Cancer therapy-related cardiovascular aging: mechanisms, monitoring, and intervention strategies

Abstract

Significant improvements in cancer survival rates have been achieved through advancements in treatment and early diagnosis. However, non-cancer-related mortality among cancer survivors continues to rise each year. Cardiovascular diseases (CVDs) related to cancer therapy now rank as the second leading cause of death in survivors, sometimes surpassing the cancer itself. Among these, cardiovascular aging represents one of the most severe side effects, often leading to detrimental structural changes such as cardiac atrophy or fibrosis, which ultimately impair cardiac function and reduce survival. Preventing or treating cardiovascular aging has emerged as a promising strategy to mitigate Cancer Therapy-Related Cardiovascular Toxicity (CTR-CVT). This review offers a comprehensive analysis of the characteristics and mechanisms underlying cancer therapy-induced accelerated cardiovascular cellular senescence, outlines current monitoring and intervention strategies, and explores future research opportunities and challenges. Enhancing the understanding of Cancer Therapy-Related Cardiovascular Cellular Senescence and Cancer Therapy-Related Cardiovascular Aging (CTR-CVA) is crucial for optimizing cancer treatment, advancing medical research, and improving clinical practice, all of which are vital for preserving cardiac health and improving the quality of life of patients with cancers.

1 Introduction

Advancements in treatment modalities and early precision diagnosis have significantly improved the survival rates of patients with cancers. According to the Cancer Research Institute, the number of cancer survivors in the United States grew from 18 million in 2022 to nearly 26 million by 2024 (1). Despite these gains, long-term survivors face the challenge of cancer treatment-related diseases, particularly cardiovascular diseases (CVDs). Cancer Therapy-Related Cardiovascular Toxicity (CTR-CVT), referring to a series of acute and chronic cardiovascular system injuries occurring after cancer treatment, has now emerged as the second leading cause of long-term morbidity and mortality among cancer survivors (2). Childhood cancer survivors (CCS) underwent chest radiotherapy are at a 10.6-fold increased risk of myocardial infarction and congestive heart failure later in life compared to their siblings (3). Consequently, exploration of the long-term underlying pathophysiological mechanisms, early prediction, diagnosis, and treatment of CTR-CVT remain key research priorities in the field of CTR-CVT (4). The establishment Cardio-Oncology marked the inception of this specialized discipline (5). Recent research has highlighted cellular senescence as a critical driver of Cancer Therapy-Related Cardiovascular Diseases (CTR-CVD). Senescent cardiovascular cells contribute to the remodeling of the extracellular matrix (ECM), disrupting normal cellular function and development, thereby increasing disease susceptibility (6, 7). This, in turn, elevates the risk of major adverse cardiovascular events (MACE) in the patients with cancers (7).

Aging is a process in which the overall functions of an organism gradually decline over time. As a key intrinsic driving mechanism underlying macroscopic aging, cellular senescence leads to the functional decline of tissues and organs and promotes the continuous progression of the aging process by inducing cell cycle arrest and senescence-associated metabolic changes. Cardiovascular aging is a physiological or pathological process characterized by structural degradation and functional decline of the cardiovascular system, with cellular senescence as its fundamental cytological basis, occurring under the influence of aging or pathological factors. With the continuous expansion and in-depth development of relevant research, the academic view that the arrest of the cellular senescence cycle is irreversible is gradually being questioned and revised (8–10), opening up a breakthrough for the intervention in cell senescence-related diseases. In recent years, the American Institute for Cancer Research has begun to pay attention to the potential value of eliminating senescent cells, including those in normal tissues (11). Previous articles have put forward the concept of the Aging-Cancer Cycle, suggesting that there is a two-way relationship between cancer treatment and aging (12). In 2024, articles in the JACC series proposed the existence of cardiovascular aging under tumor treatment (13). This type of cardiovascular aging, caused by the continuous accumulation of senescent cells in the cardiovascular system induced by cancer therapy, can be defined as Cancer Therapy-Related Cardiovascular Aging (CTR-CVA). It represents the long-term progression of acute or subacute injuries in CTR-CVT, as well as a branching manifestation of chronic injuries in CTR-CVT (Figure 1).

Figure 1

This review focuses on exploring the mechanisms of CTR-CVA, advancements in detecting and monitoring cardiovascular aging, and potential directions for future research. This article updates the existing reviews in this field, with a focus on the advanced imaging techniques currently used for identifying senescent cells and the popular therapeutic approaches. Strengthening interdisciplinary collaboration across Cardio-Oncology, materials science, molecular imaging, and artificial intelligence is crucial to support early diagnosis and intervention for CTR-CVT. In particular, effective treatments for cellular senescence could significantly improve the quality of life for cancer survivors (Figure 2).

