How aging cells may contribute to heart and blood vessel disease

Not all senescent cells exhibit identical phenotypes; there is substantial heterogeneity among them. Consequently, the biological consequences of cellular senescence are dualistic, with the process exerting multifaceted functions under different physiological and pathological conditions. Their beneficial effects are manifested as follows: first, senescent cells form temporary structures by secreting FGF4 and FGF8 to guide embryonic tissue regeneration and embryonic development, and shape placental structure and function together with matrix metalloproteinases 2 and 9. Second, senescent cells limit excessive cell proliferation to avoid further tissue damage and also promote wound healing by secreting PDGF-AA. In addition, senescent cells autonomously impede cell cycle progression by up-regulating the expression of genes such as p53, p16, and p21, thereby limiting tumor growth. At the same time, senescent cells also secrete cytokines such as IL-6 and IL-8 to promote senescence of surrounding cells, thereby limiting tumor spread in a non-autonomous manner [16, 20 –24]. Thus, cellular senescence is an effective tumor suppressor mechanism. Finally, a large body of evidence suggests that cellular senescence is associated with the process of tissue repair, in which senescent cells promote local fibrosis and recruitment of immune cells, followed by removal of damaged and senescent cells [25]. On the other hand, the deleterious effect of senescent cells is that they promote a sterile chronic inflammatory response by secreting a variety of senescence-associated SASP components, such as the secretion of IL-6, IL-1 receptor antagonist (IL-1RA), GROα and IFNγ, and MMPs, thereby destroying tissue structure and promoting tumor growth [26, 27]. SASP is a paracrine reservoir of pro-inflammatory cytokines, chemokines, growth factors, and proteases [17, 28]. Paracrine activity of senescent cells plays an important role in tissue senescence and damage repair by both accelerating tissue senescence and promoting damaged tissue repair [20, 29]. Senescent cells, although in a state of cell cycle arrest, can influence neighboring cells and tissues by secreting inflammatory factors in order to remain metabolically active; therefore, SASP has been implicated as a trigger for chronic inflammation, oxidative stress, and reduced nitric oxide bioavailability [30]. In summary, the biological effects of cellular senescence are two-sided; short-term acute cellular senescence facilitates cardiac development, embryonic angiogenesis, wound healing, and tissue repair, whereas long-term chronic accumulation of senescent cells leads to tissue dysfunction and promotes tumorigenesis, and in particular contributes to the development of age-related cardiovascular disease.

Given the complex and dual biological effects that cellular senescence demonstrates across various physiological and pathological processes, it also plays a significant dual role in the specific domain of cardiovascular disease. The research conducted by Anna Walaszczyk et al. demonstrates that the clearance of senescent cells can improve myocardial remodeling and diastolic function, as well as enhance overall survival rates following MI [31]. Furthermore, conventional drug therapies that improve cardiac function after MI also reduce the expression of senescence markers in cardiac tissue [32]. In contrast, a multitude of research endeavors have put forward the notion that cell senescence exerts a positive influence after MI [33, 34]. Notably, a reduction in the synthesis of SASP components is correlated with an exacerbation of systolic dysfunction and an augmentation of cardiac fibrosis during the post-MI period. Such a correlation implies that the SASP components located in the peri-infarct area manifest antifibrotic and cardioprotective properties [35]. Growing evidence demonstrates that cellular senescence plays a pivotal role in vascular pathologies such as atherosclerosis, with recent comprehensive reviews summarizing the underlying mechanisms [36 –39]. Cellular senescence exerts anti-atherosclerotic effects by restricting the proliferation of VSMCs and macrophages, suppressing pro-inflammatory cytokine secretion, and stabilizing plaques through p16/p53/p21/ARF-mediated mechanisms, thereby inhibiting plaque formation and reducing vulnerability [40 –42]. Interestingly, a study using an endothelial cell (EC)-specific progeroid mouse model demonstrated that EC senescence enhances NF-κB signaling pathway-mediated regulation of VCAM-1 through epigenetic modifications, leading to exaggerated inflammatory