Age serves as a major determinant in the development of heart failure and cardiovascular diseases, with the incidence of heart failure rising dramatically as individuals grow older. In individuals over 50, the frequency of heart failure increases exponentially with each advancing decade, establishing it as a primary cause of mortality among the elderly population [1, 2]. This trend is especially concerning in the United States, where the number of people aged 65 and older is steadily increasing, expected to reach 95 million by 2060 [3]. As such, the aging demographic presents a significant challenge to healthcare systems worldwide, necessitating a deeper investigation into the age-related mechanisms underlying heart failure. The process of cardiovascular aging leads to structural and functional changes in the heart, making older individuals more prone to developing heart failure [4, 5]. While cardiac function at rest may appear unaffected in many older adults, subtle impairments in diastolic and systolic function become more prevalent with age [5]. As the myocardium ages, a series of intricate processes unfolds, shaping its path toward diminishing function and eventual transition to heart failure. At molecular level, the increased vulnerability to heart failure is linked to altered DNA methylation, loss of histones, decline in sirtuins (SIRTs), telomere shortening, mitochondrial DNA mutations, reactive oxygen species, dysregulated metabolism, decline in autophagy, extracellular matrix disruption, impaired angiogenesis, clonal hematopoiesis of indeterminate potential, dysregulated inflammatory mediators, immune cell infiltration, senescence and poor regeneration during cardiovascular aging (Figure 1, Table 1) [6-8]. In this review, we focus on cardiovascular aging as the central factor driving the onset and progression of heart failure, providing a detailed examination of the molecular alterations occurring in the heart and vascular system with age. This includes an exploration of aging-related changes in the cardiovascular system, contributing to heart failure, understanding which offers hope for the development of future strategies to combat heart failure in the aging population.

In patients with heart failure, left ventricular tissue shows distinct methylation changes across several genomic regions, including promoter CpG islands, intragenic CpG islands, and gene bodies, when compared to healthy controls. Altered DNA methylation patterns are observed in peripheral blood from heart failure patients and in the genomic regions of cardiomyocytes from neonatal, healthy adult, and failing adult hearts [9, 10]. Notably, mimicking differential DNA methylation changes at the double homeobox 4 (DUX4) locus through gene knockdown results in decreased cardiac cell viability in vitro, suggesting that DUX4 may play a causal role in cardiac dysfunction [11]. Hypermethylation is also evident in hearts from rats with norepinephrine-induced cardiac hypertrophy, and inhibition of DNA methyltransferase (DNMT) activity has been shown to mitigate hypertrophy and heart failure [12]. Additionally, the regulation of N6-methyladenosine methylation by METTL3 plays a key role in the cardiac hypertrophic response, where increased methylation promotes compensated hypertrophy, while reduced methylation contributes to cardiac dysfunction [13]. These findings highlight the significant impact of DNA methylation on cardiovascular dysfunction and heart failure.

Loss of histones

Modifications to histones after translation, such as acetylation and deacetylation, as well as methylation and demethylation, are linked to cardiac dysfunction related to aging and associated diseases [14]. The loss of histone deacetylases (HDACs) such as HDAC1, 2, 3, 5, and 9 has been associated with the promotion of aging-related characteristics, including cardiac hypertrophy, dysfunction, increased susceptibility to heart injury, and shortened lifespan [15-17]. These findings highlight the significant impact of histones on cardiac dysfunction and heart failure.

Decline in SIRTs

Reduced expression of SIRT1 in cardiomyocytes from patients with advanced heart failure and animal models correlates with increased oxidative stress, inflammation, and apoptosis [18, 19]. SIRT1 mitigates oxidative stress in cardiomyocytes by regulating proteins such as manganese superoxide dismutase (MnSOD), thioredoxin1 (TRX1), and Bcl-xL, and helps prevent cardiomyocyte apoptosis via the NF-κB p65/miR-155/brain-derived neurotrophic factor (BDNF) signaling pathway, providing protection against heart failure in rats [20]. A lack of SIRT3 may impair mitochondrial function in the heart and worsen heart failure as organisms age. Additionally, SIRT3 plays a role in endothelial metabolism and angiogenesis, influencing the onset and progression of heart failure. Deletion of SIRT3 specifically in endothelial cells disrupts glucose transport, reduces glucose utilization in cardiomyocytes, and heightens susceptibility to pressure overload-induced heart failure in vivo [21, 22]. Similarly, SIRT6 has demonstrated protective effects in heart failure, with its expression reduced in patients with chronic heart failure and in animal models. Overexpression of SIRT6 improves survival rates in heart failure mice, possibly through the upregulation of telomerase [23, 24]. These findings highlight the significant impact of SIRTs on cardiovascular dysfunction and heart failure.