Figure 2

2 Cancer therapy-related cardiovascular disease and cardiovascular aging

With the evolution of Cardio-Oncology, there is a growing understanding of the complexities surrounding CTR-CVD, leading to the development of comprehensive strategies for their diagnosis, prevention, therapy, and management (14). CTR-CVD encompasses a broad spectrum of diseases, including heart failure, arrhythmia, coronary artery disease (CAD), pericardial diseases, and valvular disorders (15, 16). Several factors influence the incidence of CTR-CVD: (i) Treatment modalities: patients treated with anthracyclines often experience severe cardiac adverse events, while liposomal doxorubicin (DOX) treatment tends to have fewer cardiac complications (17–19). (ii) Therapy-related drug accumulation and dosage cycles (20, 21): High-dose DOX is primarily associated with acute declines in cardiac function or an increased incidence of arrhythmias. In contrast, low-dose DOX is linked to long-term, atypical cardiac symptoms or cardiovascular dysfunction (22). The risk of heart failure increases with cumulative DOX dosage, with incidences of 5%, 26%, and 48% when the cumulative dose reaches 400 mg/m², 550 mg/m², and 700 mg/m², respectively, with most cases manifesting within the first year of treatment (23). This study supplied the evidence that the cumulative DOX dose should not exceed 500–550 mg/m² in clinical trials (20, 21). (iii) Early and delayed side effects: The onset and pattern of CTR-CVD symptoms varied according to the cancer treatment. Radiation-induced pericarditis typically occurs shortly after exposure, while other radiation-related heart diseases often emerge 10–15 years later (24). (iv) Individual differences: Even under the same therapeutic regimen, individuals may experience distinct manifestations. Elderly patients, particularly those undergoing combination therapies, are more prone to aging-related phenomena such as palpitations, fatigue, and elevated serum biomarkers indicative of injury (7). Epidemiological studies have shown that childhood cancer survivors experience a significantly higher incidence of severe cardiovascular adverse events compared to their siblings (25). Imaging and pathological assessments of these survivors reveal alterations in cardiovascular structure and function, including ventricular remodeling, myocardial fibrosis, and valvular calcification (26).

Cellular senescence is a key factor in the onset, progression, and outcomes of various diseases, influencing the entire pathophysiological process (27). Various cancer treatments can induce celluar senescence in healthy, non-cancerous cells. The accumulation of senescent cells plays a central role in driving premature tissue aging. In CTR-CVD, the importance of cardiovascular aging is increasingly recognized by researchers. Cardiovascular aging and cellular senescence can be detected in the peripheral blood (28), cardiac electrophysiology (29), or tissue specimens (30) of patients with cancers long after treatment (Table 1). Similar to natural aging, CTR-CVA can trigger tissue remodeling phenomena such as vascular wall thickening and cardiac fibrosis, accompanied by functional deterioration manifestations such as increased arterial stiffness and decreased cardiac diastolic function. Although some pathological features and changes in clinical indicators are similar to those of natural cardiovascular aging, CTR-CVA is often more severe. The essential difference between the two is that natural aging is a slow and progressive process that follows biological laws, while cancer treatments such as radiotherapy and chemotherapy can activate cellular senescence and related signaling pathways earlier through exogenous stimulation, thereby accelerating the process of cardiovascular aging. Therefore, Cardiovascular cellular senescence has become a key link in the pathogenesis of CTR-CVD (31), a comprehensive understanding of its mechanisms is essential for the prevention and treatment of CTR-CVT.

3 Mechanisms of cancer therapy-related cardiovascular aging

Cellular senescence is the key underlying mechanism of tissue aging. Cellular senescence is characterized by a permanent proliferation arrest in response to both endogenous and exogenous stress or damage, triggering a range of intracellular phenotypic changes (37–39). The hallmarks of cellular senescence include cell cycle arrest, activation of the DNA damage response (DDR), nuclear alterations, upregulation of anti-apoptotic factors, the senescence-associated secretory phenotype (SASP), metabolic adaptation, morphological changes, increased lysosomal content, and the expression of specific cell surface markers (31, 39). Recent studies have also identified the accumulation of immunoglobulins as an important marker of senescence (40). Under prolonged stress or disease conditions, the continuous accumulation of senescent cells will lead to a decline in essential repair functions and immune clearance capabilities, alterations in intercellular communication, changes in the extracellular matrix (41), chronic inflammation, and so on. This will continuously accelerate the accumulation of cellular senescence and form a negative feedback loop, further exacerbating tissue aging. Baker et al. developed an “Inducible and Regulatable Targeted Apoptosis of Senescent Cells (INK-ATTAC)” system using transgenic technology, which targets cells expressing p16^INK4a (42). This technique allowed for the anatomical localization of senescent cells in the kidneys of aged mice and demonstrated significant efficacy in their targeted clearance. By eliminating senescent cardiac cells with AP20187, cardiomyocyte hypertrophy in aged mice was alleviated without compromising heart function (42). These findings provided valuable insight into the link between cellular senescence and cardiac aging. Similar studies lay the theoretical groundwork for the targeted clearance of senescent cells as a strategy to mitigate CTR-CVT (43). Therefore, the mechanisms underlying CTR-CVA, particularly those induced by conventional chemotherapy and radiotherapy, will be discussed in relation to markers of cellular senescence in the following sections (Figure 3).

Figure 3

3.1 Mechanisms of anthracycline-induced cardiovascular aging

Anthracyclines are first-line chemotherapy agents used to treat various malignancies, including breast cancer, lymphoma, and acute leukemia (44). DOX, epirubicin, and daunorubicin belong to the anthracycline. Among these, DOX is the earliest discovered and most widely used. Unfortunately, the cardiovascular adverse effects of DOX, a first-generation anthracycline, have been recognized in a dose-dependent manner since 1976 (45, 46). The molecular mechanisms underlying DOX-induced cardiac senescence are complex, involving DNA damage and telomere deficiency, oxidative stress, upregulation of anti-apoptotic proteins, loss of protein homeostasis, epigenetic modifications, and SASP (Table 2). It is important to note that in current cellular and animal experiments designed to establish stable cellular senescence models, the drug dosages employed in most studies—after relevant conversion—exceed the clinical threshold (<500–550 mg/m²). Consequently, the experimental results may not accurately recapitulate the authentic pathological conditions and underlying mechanisms of cardiovascular cellular senescence induced by cancer therapy in clinical practice.

3.1.1 DNA damage and telomere deficiency

DOX exerts its cardiotoxicity effects by intercalating base pairs in DNA or forming a ternary complex with topoisomerase II and DNA, which leads to DNA double-strand breaks and replication arrest—key mechanisms contributing to cardiotoxicity, cell cycle arrest, and cellular senescence (48, 84–86). Abnormalities in the DDR also play a role in DOX-induced senescence (87). Low-dose DOX activates the DDR, recruits the ataxia-telangiectasia mutated (ATM) protein, and triggers the p53-p21 pathway, ultimately inducing cellular senescence.