responses in the vascular endothelium and increased monocyte adhesion, thereby accelerating atherosclerosis progression [43]. Recent research has indicated that cardiac IR-induced senescent cardiomyocytes secrete SASP, which in turn activates maladaptive cardiac remodeling processes such as cellular hypertrophy, inflammation, fibrosis, and a reduction in regenerative capacity, eventually leading to chronic cardiac fibrosis [35, 44]. Conversely, studies have shown that IR-induced cardiomyocyte senescence can play a cardioprotective role by triggering cardiac fibroblast senescence, specifically by promoting cardiomyocyte proliferation and inhibiting the progression of fibrosis, which in turn promotes regeneration of neonatal heart [45]. In summary, Cellular senescence exhibits a significant dual role in CVDs. On one hand, clearing senescent cells or reducing their biomarker levels improves post-MI cardiac remodeling and function while exerting anti-atherosclerotic effects by inhibiting aberrant proliferation of vascular lesion cells. On the other hand, under specific pathological conditions, senescent cells confer cardioprotection through the anti-fibrotic effects of SASP components or by promoting cardiomyocyte proliferation; however, their excessive activation can also induce chronic fibrosis and maladaptive remodeling.

Endothelial cells are essential for maintaining the structural integrity and homeostasis of blood vessels [84]. Previous studies have demonstrated that endothelial cell senescence is the initiating link in the development of atherosclerosis [85]. However, senescent endothelial cells impair both endothelial integrity and permeability, consequently facilitating the accumulation of oxidized low-density lipoprotein (ox-LDL). This accumulation further stimulates the intracellular production of reactive oxygen species (ROS) and induces mitochondrial dysfunction, thereby promoting the progression of atherosclerosis [86 –89]. In cardiovascular disease studies, the shortening of telomeres in leukocytes within atherosclerotic coronary arteries has been identified as a significant characteristic of cellular senescence. This state of cellular senescence then triggers endothelial hyperinflammation through epigenetic modifications. Consequently, the process of atherosclerosis is accelerated [43]. Previous studies have shown that inhibiting telomere function induces senescence in human aortic endothelial cells (HAECs), resulting in increased expression of intercellular adhesion molecule (ICAM)-1and a decrease in activity of endothelial nitric oxide synthase (eNOS). This phenomenon has been linked to the development and progression of atherosclerosis [39]. During the aging process, the extracellular matrix of the inner wall of the blood vessels undergoes a process of hardening, leading to an increase in the permeability of endothelial cells. This increased permeability further facilitates the extravasation of leukocytes, which plays a vital role in the formation of atherosclerotic plaques [86]. Functionally abnormal senescent endothelial cells additionally exhibit reduced expression of endothelial nitric oxide synthase while showing an increased expression of pro-inflammatory molecules and adhesion molecules. These changes, in turn, trigger vascular inflammation [90 –92]. Senescence of endothelial cells leads to adverse effects, including dysregulation of blood flow and barrier dysfunction, hindering the ability of the vascular lumen to repair itself due to the inability of senescent cells to proliferate [93]. Secondary senescence, induced by IL-1β, in human endothelial cells and/or vascular smooth muscle cells, may be a mechanism that leads to the accumulation of senescent cells. This mechanism potentially contributes to the development of atherosclerosis and its associated complications. IL-1β can additionally contribute to endothelial cellular senescence in human EC by up-regulating CUX1 expression or down-regulating SATB2 expression [94]. Endothelial cell senescence leading to atherosclerosis is promoted by SIRT6 deficiency or miR-217 overexpression. FOXM1, a key transcription factor for cell cycle progression and senescence, plays a critical role. FOXM1 overexpression ameliorates endothelial cell senescence induced by SIRT6 deficiency, thereby alleviating atherosclerosis [95, 96]. In summary, given the pivotal driving role of endothelial cell senescence in atherosclerosis, the development of anti-aging therapies targeting telomere function, miROS, or the miR-217/SIRT6 regulatory axis may provide novel therapeutic targets for improving vascular repair capacity and inhibiting plaque progression.

