on multiple organic cation transporters that regulate its intestinal absorption, tissue distribution, and renal elimination, influencing its availability and overall therapeutic activity within cardiovascular tissues. Among different pharmacologic interventions, metformin exerts broad anti-senescence effects within the cardiovascular system. It is done by ameliorating VSMC senescence, restoring autophagic flux, and preserving endothelial and mitochondrial function. Through activation of AMPK and upregulation of sirtuin 3 (SIRT3), metformin enhances mitochondrial biogenesis and energy balance, reduces oxidative stress, and delays vascular aging. Moreover, it suppresses VSMC proliferation, inflammation, and calcification, thereby attenuating atherosclerotic plaque formation and promoting vascular homeostasis. In this manner, metformin acts through both AMPK-dependent and AMPK-independent pathways to inhibit fibrotic remodeling, improve contractile efficiency, and maintain cardiometabolic resilience during aging [185].

Resveratrol is a natural phenolic compound found in plants such as grapes, peanuts, and Veratrum grandiflorum, known for its potent antioxidant and anti-inflammatory properties. It acts primarily as an activator of SIRT1, a key anti-aging regulator involved in DNA repair and cellular stress responses, and exerts anti-inflammatory effects through inhibition of NF-κB signaling. In cardiovascular research, resveratrol has been shown to protect endothelial and myocardial cells, reduce oxidative stress, and suppress SASP-related cytokines such as TNF-α and IL-1β. Clinical studies in post-infarction and cardiovascular patients suggest that short-term resveratrol supplementation can improve endothelial function and reduce inflammatory markers. While resveratrol shows promise, its therapeutic efficacy remains limited by poor systemic bioavailability and rapid metabolism; these factors contribute to the inconsistent outcomes observed in small-scale human trials and currently prevent definitive conclusions regarding its clinical use in cardiovascular disease [182,186].

In parallel with resveratrol’s effects, rapamycin is another well-characterized senomorphic agent with documented anti-aging and cardiovascular protective actions. As a potent mTOR inhibitor, numerous studies have demonstrated that rapamycin reduces cellular senescence and inhibits the secretion of SASP markers across various cell lines, thereby extending lifespan. Its derivatives, collectively known as rapalogs (including rapamycin, everolimus, and tacrolimus), are widely used in cardiovascular medicine as components of drug-eluting stents, where they prevent in-stent restenosis through local anti-proliferative and immunosuppressive effects mediated by mTOR inhibition. Within senescent cells, mTOR blockade mitigates NF-κB signaling and downregulates IL-1A expression, reducing inflammatory activity. Experimental models have shown that systemic rapamycin therapy ameliorates cardiac hypertrophy and stiffness and improves longevity in aged mice. Nevertheless, despite these promising effects, broader cardiovascular application remains constrained by its potential immunosuppressive and hyperlipidemic side effects [182,186].

Altogether, senotherapeutic interventions represent a rapidly evolving field. However, translating these findings to human clinical practice requires overcoming significant challenges, including low bioavailability, off-target toxicities, and the need for long-term safety data to ensure that therapeutic benefits outweigh the risks of systemic intervention.

The clinical translation of senotherapeutics—encompassing both senolytic and senomorphic agents—is currently constrained by several complex biological and pharmacological barriers. While preclinical evidence suggests significant potential for mitigating age-related pathologies, the transition to human application requires a nuanced understanding of the risks associated with the systemic modulation of senescence. These hurdles are particularly pronounced in the context of CVD, where patients often present with multi-morbidity and complex polypharmacy.

Accurate detection of cellular senescence in the cardiovascular system requires marker panels, not single assays. In practice, three domains should be profiled together: durable cell-cycle arrest (p16INK4a, p21Cip1), the DDR (e.g., γH2AX with Tumor suppressor p53-binding protein 1 (53BP1)/, Ataxia Telangiectasia Mutated (ATM)/, Checkpoint Kinase 2 (CHK2), and the pro-inflammatory SASP. It is advisable to use at least two independent markers plus one functional readout, and to include explicit negatives for proliferation (e.g., kiel-67 antigen Ki-67, 5-ethynyl-2′-deoxyuridine (EdU)) to avoid false positives in mixed tissues [190,191,192]. Because acute stress can raise p21 without stable arrest, time-course sampling and co-staining with proliferation indices can be helpful. In vessels, TAF supports persistent DDR typical of senescent EC and VSMC; reporting counting criteria and image-acquisition settings is recommended for reproducibility [191,193]. The senescence-associated β-galactosidase (SA-β-gal; pH 6.0) is supportive but non-specific and is generally not used alone. Given that SASP factors can arise from immune activation, it is helpful to specify cell-identity markers and pre-analytics (processing delay, storage) to limit confounding. A concise reporting checklist—assays, controls, thresholds for positivity, and planned analyses—improves comparability across cohorts [191].

Blood-based readouts enable repeated, minimally invasive assessment of organism-level senescence burden. Three complementary classes dominate: leukocyte telomere length (LTL), extracellular vesicles (EVs), and circulating microRNAs (miRNAs). Shorter LTL associates with higher cardiovascular risk; translation requires harmonized assays (qPCR vs. Southern), control for leukocyte subsets, and use of internal calibrators when pooling data [194,195]. For EVs, diagnostic value improves when origin and cargo are characterized together under Minimal Information for Studies of Extracellular Vesicles 2023 (MISEV2023) guidance [196] with transparent reporting of quantification methods (e.g., nanoparticle tracking, small-particle flow cytometry), EV markers (tetraspanins cluster of differentiation 9/63/81, CD9/CD63/CD81), and controls for co-isolates (apolipoprotein A1 [ApoA1], albumin). Pre-analytics (anticoagulant, processing delay, freeze–thaw cycles) markedly affect EV particle counts and size distributions; it is advisable to include size-reference beads and swarm-detection checks to prevent event overestimation, and authors should state the thresholds and maximum event rates used during acquisition [196,197]. miRNA panels can aid risk stratification and treatment monitoring if normalization is explicit and hemolysis is controlled (e.g., microRNA-451/microRNA-23a ratio), noting that platform choice (qPCR panels vs. small-RNA sequencing) shifts detectability and fold-change estimates [198]. Panels combining LTL + EV features + miRNA dynamics may outperform single markers, but will require validation in external cohorts with prespecified minimal clinically important differences (MCIDs) and quality-control failure criteria to reduce analytic flexibility [176,194,196]. Integrating circulating readouts into interventional studies (exercise, diet, senotherapeutics) strengthens the mechanism from biomarker to outcome chain [199].