As telomeres shorten with each cell division, they eventually reach a critical length that triggers entry into cellular senescence (14). DOX exposure accelerated this process by aggravating telomere attrition. Telomere attrition, a progressive loss of protective caps at chromosome ends, is another key factor in DOX-induced cardiomyocyte senescence. A low dose of 0.1 µM DOX downregulates the expression of telomeric repeat-binding factor 1 (TRF1) and telomeric repeat-binding factor 2 (TRF2) through MAPK and p53-mediated pathways, impairing telomere protection and exacerbating telomere damage and cellular senescence (48, 51). Moreover, telomere attrition activates the DDR, culminating in senescence in neonatal rat cardiomyocytes. In contrast, high doses of DOX promote early cardiomyocyte apoptosis by reducing TRF2 levels and increasing TRF1 expression (49). Similar results have been observed in senescent smooth muscle cells.

3.1.2 Oxidative stress

Redox reactions are central to fundamental biological processes in humans. According to the “Free Radical Theory of Aging,” aging is primarily driven by the overactivation of free radical reactions or excessive accumulation of ROS (88). The overaccumulation of ROS can damage biological macromolecules, such as lipids and proteins, leading to oxidative stress, cell senescence, and ultimately organ failure. In a DOX-induced mouse model of cardiomyopathy, cardiomyocyte senescence was linked to the upregulation of thioredoxin-interacting protein (TXNIP), which inhibited thioredoxin activity and disrupted intracellular antioxidant balance (56). DOX-treated HL-1 cardiomyocytes exhibited features of cellular senescence, including reduced mitochondrial membrane potential, increased ROS, and elevated malondialdehyde (MDA) levels, which were associated with higher expression of lincRNA-p21 and activation of the Wnt/β-catenin signaling pathway (53).

3.1.3 Anti-apoptotic proteins

Apoptosis and cellular senescence represent two distinct cellular responses to damage. Senescent cells are highly resistant to apoptosis due to the upregulation of various anti-apoptotic proteins, such as members of the Bcl-2 family, Survivin, and XIAP (X-linked inhibitor of apoptosis protein) (89). In DOX-treated cardiomyocytes, the upregulation of these anti-apoptotic proteins contributes to a senescent, pro-inflammatory phenotype (90). Furthermore, activation of anti-apoptotic signaling pathways, including the PI3K/Akt pathway (90, 91), the Nrf2 pathway, and the NF-κB-IAP pathway, has also been observed in the senescence cardiomyocytes (92, 93). Clearing senescent cells by downregulating these anti-apoptotic proteins can alleviate chemotherapy-induced cardiovascular aging (66, 68). The novel senolytic agent ABT-263 (Navitoclax), which targeted the Bcl-2 family, effectively induced apoptosis in DOX-induced senescent cardiomyocytes and primary human umbilical vein endothelial cells (HUVECs) (68). However, ABT-263 failed to induce apoptosis in senescent somatic hybrid cells, likely due to differences in the levels of anti-apoptotic proteins (66).

3.1.4 Protein homeostasis

Protein homeostasis is essential for maintaining cellular structure and function, preventing the accumulation of metabolic waste, and playing a pivotal role in cardiovascular aging and cardiac myocyte renewal. Autophagy, the lysosomal degradation of misfolded and aggregated proteins as well as damaged organelles, is a key process in protein homeostasis. Therefore, autophagy regulates cardiovascular aging and the renewal of cardiac myocytes by maintaining protein homeostasis. In DOX-treated cardiomyocytes, a loss of autophagy-related gene 4a (ATG4a), a mediator of autophagosome formation and maturation, triggered cardiomyocyte senescence (58). The senescence induced by DOX treatment can be alleviated by exosomes derived from mesenchymal stem cells (MSCs) that express LncRNA-MALAT1⁺. This effect is mediated by inhibiting miR-92a-3p and promoting ATG4a expression and autophagosome formation. AMPK, a key kinase involved in energy homeostasis and a known positive regulator of autophagy, plays a key role in regulating cardiomyocyte senescence. Activation of AMPK can delay or prevent cancer therapy-related cardiovascular senescence and diseases. Yusei Fujioka et al. found that DOX-induced senescent fibroblasts increased the secretion of extracellular vesicles (EVs) with characteristics of autophagy activation, possibly through AMPKα activation (94). However, whether autophagy induced by EVs is protective or exacerbates cardiac pathology requires further investigation.

3.1.5 Epigenetic modifications

Epigenetic alterations, such as modifications in the genome, heterochromatin disruption, DNA methylation patterns, and histone modifications (e.g., histone acetylation), are critical for gene expression regulation. Loss of epigenetic information has been demonstrated in progeroid mice (8, 95). Compared to newborns, aged populations exhibit lower DNA methylation levels, with a 7% reduction in the methylation status of neighboring cytosine—phosphate—guanine (CpG) sites (96, 97). DOX has been shown to alter the metabolism of S-adenosylmethionine (SAM), a key methylation donor, and decrease global DNA m5C levels in cardiac tissue (52). Given the role of DNA methylation in senescence, it is plausible to speculate that DNA methylation plays a role in DOX-induced cardiovascular senescence.

In addition to DNA methylation, histone acetylation has recently been implicated in the development of cardiovascular aging (98). A decline in histone acetylation alters chromatin structure, which may disrupt the binding of transcription factors and repair enzymes to DNA, interfering with the normal cell cycle and promoting cellular senescence (99). In DOX-treated rats, an upregulation of histone deacetylases (HDACs) and downregulation of histone acetylation regulatory genes, such as CBP and Ep300, were observed (52, 100). Together, these alterations in DNA methylation and histone acetylation play a pivotal role in cardiovascular aging. Targeting these specific epigenetic modifications may offer a novel strategy for mitigating cytotoxic drug-induced senescence.