A study showed that by eliminating Senescent cells(SNCs) as they accumulate during atherogenesis, hypercholesteremic Ldlr^−/− mice develop fewer lesions and lesions that do form are smaller and more stable. SNCs do so by antagonizing IGF-1 through the secretion of insulin-like growth factor-binding protein 3 (IGFBP-3). These data indicate that the intermittent use of senolytic agents or IGFBP-3 inhibition in combination with lipid-lowering drugs may provide therapeutic benefit in atherosclerosis [111]. Chronic clearance of senescent cells improves established vascular phenotypes associated with aging and chronic hypercholesterolemia, and may be a viable therapeutic intervention to reduce morbidity and mortality from cardiovascular diseases [112]. Johmura et al. results suggest that glutaminase 1 (GLS1) is an essential gene for the survival of human senescent cells, and that inhibition of glutaminase reduces atherosclerotic plaque formation [113]. Suda M et al. study showed that glycoprotein nonmetastatic melanoma protein B (GPNMB) expression was upregulated in vascular endothelial cells and/or leukocytes of patients and mice with atherosclerosis. Genetic ablation of Gpnmb-positive cells attenuated senescence in adipose tissue and improved systemic metabolic abnormalities in mice fed a high-fat diet, and reduced atherosclerotic burden in apolipoprotein E knockout mice on a high-fat diet [114]. The combination of D & Q, another anti-aging drug, can reduce the expression level of aging markers in hypercholesterolemia mice, improve vascular vasomotion, and inhibit arterial calcification [115]. Bcl-2 inhibitors such as ABT-263 have been proven to selectively eliminate senescent cells during atherosclerosis, thereby delaying the progression of the disease [107]. Furthermore, SIRT1, as an anti-aging agent, has been extensively studied in the context of EC senescence and atherosclerosis. The earliest experimental evidence has shown that chemical or siRNA inhibition of SIRT1 leads to senescence in HUVECs via enhancing the acetylation and activity of p53 [116]. Overexpression of SIRT1 prevents H2O2-induced EC senescence and downregulation of eNOS [116]. Subsequent studies demonstrated that overexpression of SIRT1 in the endothelium can improve vascular stiffness and attenuate the development of atherosclerosis, probably by activating eNOS and promoting NO production and preventing EC senescence [116 –118]. Interestingly, global Sirt1 heterozygous KO enhances endothelial inflammation, without affecting eNOS activity, in atherosclerotic Apoe^−/− mice [119]. SIRT1 in hematopoietic cells also prevents foam cell formation and reduces atherosclerosis [120]. Previous studies have demonstrated that SIRT1 can activate FOXO3a through deacetylation, thereby upregulating the expression of the MnSOD gene and enhancing its transcriptional activity. Through the SIRT1/FOXO3a/MnSOD axis, SIRT1 inhibits oxidative stress and the generation of reactive oxygen species (ROS), protects vascular endothelium, and improves cardiac function [121]. Zhang et al. discovered that upregulating the expression of SIRT1 can inhibit oxidative stress and inflammatory responses by regulating the AMPK/SIRT1/NF-κB signaling pathway, thereby improving the progression of atherosclerosis [122]. Downregulation of SIRT1 causes OVX-induced arterial senescence and atherosclerosis in ApoE-KO mice. Administration of estrogen or SERM enables OVX mice to restore these alterations by SIRT1 induction [123]. In conclusion, the above studies provide theoretical studies for targeting cellular senescence-related therapies for mitigating the development of atherosclerosis (Table 1).