Telomere shortening

Telomere length has emerged as a significant biomarker of cellular aging [25]. Mice with TERC gene deficiency undergo significant telomere shortening, leading to increased p21-mediated cell cycle arrest in cardiomyocytes, culminating in cardiac aging and dysfunction [26, 27]. In mice, partial aortic constriction reduces the expression of telomeric repeat-binding factor 2 (Trf2), a shelterin protein, which accelerates telomere shortening and induces cardiomyocyte apoptosis, while overexpressing Tert or Trf2 alleviates these effects [28]. Although telomere length in human myocardium decreases with age [29] and correlations between shortened telomeres, reduced TRF2 levels, and increased apoptosis in end-stage heart failure patients have been observed [28], contradictory findings suggest that telomere attrition in heart failure may not reflect typical cardiac aging, as it is associated with substantial DNA damage in cardiomyocytes [30]. These findings highlight the significant impact of telomere shortening on cardiovascular dysfunction and heart failure.

Mitochondrial DNA mutations

Elevated mitochondrial DNA mutations undermine the integrity of mitochondria, disrupting mitochondrial biogenesis and leading to an increased production of reactive oxygen species [31]. The "Mutator" mice, which carry a homologous mutation in the mitochondrial polymerase gamma (Polgm/m), exhibit impaired mitochondrial function, and the development of early aging traits, including cardiac hypertrophy, dilated cardiomyopathy, and fibrosis, leading to an average lifespan of just 12 months [32, 33]. When these Polgm/m mice are crossed with antioxidant catalase (mCAT) overexpressing mice, there is a partial restoration of the cardiac aging and heart failure phenotypes [34]. Deletion of Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (Pgc-1α), a crucial regulator of mitochondrial biogenesis, results in cardiac impairment as early as 7 to 8 months of age in mice [35]. Overexpression of the myocardial Twinkle (Twnk) helicase in mice accelerates mitochondrial DNA deletions, contributing to the development of arrhythmias as they age [36]. Mutations in the p66Shc gene, which modulates reactive oxygen species production, result in reduced mitochondrial reactive oxygen species, increased resistance to reactive oxygen species-induced apoptosis, and a longer lifespan [37]. These findings highlight the significant impact of mitochondrial mutations on cardiovascular dysfunction and heart failure.

Reactive oxygen species

Mitochondrial reactive oxygen species may impair the mitochondrial respiratory chain, leading to oxidative stress, DNA and protein damage, lipid peroxidation, and the opening of the mitochondrial permeability transition pore (MPTP). This cascade triggers the release of cytochrome C, which initiates chronic proteome alterations and apoptosis, contributing to acute cardiovascular events and heart failure [38]. Additionally, mitochondrial reactive oxygen species have been implicated in the activation of the NLRP3 inflammasome and the induction of cardiomyocyte pyroptosis in dilated cardiomyopathy, highlighting a novel mechanism in heart failure onset and progression [39]. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) is a major source of reactive oxygen species, promoting lipid peroxidation of the mitochondrial membrane and activation of redox-sensitive mitochondrial potassium channels, which further generates mitochondrial reactive oxygen species from the electron transport chain [40]. The overexpression of NOX intensifies oxidative stress in aging blood vessels. This elevated oxidative environment, in turn, activates inflammatory pathways such as NF-κB [41]. Impaired nitric oxide (NO) signaling manifests endothelial dysfunction, an increase in oxidative stress, and persistent inflammation. Reduced endothelial NO synthase (eNOS) activity leads to lower NO availability, a situation worsened by high levels of reactive oxygen species, especially superoxide anions, which combine with NO to form peroxynitrite, thereby reducing NO’s ability to induce vasodilation in smooth muscle cells [42]. In contrast, mitochondrial-specific overexpression of the antioxidant mCAT has been shown to extend lifespan by mitigating cardiac aging and reducing oxidative damage to mitochondrial DNA and proteins [43, 44]. These findings highlight the significant impact of reactive oxygen species on cardiovascular dysfunction and heart failure.