3.1.6 Senescence-associated secretory phenotype (SASP)

Senescent cells typically exhibit a distinctive secretion profile, including various proinflammatory cytokines, chemokines, growth factors, and proteases, collectively referred to as SASP. The SASP both results from and drives cellular senescence. DOX-induced senescent cardiomyocytes secrete SASP factors that contribute to chronic low-grade inflammation, disrupting cardiac structure and function (70). Furthermore, inflammation-induced SASP can exacerbate DNA and telomere damage, while directly influencing cell cycle arrest. Key inflammatory regulators, including NF-κB, p38/MAPK, and C/EBPβ, are activated and promote SASP secretion in DOX-treated mice and cells (101–103). Additionally, SASP factors secreted by DOX-induced senescent cardiomyocytes can propagate senescence in neighboring cells through exosomal delivery (103). The oxidative stress associated with SASP factors may also be driven by the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome (104). The SASP is diverse, with both pro-inflammatory and anti-inflammatory factors potentially arising from the same stressor. Analyzing, evaluating, and strategically targeting the elimination of SASP represents a critical approach to alleviate the burden of cardiac aging.

In addition to the mechanisms mentioned earlier, alterations in mitochondrial structure, quantity, and function are also critical contributors to cardiac aging. Mitochondria, the primary energy-producing organelles, play an essential role in DOX-induced cardiovascular senescence (85, 105). DOX treatment disrupts mitochondrial quality control (MQC) and suppresses mitochondrial biogenesis through the peroxisome proliferator-activated receptor gamma co-activator 1-Alpha/Beta (PGC-1α/β) pathway (106), leading to a reduction in mitochondrial DNA and insufficient ATP production in the heart (52), thereby promoting the senescence phenotype (107, 108). Notably, DOX induces mitochondrial membrane destabilization via the activation of BAX/BAK-mediated mitochondrial permeability transition pores (mPTPs), where VDAC serves as a critical component. This cascade leads to the extrusion of mtDNA into the cytosol, thereby triggering the cGAS-STING inflammatory axis and driving cardiomyocyte senescence (78). The processes of mitochondrial fusion and fission are also vital in maintaining mitochondrial ROS homeostasis (109). A decrease in fusion coupled with an increase in fission promotes excessive ROS accumulation in cells, accelerating cellular senescence (73). Prolonged low-dose DOX treatment recruits dynamin-related protein 1 (DRP1) via overactivated ERK, which interacts with fission proteins such as Fis1 and mitochondrial fission factor (MFF) on the outer mitochondrial membrane, leading to exacerbated mitochondrial fragmentation in cardiomyocytes. This fragmentation causes electron leakage and excessive ROS accumulation, which further induces cardiomyocyte senescence (72). Mitochondrial autophagy, a key aspect of MQC, plays a critical role in removing damaged mitochondria. This process involves the PTEN-induced putative kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin. Parkin has been shown to mitigate DOX-induced cardiac aging by promoting K63-linked polyubiquitination of TBK1, activating the TBK1/P62 signaling pathway, and facilitating type II mitophagy (60, 110).

3.2 Mechanisms of other chemotherapeutic agents-induced cardiovascular aging

Various chemotherapeutic agents, including platinum-based drugs, taxanes, antimetabolites and alkylating agents, contribute to treatment-induced senescence. Cisplatin can inhibit the CaMKKβ/AMPK signaling pathway and suppresses Sirtuin 3 (SIRT3) expression. As a key mitochondrial deacetylase, SIRT3 inhibition can lead to ROS accumulation and induces senescence in renal tubular cells (111). Paclitaxel, a microtubule-stabilizing agent, is known to induce cell cycle arrest and cause premature senescence in MSCs (112). Yet, Macías et al. reported that paclitaxel ameliorated abnormal heart rate variability and sinoatrial block in mice with Hutchinson-Gilford Progeria Syndrome (HGPS) (113). This indicates that cell type, disease background and other variables can be used in the study of paclitaxel in the field of aging, and its effect and mechanism of aging in the cardiovascular system warrant further investigation.

5-fluorouracil (5-FU) inhibits the expression of nitric oxide synthase (eNOS) and Sirtuin 1 (SIRT1) by activating the p38/JNK pathway, inducing endothelial senescence and dysfunction. Conversely, glucagon-like peptide-1 (GLP-1) alleviates 5-FU-induced endothelial senescence by moderately activating ERK1/2, PI3K, and PKA pathways (114). Alkylating agents, such as cyclophosphamide, ifosfamide, and busulfan, may induce premature ovarian cellular senescence by inhibiting the TrkB/Akt/ERK axis (115). The activation of ERK1/2 in the aging heart is typically impaired; Research have suggested that transduction of constitutively active MEK (CaMEK) can activate ERK1/2 signaling, inhibit mitochondrial fragmentation, and thereby alleviate ischemic damage in the aging heart (116). All the above studies indicate that balancing the MEK/ERK pathway may play an important role in protecting cellular functions, maintaining mitochondrial homeostasis, and delaying CTR-CVA (117, 118). Chen et al. demonstrated in a chronic rhinosinusitis (CRS) model that MEK1/2 and WNT2B signaling can synergistically promote mucosal repair and epithelial remodeling (119). The core logic of “MEK/WNT synergistic regulation of tissue repair” may provide a crucial regulatory node for improving tumor therapy-induced vascular endothelial dysfunction and CTR-CVA. Additionally, the impact of numerous other drugs on cardiovascular aging, including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors, remains insufficiently explored.