Cellular senescence can interact with various pathological mechanisms in heart failure, such as mitochondrial dysfunction, autophagy disruption, and the activation of the neurohumoral system [145 –147]. Pim1 functions as a conserved serine/threonine protein kinase with various protective effects on mitochondrial function and telomere length. Furthermore, research has found that Pim1-deficient mice develop heart failure and exhibit elevated levels of markers associated with aging, including p16, p53, and SA-β-gal. Additionally, deterioration of mitochondrial structure and function is observed within cardiac tissue [148, 149]. PI3K inhibition induces autophagy, preserves cardiac function, and decreases levels of p16, p21, p53, and select SASP components in cardiac tissues of aged mice, suggesting a relationship between autophagy and aging during heart failure [150]. Cardiac pathological conditions like myocardial infarction and hypertension result in a gradual accumulation of senescent cells in cardiac tissue. These senescent cells contribute to the development of heart failure by increased fibrosis, inflammation, and oxidative stress, among other responses [115]. Myeloid-derived suppressor cells (MDSCs) derived from the myeloid lineage accumulate within aging tissues. These cells have been shown to be linked to various aging-related diseases [151]. Granulocytic myeloid-derived suppressor cells (G-MDSCs) can potentially inhibit fibroblast senescence and programmed cell death by modulating the FGF2-SOX9 signaling pathway in fibroblasts and induce cell cycle arrest. Additionally, they have the potential to promote cardiac fibrosis and impair cardiac diastolic function, ultimately increasing the risk of heart failure [151]. In addition, cardiomyocyte senescence leads to hypertrophy and fibrosis in the senescent heart, and elimination of these senescent cells may promote cardiomyocyte regeneration [145]. Overall, cellular senescence is an important pathological mechanism underlying heart failure, exacerbating the reduction of myocardial contractility, impaired myocardial diastolic function, and the worsening of cardiovascular disease. Prevention and treatment of cellular senescence in heart failure are crucial measures to protect heart health and prevent the development of cardiovascular diseases. Hence, developing therapeutic methods or drugs to reverse cellular senescence may be a promising research direction.

The targeted cell senescence-related treatment aims to improve heart function by regulating the process of cell senescence. SIRTs are enzymes with anti-aging properties, and many studies have shown that SIRTs play an influential role in processes related to heart failure (HF), such as cardiac hypertrophy, cell death, and oxidative stress. SIRTs are also involved in cardiac remodeling and in HF development [98]. Therefore, during heart failure, SIRT6 is able to exert a protective mechanism in preventing the differentiation of fibroblasts towards myofibroblast differentiation [98]. Inadequate peroxisome proliferator-activated receptor-γ coactivator 1-αactivity triggers mitochondrial dysfunction and heart failure. Nevertheless, SIRT1 enhances PGC-1αactivity through the restoration of metabolic function in the failing myocardium, thus alleviating the condition of heart failure [152]. The Inhibition of PPARα and SIRT1 worsens heart failure by promoting impaired mitochondrial function through the estrogen-related receptor gene expression cascade [153]. G-MDSCs induce cardiac fibrosis by promoting the proliferation of cardiac fibroblasts. Fibrosis associated with cellular senescence is an important pathological factor in Heart Failure with Preserved Ejection Fraction. G-MDSCs serve as a new antifibrotic therapeutic target for HFpEF [151]. Previous studies have shown that the p53 pathway plays a crucial role in the progression from left ventricular hypertrophy to heart failure [140]. Inhibiting either p53 or p16 has been demonstrated to extend the lifespan of various cell types. Thus, inhibiting p53 in endothelial cells holds promise as a new target for treating HFpEF [154]. Ischemic heart disease (ICM), resulting from underlying coronary artery disease, represents the leading cause of heart failure and is a significant contributor to mortality among individuals diagnosed with heart failure. Previous studies have demonstrated that the expression levels of the aging-associated signature (CSA) genes MYC, STAT3, and MAP2K1 were significantly reduced in ischemic heart disease. These three CSAs have the potential to serve as both biomarkers and therapeutic targets for the development of novel therapeutic strategies for heart failure [138]. Because senescent cells generally possess anti-apoptotic properties, anti-apoptotic protein Bcl-2 inhibitors such as ABT-263 have been shown to improve left ventricular contractile function, reduce myocardial fibrosis and hypertrophy, and inhibit heart failure [115]. Hence, targeting cellular senescence-associated therapy may be a novel therapeutic avenue for heart failure with preserved ejection fraction. Further research and exploration are needed to determine whether targeting cellular senescence can be an effective treatment for heart failure (Table 1).