Dysregulated metabolism

In the aging heart, insulin resistance impairs the ability of cells to uptake glucose by disrupting glucose transporter activity, resulting in an increased reliance on fatty acids for energy production. This shift toward fatty acid metabolism undermines metabolic flexibility, leading to mitochondrial dysfunction and an increase in the generation of reactive oxygen species [45]. Alterations in the signaling pathways associated with insulin receptor substrates (IRS) and the AMP-activated protein kinase (AMPK) are critical contributors to this metabolic dysregulation [46]. Insulin resistance may lead to elevated levels of circulating free fatty acids (FFAs), which promote lipid accumulation within cardiomyocytes. This accumulation, due to diminished lipid oxidation, induces lipotoxicity, further compromising cardiac function [47, 48]. Additionally, age-related disruptions in the metabolic signaling pathways, such as peroxisome proliferator-activated receptors (PPARs) signaling pathway and the activation of the mechanistic target of rapamycin (mTOR) pathway exacerbate cardiac hypertrophy, fibrosis, and defective autophagic processes, which are hallmark features of heart failure [49]. These findings highlight the significant impact of metabolic dysregulation on cardiovascular dysfunction and heart failure.

The decline in autophagy with age is linked to mitochondrial dysfunction and oxidative stress in the aging heart, which results in both structural and functional damage [50]. The activation of mTOR, [51, 52], along with the inhibition of autophagy-promoting factors like SIRT1 [53], exacerbates decline in autophagy and contributes to cardiac dysfunction. Mice lacking the lysosome-associated membrane protein 2 (Lamp2) exhibit cardiac dysfunction alongside pathological alterations in multiple organs, including the arteries, skeletal muscle, pancreas, and liver, ultimately leading to premature death [54]. In Atg5 knockout mice, disorganized sarcomere structures and fragmented mitochondria are observed, leading to cardiomyopathy and impaired systolic function in older animals [50]. Conditional knockout of Atg5 or Atg7 in cardiomyocytes results in severe cardiomyopathy, significant contractile dysfunction, and early mortality [55, 56]. The deletion of Glycogen synthase kinase 3 alpha (Gsk3α) promotes the accumulation of vacuoles and sarcomere disarray, classic signs of decline in autophagy, while also disrupting mitochondrial function, contributing to cardiomyopathy and a reduced lifespan [57]. Chronic activation of protein kinase B (Akt) in cardiomyocytes inhibits autophagy, promoting age-related cardiac hypertrophy, fibrosis, and contractile dysfunction in transgenic mice [58]. Mice with a mutation in the heat shock protein B family (HSPB6)S10F undergo decline in autophagy due to impaired interaction between HSPB6 and Beclin-1 (Becn1), resulting in heart failure and early mortality [59]. Interestingly, Becn1 expression has been shown to exacerbate hypertrophy, fibrosis, and pressure-overload-induced heart failure [60]. Additionally, the age-related and p53-dependent upregulation of microRNA (miR)-22 leads to decline in autophagy, cardiac remodeling, and dysfunction, with elevated circulating miR-22 levels correlating with early mortality in heart failure patients [61]. These findings highlight the significant impact of decline in autophagy on cardiovascular dysfunction and heart failure.

The composition of the extracellular matrix is pivotal in regulating both cardiomyocyte maturation and cell cycle dynamics, but it is often disrupted in various cardiac diseases [62, 63]. Disruptions in the extracellular matrix stems from an imbalance in matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) and result in extracellular matrix remodeling marked by enhanced collagen accumulation and elastin degradation [64]. Additionally, dysregulated mechanosignaling pathways involving transcriptional co-activators such as yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) due to mechanical stress play a critical role in arterial stiffness during vascular aging, further influencing heart failure progression [65]. The increased stiffness of arteries imposes additional workload on the heart, forcing it to pump blood through less compliant vessels, creating a setting that promotes the onset of heart failure  [66]. These findings highlight the significant impact of extracellular matrix disruption on cardiovascular dysfunction and heart failure.

Impaired angiogenesis disrupts the formation of new blood vessels and is a key factor in vascular aging. The reduced expression of pro-angiogenic factors, particularly vascular endothelial growth factor (VEGF), limits endothelial cell proliferation and the formation of new blood vessels [67]. In heart failure, insufficient angiogenesis diminishes the heart's ability to adapt to varying demands, ultimately resulting in an inadequate blood supply to cardiac tissues [68]. In addition, the disruption in NO turnover hampers the ability of blood vessels to dilate properly, negatively affecting blood flow regulation [42]. Lower NO levels can also impair cardiomyocyte contractility, leading to reduced left ventricular diastolic compliance in a cyclic GMP-dependent protein kinase G (PKG)-dependent manner [69]. Furthermore, endothelial dysfunction can restrict oxygen and nutrient supply to cardiomyocytes, resulting in inadequate coronary perfusion, worsening cardiac function, and contributing to the development of heart failure [70]. These findings highlight the significant impact of impaired angiogenesis on cardiovascular dysfunction and heart failure.