3.3 Mechanisms of radiotherapy-induced cardiovascular aging

Approximately 50% of patients with cancers undergo radiation therapy (120), including those with advanced nasopharyngeal carcinoma, lung cancer, liver cancer, esophageal cancer, and breast cancer (121, 122). Similar to DOX, high-energy ionizing radiation directly damages DNA and telomeres, leading to genomic instability, oxidative stress, and cellular senescence. Consequently, senescence plays a detrimental role in the onset and progression of radiation-induced cardiotoxicity (RIC). Endothelial cells, key components of the cardiovascular system, are particularly prone to senescence or permanent cell-cycle arrest after exposure to moderate or high radiation doses (123). These cells are critical initiators of RIC and are highly susceptible to radiation-induced senescence (124–126). Park et al. demonstrated that overexpression of GDF15 in human aortic endothelial cells (HAECs) promoted ROS production, overactivated the ERK signaling pathway, and induced the cellular senescence via the p16^INK4a-Rb pathway following ionizing radiation exposure (81).

In addition to direct radiation-induced damage, the radiation-induced by-stander effect (RIBE) also plays a significant role in cellular senescence (127, 128). The ROS and SASP factors released by irradiated cells can cause oxidative damage and chronic inflammation in neighboring cells. Zhang et al. observed a shift from an acute stress-associated phenotype (ASAP) to SASP in stromal cells exposed to radiation (129). Various cytokines and chemokines, including interleukins, TNF-α, and TGF-β, are secreted by irradiated cells under radiation stress and can affect adjacent non-irradiated cells via gap junctions, paracrine signaling, or exosome-mediated communication (128, 130). Consequently, the bystander effect has significant implications for radiation-induced cardiovascular aging.

4 Monitoring of cancer treatment-related cellular senescence and cardiovascular aging

Cardiovascular aging and cellular senescence are primarily monitored through biomarkers, histological analysis, and functional evaluations. Non-invasive tracking of cardiovascular aging and cellular senescence is essential for diagnosis and predicting disease progression. Currently, most non-invasive tracking senescence indicators are indirect evidence, such as using cine-MRI to assess arterial strain as a surrogate for vascular aging. Common imaging indicators for monitoring cardiovascular aging include myocardial mass, tissue composition, ventricular volumes, systolic and diastolic function, left ventricular (LV) strain, and left atrial volumes and function (131). The following sections will highlight the latest research in three key areas of cardiovascular aging monitoring: cytological, functional, and histological assessments.

4.1 Biomarker-based cancer treatment-related cardiovascular aging monitoring

Imaging and monitoring of senescent cells have gained significant attention in recent years, with the development of simplified tools for effective detection. The combination of cellular senescence biomarkers with optical or imaging techniques has enabled the creation of specific tracers for real-time monitoring of senescent cell distribution and dynamic changes in living organisms, providing more intuitive guidance for clinical applications. Beyond ex vivo analyses, such as blood or omics studies, the primary in vivo monitoring tools for cellular senescence are largely based on biomarkers like SA-β-gal (132), ROS, and p16^INK4a, often using PET or MRI imaging. However, while these tools excel at detecting senescent cancer cells, their application for monitoring cardiovascular senescence remains limited.

4.1.1 Monitoring tools based on β-galactosidase (SA-β-gal)

β-Galactosidase is a classic biomarker for cellular senescence monitoring. β-Gal-based probes typically consist of two key components: a recognition group (β-galactoside) and a fluorescent reporting group. Upon hydrolysis by the elevated β-galactosidase in senescent cells, the probe is activated, emitting fluorescence.

Among various materials, aggregation-induced emission (AIE) materials are distinguished by their exceptional photostability and sensitivity to aggregation environments. Cen et al. developed the QM-β-gal probe, incorporating an AIE luminogen (AIEgen), which effectively detects DOX-induced senescent cancer cells (132). Notably, the QM-β-gal probe maintains stable in vivo imaging for up to 14 days post-injection, offering significant potential for monitoring cancer cell recurrence and metastasis. However, the probe was unable to detect cellular senescence in the heart, likely due to the lower cumulative dose of DOX compared to conventional doses used in cardiovascular aging models, coupled with a relatively short tissue sampling time (132). Recently, the β-Gal-targeting PET imaging probe, ⁶⁸Ga-BGal, was designed to directly monitor cellular senescence in live animals, highlighting its considerable clinical translation potential (133).

Notably, not all β-galactosidase-positive cells are necessarily senescent, indicating that false-positive results must be considered in clinical practice.

4.1.2 Monitoring tools based on reactive oxygen species

Excessive accumulation of hypochlorous acid (HClO) is a major contributor to elevated intracellular ROS levels, which serve as a hallmark of senescent cells. Consequently, HClO represents a promising target for monitoring cellular senescence. Li et al. developed a novel probe to detect HClO levels both in vitro and in vivo, which can effectively differentiate senescent cells from non-senescent ones in cardiac tissues. The near-infrared fluorescent probe SA-HCy-1 responds to three key indicators—SA-β-gal, high ROS levels, and elevated lysosomal pH—enabling the visualization of short-term senescence in live cells within a skin photoaging mouse model (134). However, its clinical applicability requires further investigation, particularly regarding its correlation with classical markers, such as p21^cip1 and p16^INK4a.

4.1.3 Other monitoring tools

Radioactive tracers targeting p16^INK4a allow for in vivo imaging of cellular senescence via positron emission tomography (PET) (135). Monitoring telomerase activity and the expression of human telomerase reverse transcriptase (hTERT) in CD34(+) circulating progenitor cells has emerged as a simple and effective method for assessing cardiac aging (136). Moreover, SASP expression in plasma has been more strongly linked to cardiovascular aging, suggesting SASPs as potential biomarkers for monitoring this process (137).