The field of cardiac electrophysiology seeks to comprehend the normal function of electrical activity in the heart. Simultaneously, the atrial and ventricular muscles contract and relax, displaying rhythmic contractions that are reflected in the electrochemical activity of depolarization and repolarization in the heart [155]. Alterations in circadian rhythms impact various aspects of human cardiac electrophysiology, such as heart rate, QT interval, QT interval dispersion, and ventricular occlusion. Moreover, the effects of aging on circadian rhythm alterations have been documented in heart gene expression. These changes can potentially contribute to cardiovascular dysfunction or disease [156]. Natriuretic peptides (NPs) constitute a group of cardioprotective hormones involved in the regulation of cardiac structure and electrophysiology. They have been shown to modulate atrial conduction and arrhythmogenesis by affecting atrial fibrosis. In aged NPR-C^−/− mice, the left atrium exhibited the highest levels of atrial stromal fibrosis due to the loss of NPR-C. This loss also leads to a reduced lifespan and accelerates the onset of senescence. Additionally, a shortened atrial action potential duration can increase susceptibility to atrial fibrillation as senescence increases [157]. Aging can regulate atrial and pulmonary vein electrical activity through mechanisms such as mechanoelectrical feedback, imbalances in calcium levels, oxidative stress, and metabolic irregularities. Overall, senescence at the cellular level has significant impacts on the electrophysiology of the heart, potentially resulting in impaired autoregulation at pacemaker sites, impaired conduction function, modified action potentials, and abnormalities in ion channels, consequently increasing the likelihood of arrhythmias.

Atrial fibrillation (AF) is widely recognized as a significant arrhythmia among older individuals, with its morbidity and mortality rates escalating with advancing age. AF pathogenesis primarily involves remodeling of the heart's electrical system and structural alterations, and aging significantly contributes to the development of electrical and structural remodeling in the atria, resulting in heightened vulnerability to AF. As individuals age, the interplay between reduced cardiomyocyte function, oxidative stress, calcium dysregulation, apoptosis, and atrial myocyte fibrosis induces alterations in both the electrical and structural remodeling of the atria, thereby facilitating the onset and persistence of AF [158]. As individuals age, the normal conduction system of the heart(including the sinusoatrial node, atrioventricular node, and His-Purkinje fibers) experiences infiltration by senescent cells and fibrofatty tissue, as well as collagen, amyloid, lipid, and elastic tissue infiltration. This infiltration consequently modifies the intricate interactions among the ion channels involved in depolarization and repolarization [159]. Additionally, atrial conduction that is slow and inhomogeneous, along with lower atrial unipolar voltage, can contribute to an elevated vulnerability to age-related atrial fibrillation [160]. When the myocardium ages, there are failures in intracellular signaling and cellular processes, resulting in the senescence of cardiomyocytes and their apoptosis. Additionally, oxidative stress impacts the function of the sodium and calcium channels, consequently causing increased conduction and a longer period of inactivity. Myocardial heterogeneity increases as a result of the aging process, creating a setting that easily triggers refractory and triggered activities, resulting in the occurrence of arrhythmias [161 –166]. The primary electrophysiological characteristics consist of a shortened refractory period in the atria along with reduced adaptation of action potential timing based on frequency [167, 168]. Aging-induced alterations in delayed rectifier potassium current, or diminished plateau potentials, result in an extended duration of action potentials in the atrial myocardium of aged dogs, as well as modifications in atrial action potentials during advanced age. This can cause attenuated conduction of premature beats, consequently prompting the early occurrence of slow conduction premature beats that may additionally contribute to the development of atrial fibrillation [169]. Previous