Clonal hematopoiesis of indeterminate potential refers to the expansion of hematopoietic cells harboring somatic mutations, increases with age and is linked to higher mortality rates [71]. Given that clonal hematopoiesis of indeterminate potential is commonly observed in asymptomatic, cancer-free elderly individuals and its connection to cardiac diseases, it suggests a potential causal relationship between somatic mutations and age-related heart failure [72, 73]. Clonal hematopoiesis of indeterminate potential in peripheral blood cells has been associated with a two-fold increase in the risk of coronary heart disease or early-onset myocardial infarction [72, 74]. In elderly individuals with heart failure and clonal hematopoiesis of indeterminate potential, especially those carrying dual somatic mutations in DNMT3A and TET2, elevated circulating IL-6 suggests a possible role for clonal hematopoiesis in the development of heart failure [75]. Supporting this, research indicates that TET2 deficiency accelerates age-related cardiac dysfunction, leading to pronounced hypertrophy and fibrosis in the heart [76]. These findings highlight the significant impact of clonal hematopoiesis of indeterminate potential on cardiovascular dysfunction and heart failure.

NF-κB activation triggers the production of pro-inflammatory cytokines, such as IL-1α, IL-1β, IL-6, IL-17, and TNF-α, which collectively promote key features of heart failure, including cardiomyocyte hypertrophy, fibrosis, and impaired contractility [77]. Cardiomyocytes release cytokines such as monocyte chemoattractant protein-1 (MCP1), C-X-C motif chemokine ligand 1 (CXCL1), interleukin 6 (IL-6), IL-18, and IL-33, triggered by CaM kinase II (CaMKII)-mediated NFκB activation [78]. The increased expression of pro-inflammatory cytokines is linked to the upregulation of Toll-like receptor-4 (TLR-4), a phenomenon associated with aging that is evident in both myocardial tissue and circulating monocytes of chronic heart failure patients [79]. In ischemic heart failure models, IL-1 levels rise sharply within hours, mirroring the progressive decline in cardiac function [80]. Furthermore, administration of recombinant IL-1β induces myocardial dysfunction in experimental mouse models [81]. Elevated levels of IL-6 and IL-18 are strongly correlated with cardiovascular diseases and heart failure in elderly individuals [82]. Studies in animal models reveal that cardiac IL-6 expression increases with age, while IL-6 deficiency helps prevent age-related cardiac dysfunction [83]. Additionally, circulating IL-6 levels are linked to the accelerated aging of T-lymphocytes and are predictive of survival in heart failure patients [84]. TNF-α further exacerbates heart failure by impairing cardiac contractility, while balancing its expression with anti-inflammatory cytokines like IL-10 could mitigate inflammation and oxidative stress associated with heart failure [85]. In the acute inflammatory phase, self-DNA released by damaged cardiomyocytes is detected by the cytosolic pattern recognition receptor cyclic GMP-AMP synthase (cGAS), which activates an inflammatory cascade via the cGAS-STING-IRF3 signaling pathway [86]. These findings highlight the significant impact of dysregulated inflammatory mediators on cardiovascular dysfunction and heart failure.

Circulating chemokines and cytokines recruit different immune cells including monocytes and neutrophils while activating tissue-resident macrophages [87]. Neutrophils play a vital role in transitioning from acute inflammation to the repair phase, where macrophages clear damaged tissue, produce profibrotic cytokines, and recruit additional monocytes [88]. These processes are essential for cardiac repair and the survival of border zone cardiomyocytes [89], although they can overwhelm the systemic circulation in cases of severe injury or chronic inflammation, resulting in adverse remodeling [90]. Interactions between stressed cardiomyocytes and surrounding immunoreactive cells—such as fibroblasts, endothelial cells, and resident immune cells—can perpetuate the persistent low-grade inflammation seen in heart failure [91, 92]. Persistent inflammation drive maladaptive remodeling, characterized by hypertrophy and excessive fibrosis, and require infiltration of CC motif chemokine receptor 2 (CCR2+) monocyte-derived macrophages to replace resident macrophages [93]. Notably, neutrophils infiltrate before CCR2+ monocytes, suggesting a potential synergistic recruitment by resident macrophages and infiltrating neutrophils [93]. Terminally differentiated CD4+ T lymphocytes serve as markers of myocardial inflammation associated with aging [94]. These findings highlight the significant impact of dysregulated inflammatory mediators on cardiovascular dysfunction and heart failure.