4.2 Function-based cancer treatment-related cardiovascular aging monitoring

Cardiovascular aging and cellular senescence are typically associated with functional changes, including reduced cardiac contractility, impaired diastolic function, decreased vascular elasticity, and abnormal cardiac conduction. Functional monitoring indicators for cardiovascular aging include left ventricular ejection fraction (LVEF), the E/A ratio, global longitudinal strain (GLS), and pulse-wave velocity (PWV) (16). Selecting appropriate and accessible functional monitoring metrics will aid in the indirect diagnosis and early prediction of cancer treatment-related cardiovascular aging.

4.2.1 Monitoring of cardiac contraction

Impaired cardiac contractility during cancer treatment is primarily attributed to factors such as cardiomyocyte loss, myocardial microvascular remodeling, reduced coronary perfusion, and collagen deposition in the myocardium. The conventional quantitative parameter for assessing cardiac contractile function is LVEF, which commonly declines in the early stages of cancer treatment-related cardiovascular aging (138). Thus, traditional CTR-CVT LVEF data can serve as a useful benchmark. Three-dimensional transthoracic echocardiography (3D TTE) is the preferred method for LVEF evaluation. In cases where 3D echocardiography is not feasible, the modified two-dimensional (2D) Simpson's biplane method can be used as an alternative (139, 140). Notably, cancer treatment-related cardiovascular aging often occurs with preserved ejection fraction. Therefore, a normal LVEF value cannot rule out cardiac contractility dysfunction.

4.2.2 Monitoring of diastole

Cancer treatment induces cardiac fibroblast transformation into myofibroblasts, which secrete excessive collagen, leading to cardiac fibrosis. This fibrosis alters the mechanical properties of the heart chambers, increasing stiffness and reducing elasticity (141). Additionally, cancer therapies can impair calcium transport proteins and disrupt calcium homeostasis in cardiomyocytes, contributing to diastolic dysfunction. Diastolic function indicators are therefore valuable for indirectly assessing cancer treatment-related cardiovascular aging. Early-stage DOX-induced cardiomyopathy is primarily characterized by diastolic dysfunction (142, 143). Radiotherapy can also cause diastolic dysfunction, often linked to cardiomyocyte damage, microvascular occlusion, and ECM remodeling. Additionally, DOX treatment induces collagen deposition in the atrial walls, leading to increased stiffness, which can be indexed by the diastolic capacity of the left atrium (LA). This suggests that LA diastolic capacity may also serve as a indicator for cancer treatment-related cardiovascular aging (144, 145). Magnetic resonance radiomics, based on major and minor axis lengths and 2D diameter imaging, has revealed a reduction in LA chamber size that is strongly associated with cardiovascular aging, highlighting the potential value of magnetic resonance radiomics in monitoring cancer treatment-related cardiovascular aging (146).

4.2.3 Monitoring of strain

Myocardial strain capacity is influenced by muscle length and angles, encompassing longitudinal, radial, and circumferential dimensions. A decline in myocardial strain capacity is a hallmark of aging cardiovascular systems, suggesting that strain capacity also serves as a functional indicator of cancer treatment-related cardiovascular aging. Key quantitative imaging indicators for myocardial strain capacity include global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), left ventricular twist (LV Twist), and Torsion (146). GLS, in particular, is recommended for evaluating left ventricular strain in CTR-CVD and can be used to indirectly monitor cancer treatment-related cardiovascular aging (147).

4.2.4 Monitoring of conduction

Dysfunction of the cardiac conduction system is associated with a range of physiological and pathological cardiovascular changes (148, 149). Cancer treatment-related cardiovascular aging exhibits similar characteristics to general organ aging (29), including a reduction in heart rate and QT interval prolongation (150, 151). Baseline electrocardiogram (ECG) monitoring prior to treatment, incorporating the Fridericia correction method (QTcF) (152), along with dynamic ECG (Holter monitoring), are common tools for tracking transient arrhythmias and conduction abnormalities.

The integration of AI, wearable devices, electronic stethoscopes, and ECG technology (153) has enabled the application of deep learning models to more precisely assess conduction system dysfunction, predict cancer treatment-related cardiovascular aging, and guide drug administration (154, 155). Significant alterations in the QT interval, exceeding established thresholds, signal the need to promptly discontinue non-essential medications during cancer treatment-related cardiovascular aging (150, 156, 157). However, it is important to recognize that current machine learning models are limited by data constraints, and the performance of external applications still requires optimization.

4.3 Histology-based cancer treatment-related cardiovascular aging monitoring

Histological monitoring offers more direct structural insights into CTR-CVA, facilitating dynamic evaluations. Given the high risks associated with pathological biopsy, current histological indicators primarily rely on imaging parameters to indirectly assess myocardial mass, cardiac fibrosis, myocardial perfusion, coronary artery calcification (CAC), and valvular calcification.

High levels of oxidative stress and chronic inflammation are potential mechanisms driving vascular aging associated with cancer therapies (158). CMR first-pass perfusion imaging, which assesses myocardial perfusion index (PI), may reveal alterations in cardiac microcirculation in patients undergoing prolonged chemotherapy, serving as a valuable reference for CTR-CVA evaluation (159). Radionuclide myocardial perfusion imaging, reflecting myocardial perfusion via radiolabeled compound uptake by myocardial cells, could also become a useful tool for CTR-CVA assessment. Additionally, automated coronary calcium scoring from CT scans offers significant advantages in evaluating the extent of coronary aging in patients with cancers. PET/CT has been shown to effectively monitor CAC (160, 161), though clinical studies specifically addressing CAC resulting from both aging and cancer treatment remain scarce. Certain chemotherapeutic agents, such as alkylating drugs, may induce ovarian insufficiency, leading to decreased estrogen levels (162). Therefore, changes in estrogen levels must be considered when monitoring arterial stiffness in patients undergoing cancer treatments. Addressing these challenges requires personalized assessment, monitoring, and follow-up to optimize patient care.