studies have shown a significant age-related prolongation of P-wave duration and dispersion in older dogs, resulting in a reduction of atrial conduction velocities. A decrease in the depolarizing current ICa-L or an increase in the repolarizing current can contribute to a reduction in the action potential (AP) plateau. Nonetheless, a decrease in ICa-L is likely the primary cause of the diminished plateau potential in left atrial (LA) cardiomyocytes of aged dogs [170]. Additionally, the values of APD90 and effective atrial occlusion exhibited lengthening in elderly RA, whereas they showed shortening in elderly LA [171]. Differences in Action Potentials between RA and LA and the shortening of atrial action potential duration (APD) provide an electrophysiological explanation for the presence of foldback and the development of atrial fibrillation [158]. Senescence of endothelial cells or fibroblasts can lead to remodeling of the atria through the activation of proinflammatory and profibrotic signaling pathways, which increases vulnerability to the development of atrial fibrillation [115]. The aging process is often accompanied by cardiomyocyte apoptosis and necrosis. This is accompanied by elevated levels of peripheral inflammation, reactive oxygen species, and the senescence-associated secretory phenotype. As a compensatory response, there is cellular hypertrophy and an accumulation of extracellular matrix in the periphery. Additionally, fibroblast proliferation and macrophages polarization towards the M1 phenotype further contribute to pathological changes in myocardial tissues, ultimately leading to an increased vulnerability to atrial fibrillation [158]. Cardiomyocyte senescence causes a decline in myocardial contractility and the development of abnormal conduction patterns, leading to cardiomyopathy or arrhythmias. It may further increase the risk of ventricular arrhythmias. The heightened levels of ROS in senescent rat ventricular cardiomyocytes hinder their ability to synchronize with electrical pacing, indicating an elevated risk of arrhythmias [172 –174]. Endothelial and fibroblast senescence have been observed to be associated with atrial fibrillation. There is a positive correlation between the expression levels of senescence-related markers p53 and p16 and the severity of atrial fibrillation [175, 176]. In conclusion, there remain several unanswered questions regarding the role of cellular senescence in atrial fibrillation. Future studies should thoroughly investigate its underlying mechanisms, aiming to establish a theoretical basis for the treatment of atrial fibrillation.

The combination therapy of dasatinib and quercetin (D&Q) has shown potential effects in anti-aging and clearing senescent cells. Julian U G Wagner et al. showed that 2 months of D&Q treatment in aged mice (18–20 months old) reduced vulnerability to arrhythmia due to age-related reversal of ventricular neural innervation [177]. Meanwhile, quercetin, a type of antifibrotic agent, has demonstrated effectiveness in decreasing atrial fibrosis and the subsequent onset of AF in rodent models. Furthermore, Quercetin may alleviate AF by inhibiting fibrosis of atrial tissues through inhibiting TGF-β/Smads pathway via promoting miR-135b expression [178]. Despite receiving increasing attention, radiofrequency ablation is not entirely effective in preventing high recurrence rates for patients after the procedure. Radiofrequency ablation and traditional antiarrhythmic drugs are insufficient in meeting the increasing treatment demand for older patients with enlarged atria. Currently, the primary treatment approach for atrial fibrillation involves the management of ventricular rate, restoration of sinus rhythm, and prevention of blood clot formation. These treatments primarily aim to alleviate the patient's symptoms, mitigate complications, but do not address the underlying cause of atrial fibrillation. Several recent studies firmly establish the significance of cellular senescence in the pathogenesis of atrial fibrillation. However, limited studies have been conducted regarding the treatment of arrhythmias, such as atrial fibrillation, through mediating or eliminating cellular senescence. Hence, intervening in the senescence process is likely to create new treatment opportunities for atrial fibrillation (Table 1).