Senescence

In aging hearts, there is a marked upregulation of senescence markers such as p53 and p16Ink4a, contributing to pathological changes like hypertrophy, mitochondrial dysfunction, increased cardiomyocyte death, reduced contractility, and heart failure [95, 96]. Senescent cells accumulate progressively over time, exerting harmful paracrine effects on surrounding cells and systemic consequences on distant tissues via senescence-associated secretory phenotype (SASP) [97]. Recent studies indicate that these senescent cells play a crucial role in cardiac remodeling and dysfunction with aging [95, 98]. In addition to the traditional proinflammatory SASP factors—IL-1α, IL-1β, IL-6, and TNF-α—which promote localized and systemic inflammation, emerging research highlights a wider array of secreted proteins and RNAs contributing to aging-related diseases such as heart failure [7, 99]. Cardiomyocytes in senescence can induce similar changes in neighboring cells by secreting nontraditional SASP factors, such as endothelin 3 (Edn3), transforming growth factor beta 2 (Tgf-β2), and growth differentiation factor 15 (Gdf15), as revealed by studies on cardiomyocytes isolated from old mice [100]. Age-related cellular senescence induces an inflammatory phenotype in both vascular and myocardial endothelial cells, as seen in the hearts of senescence-accelerated mouse models. These changes contribute to diastolic dysfunction and left ventricular hypertrophy, which are often present in heart failure [101]. These findings highlight the significant impact of senescence and SASP on cardiovascular dysfunction and heart failure.

Poor regeneration

Following cardiac injury, heart failure models show an increase in cell cycle activity [102], resembling the regenerative potential seen in neonatal cardiomyocytes, which can replicate and aid in cardiac repair [103, 104]. However, as cardiomyocytes mature postnatally, they undergo significant changes that progressively reduce their ability to proliferate [105]. Despite this, the enhanced cell cycle activity in damaged hearts typically leads to polyploidy rather than effective cardiomyocyte regeneration [106]. Adult cardiomyocytes exhibit a renewal rate ranging from 0.5% to 2% annually, suggesting a modest, albeit restricted and regenerative ability within the heart [107, 108]. This regenerative capacity primarily arises from the replication of existing cardiomyocytes rather than differentiation of stem cells [109]. However, this renewal process diminishes with advancing age, reflecting a reduced capacity to replace lost cardiomyocytes. This is particularly significant because even small-scale, experimentally induced loss of cardiomyocytes can lead to cardiomyopathy and mortality [110]. These findings highlight the significant impact of poor regeneration on cardiovascular dysfunction and heart failure.

The growing global incidence of heart failure among aging populations calls for innovative therapeutic approaches. Cardiovascular aging contributes to heart failure through diverse molecular mechanisms, including altered DNA methylation, loss of histones, decline in sirtuins (SIRTs), telomere shortening, mitochondrial DNA mutations, reactive oxygen species, dysregulated metabolism, decline in autophagy, extracellular matrix disruption, impaired angiogenesis, clonal hematopoiesis of indeterminate potential, dysregulated inflammatory mediators, immune cell infiltration, senescence and poor regeneration (Figure 1, Table 1). As the role of aging in heart failure becomes clearer, new therapeutic candidates and strategies are being identified, with the goal of translating these insights into clinical interventions that address specific aspects of aging in heart failure patients. However, due to the complexity of biological aging, a single intervention is unlikely to fully resolve age-related cardiac dysfunction. Analyzing molecular signatures linked to cardiac aging could pave the way for personalized therapies, advancing precision medicine in heart failure care [111]. Biomarker discovery is instrumental in identifying individuals at high risk, allowing for the development of targeted therapeutic strategies tailored to specific molecular profiles [112]. These approaches have the potential to significantly mitigate the features of age-related heart failure, heralding a new era in heart failure management while also benefiting other cardiovascular diseases.

Acknowledgments

No applicable.

Ethics approval

No applicable.

Data availability

The data will be available upon request.

Funding

None.

Authors’ contribution

DG and KOBY contributed to the conception, design, writing of this review article, drawing figures, make data table and submitted the final version of the manuscript.

Competing interests

None.

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