Given these indicators, refining conventional monitoring methods for CTR-CVA is essential. Establishing a comprehensive baseline for cardiovascular aging is critical. More high-quality randomized controlled trials (RCTs) should be prioritized, and long-term follow-up assessment protocols should be systematically adopted to achieve a more comprehensive, objective, and accurate comprehensive evaluation of CTR-CVA. Developing a non-invasive imaging system capable of monitoring aging from cellular senescence to histological and functional changes could significantly enhance clinicians' ability to detect early cardiovascular aging in patients and foster more precise interventions, ultimately improving survival outcomes.

5 Treatment of cancer treatment-induced cardiovascular aging

Cellular senescence is an important influencing factor of CTR-CVT. Therefore, anti-aging interventions may mitigate the progression of CTR-CVT and CTR-CVA. Current strategies for preventing and treating cardiovascular aging can be divided into pharmacological and non-pharmacological approaches. Currently, the prevention and management of CTR-CVA remain challenging.

5.1 Pharmacotherapy

Anti-aging drugs, or senotherapeutics, are designed to target both intracellular senescence-associated pathways and extracellular membrane proteins specifically upregulated in senescent cells. These agents are categorized into senolytics and senomorphics. Senolytics selectively eliminate senescent cells, whereas senomorphics modulate the SASP without inducing cell death. Immunotherapy, an emerging approach, aims to specifically eliminate senescent cells by targeting unique surface markers (Table 3).

5.1.1 Senolytics

Senolytics primarily induce the death of senescent cells, effectively preventing their accumulation in tissues. Regimens for senolytic therapy include combinations such as dasatinib and quercetin (D + Q), navitoclax (ABT-263), fisetin, proxofim (FOXO4-DRI), and HSP90 inhibitors.

Among these, D + Q has emerged as the most promising senolytic combination for promoting the clearance of senescent cells (212, 213). D + Q facilitates senescent cell elimination by inhibiting anti-apoptotic pathways, including the Ephrin B (EFNB) serine protease inhibitors (Serpins) and the PI3K/AKT pathway (214). Wagner et al. demonstrated that D + Q effectively reverses cardiac dysfunction induced by cellular senescence in animal models (215), while Roos et al. confirmed its efficacy in improving age-related vascular dysfunction (216). Notably, different senescent cells show certain selectivity for anti-aging drugs. For instance, the advantage of dasatinib in dealing with senescent adipocytes cannot be transferred to senescent endothelial cells, which are obviously more sensitive to quercetin treatment (214).

Navitoclax (68), a BCL-2 family inhibitor, is a classic agent used to mitigate chemotherapy-induced cardiovascular cellular senescence. Despite a long research history, its clinical translation is currently unfeasible due to safety issues such as induction of acute platelet toxicity. Fisetin (173), a natural flavonoid, exhibits senolytic activity through its metabolic byproducts. FOXO4 (217) neutralizes drug-induced toxicity and eliminates senescent cells in a DOX-induced kidney aging model by modulating p53. HSP90 inhibitors, such as 17-DMAG and alvespimycin (218), affect the PI3K/AKT/mTOR senescence-related pathway, triggering senescent cell apoptosis (219).

5.1.2 Senomorphics

In addition to senolytic strategies, senomorphics offer another promising approach to mitigate age-related side effects. Most senomorphics exert their effects by modulating the signaling or transcriptional regulators of the SASP, including the NF-κB, JAK-STAT, and mTOR pathways (220). Metformin, a well-established senomorphics agent, reduces SASP expression and inhibits DOX-induced endothelial cell senescence by suppressing the JNK and NF-κB pathways (70). Long-term rapamycin treatment in senescent cardiac progenitor cells (CPCs) suppresses mTOR signaling, activates the JAK-STAT3-PIM1 pathway, decreases senescence marker expression, and restores clonogenic, migratory, and differentiative potential (221). Additionally, natural compounds such as curcumin and resveratrol (a SIRT1 activator) have been shown to regulate the mTOR pathway, mitigating low-dose anthracycline-induced cardiovascular aging (222). Rutin, an antioxidant plant compound, inhibits SASP expression across various cell lineages, including IL-6, IL-8, IL-1α, IL-1β, CXCL3, MMP3, and GM-CSF (223). In summary, while senomorphics exhibit milder anti-aging effects compared to senolytics, they are associated with lower cytotoxicity and fewer side effects.

5.1.3 Immune-activating therapies

Immunotherapy is an emerging strategy aimed at specifically eliminating senescent cells by targeting distinct surface markers. Under normal physiological conditions, immune cells can effectively clear senescent cells. However, in pathological or aging states, senescent cells may evade immune surveillance, hindering their clearance (224). Additionally, senescent cells actively create an immunosuppressive environment that facilitates their survival. Thus, immunotherapies targeting cellular senescence present a promising approach for treating CTR-CVA. Katsuumi G. et al. demonstrated that canagliflozin, an SGLT2 inhibitor, downregulates PD-L1, restoring immune surveillance and promoting the clearance of senescent cells (211, 225). Anti-aging vaccines have also been developed to induce specific immune memory and actively remove senescent cells. For example, the ATRQβ-001 vaccine has been shown to slow the decline in cardiac function associated with cardiovascular aging (226).

Selective neutralizing or blocking antibodies, often categorized as senomorphic agents, have emerged as another therapeutic avenue (227). Lister et al. demonstrated that an Ephrin-B2 neutralizing antibody (B11) could suppress the SASP in senescent fibroblasts, thereby mitigating pulmonary fibrosis in mice. Furthermore, serum chemokine CCL17 has been identified as a potential biomarker for diagnosing and monitoring vascular stiffness and aging. Knockout of CCL17 in mice has been shown to slow vascular remodeling and inhibit vascular aging (210). The integrin family also may provide novel targets for the prediction and intervention of CTR-CVA. Sun et al. demonstrated that integrin β4 (ITGB4) can induce celluar senescence of vascular endothelial cells by activating the H-ras/caveolin-1/AP-1 axis, thereby exacerbating endothelial dysfunction (228). In cancer therapy, the signaling of the integrin-β family (ITGB4/ITGA3/5/6) may be overactivated (117), which can lead to endothelial celluar senescence, vascular sclerosis, and myocardial dysfunction through signal transduction (229, 230). Therefore, identifying key cytokines in the context of cancer treatment and targeting them to improve the inflammatory microenvironment is critical, as this may enhance therapies aimed at addressing cardiovascular aging.

However, the low specificity of immunotherapy may lead to immune overactivation, particularly given the heterogeneity of senescent cells. Consequently, careful selection of antigens and rigorous safety testing of vaccines are essential for clinical applications. Recently, urokinase-type plasminogen activator receptor (uPAR)-specific CAR-T cells have shown promise in efficiently eliminating senescent cells in a pulmonary fibrosis mouse model, representing a potential strategy for aging-related diseases (231).

5.2 Non-pharmacological therapy

In addition to pharmacological interventions, supportive therapies—such as dietary modifications, physical exercise, and mental health support—are also recommended to mitigate the progression of cardiovascular aging (232).

Dietary interventions play a key role in reducing ROS production, limiting the accumulation of nuclear and mitochondrial DNA damage, and maintaining mitochondrial homeostasis. Long-term caloric restriction has been consistently linked to a reduced incidence of age-related diseases (233, 234). Intermittent fasting, caloric restriction, and glucose restriction may elevate NAD⁺ levels, potentially offering protective effects against stress-induced cardiovascular aging (235). Nevertheless, as current evidence primarily comes from preclinical studies, clinical translation should proceed with caution to avoid synergistic toxicity. Moreover, methionine restriction and ketogenic diets contribute to improved cellular metabolism and aging mitigation. Aerobic exercise training (AET) has been shown to promote myocardial ischemia recovery by preventing the reduction of circulating endothelial progenitor cells in mice treated with a combination of doxorubicin and cyclophosphamide (32). Given the similarities in the mechanisms between cancer treatment-induced cardiovascular aging and cellular senescence, the supportive therapies outlined above may offer promise in addressing cancer treatment-induced cardiovascular aging.

Additionally, insufficient sleep is a significant risk factor for accelerating cardiovascular aging (236). A quiet, safe sleep environment and adequate rest are essential to prevent cellular damage and senescence. Psychological distress, mental stress, and cognitive biases associated with cancer and its treatments also require attention and support from both society and family.

6 Discussion

Advancements in cancer therapy have significantly improved the survival rates of patients with cancers. However, this progress has been accompanied by an escalating risk of cardiovascular toxicities in these patients. Striking an optimal balance between minimizing cancer treatment-related cardiac events and maximizing antitumor efficacy remains a challenge. Numerous studies have highlighted cellular senescence as a critical initiator and mediator of therapy-induced late side effects. This review focuses on exploring the relationships among cellular senescence, CTR-CVA, and CTR-CVT, aiming to build a bridge between the field of Aging and the field of Cardio-Oncology.

Cellular senescence is considered as a key initiator and mediating factor of CTR-CVT. In the field of Cardio-Oncology, CTR-CVT is a broad term that encompasses various cardiac toxicities under different treatment modalities, including all the adverse effects of cancer treatments on the cardiovascular system. As one of the core subsets of CTR-CVT, CTR-CVA possesses non-negligible independent research value, which is mainly manifested in the following aspects. (i) Differences in intrinsic mechanisms. Traditional CTR-CVT mostly emphasizes the damage caused by tumor treatments to cardiovascular cells. The intrinsic mechanisms are mostly apoptosis or necrosis of cells. In contrast, CTR-CVA emphasizes the long-term maintenance of a non-lethal pathway. The intrinsic mechanism is the activation of cellular senescence and related pathway, which ultimately leads to the acceleration of tissue aging. It has a more obvious time dependence, so the latency period is longer. (ii) Differences in the focuses of monitoring and intervention. The monitoring of CTR-CVA, on the basis of that of CTR-CVT, introduces the focus on the pathology of cellular senescence and tissue aging. The key points of intervention are to reduce senescent cells, improve the senescent phenotype, and rejuvenate the cardiovascular environment. However, the precise molecular mechanisms of CTR-CVA remain unclear, and the role of senescence in some cancer drugs prone to causing cardiotoxicity (such as immunotherapeutic agents) has not been validated by basic experiments, which hinders the development of targeted therapies.

Additionally, the lack of accurate monitoring methodologies for CTR-CVA presents another major challenge. To mitigate the side effects of CTR-CVA, future research should focus on the following areas: (i) Large-cohort, multi-center studies to identify precise humoral and imaging biomarkers of cardiac aging, which would enable early prediction of CTR-CVA onset, diagnosis of its severity, and assessment of the efficacy of related treatments; (ii) The use of advanced models such as organoids and engineered mouse models to investigate the molecular mechanisms underlying the onset and progression of CTR-CVA, thereby identifying potential therapeutic targets (iii) The development of high-throughput screening technologies to identify targeted drugs for CTR-CVA treatment, enhancing treatment specificity while minimizing toxicity to normal tissues and organs. Emerging technologies like single-cell sequencing, spatial transcriptomics, and artificial intelligence are highly relevant to the rapidly evolving field of cardio-oncology, offering significant promise for both research and clinical care. Through interdisciplinary collaboration among oncologists, cardiologists, materials scientists, and engineers, we aim to integrate cancer treatment with cardiovascular aging management across clinical pathways. By combining multi-omics technologies with AI-assisted detection, this approach will enable precise diagnosis, effective prevention, and systematic management of CTR-CVA, ultimately improving long-term outcomes for patients with cancers and survivors.

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