Heart failure represents a progressive cardiovascular condition characterized by elevated natriuretic peptide levels and objective manifestations of pulmonary or systemic congestion resulting from underlying structural or functional cardiac abnormalities.1, 2, 3, 4, 5 The global epidemiological landscape reveals a concerning prevalence, with approximately 64 million individuals affected and an incidence rate of 1–3 percent worldwide. Despite advancements in medical interventions, the prognosis remains challenging, with mortality rates approximating 20 % within one year and escalating to 50 % by five years post-hospitalization.6 Cardiovascular disease is the leading cause of death worldwide, and age is its most important independent risk factor.7 Cardiac senescence refers to the extensive metabolic recombination and morphological and functional dedifferentiation of various cellular components of the heart with the increase of age, which leads to structural changes in the heart and continuous cardiac function decline. Studies have shown that cardiac aging is closely related to the poor prognosis of various cardiovascular diseases.8 Epigenetic modification is a reversible genetic mechanism that causes heritable changes in gene-phenotype without changes in the basic DNA sequence and is considered a key regulatory mechanism mediating the deterioration of cell function during aging.9 As an essential type of epigenetic modification, more and more evidence shows that histone modification changes represented by histone methylation, acetylation, and phosphorylation play a key role in the occurrence and development of cardiac aging and related cardiovascular diseases.10 Contemporary research has increasingly focused on elucidating the intricate molecular mechanisms governing heart failure progression. Epigenetic regulation is a critical framework for understanding phenotypic variations without genetic sequence modifications.11

This sophisticated regulatory mechanism encompasses diverse molecular processes, including chromatin remodeling, DNA methylation, and histone modifications, such as methylation, acetylation, and phosphorylation. Epigenetics facilitates non-genetic cellular memory accumulation throughout an organism’s lifetime, potentially contributing to pathogenesis in cardiovascular disorders, cancer, and hereditary conditions.12 Notably, epigenetic alterations often manifest early in disease development, presenting potential biomarkers for diagnostic, prognostic, and therapeutic strategies. The cardiac microenvironment demonstrates intricate epigenetic regulation across multiple cell types, including cardiomyocytes, fibroblasts, endothelial cells, and progenitor cells. This dynamic regulatory mechanism enables adaptive responses to metabolic stress and environmental challenges. Emerging research suggests that stress-activated cardiac signaling cascades may drive pathological cardiac remodeling, with epigenetic signals playing a pivotal role in orchestrating transcriptional modifications associated with heart failure progression. The nuanced understanding of these epigenetic mechanisms offers promising avenues for future therapeutic interventions and personalized medical approaches in managing this complex cardiovascular syndrome. This paper reviewed the effects of histone modification on gene expression and cardiac function during cardiac aging and discussed the key role and regulatory mechanism of epigenetic modification in cardiac aging and related cardiovascular diseases.

As the heart ages, several metabolic alterations contribute to its functional decline (Fig. 1). Below, we outline the key metabolic changes associated with the heart’s aging process.13

Myocardial lipid catabolism is significantly reduced in an aging heart compared to a young, healthy heart. As the heart ages, pathophysiological changes, such as ventricular hypertrophy and diminished contractile function, are observed.14 These changes often coincide with a shift from glucose oxidation to anaerobic glycolysis as the primary energy source.15 Additionally, the aging process is marked by dysfunction in cellular insulin signaling and mitochondrial structure, which are closely linked to insulin resistance independent of obesity.16,17 Precisely, impaired glucose transporters (GLUTs) function in the aging heart results in increased fasting blood insulin and glucose levels, subsequently elevating circulating glucose levels.18 Recent research suggests that cells cultured in high-insulin or hyperglycemic environments experience accelerated cellular senescence.19,20

The development of insulin resistance and glucose intolerance with age has been associated with impaired cardiac function, as well as an increased risk for diabetes, cardiovascular disease, and stroke.21 Evidence from positron emission tomography (PET) imaging of radio-labeled glucose absorption in elderly hearts has shown significant insulin resistance and impaired glucose utilization, which corresponded with a reduction in fatty acid (FA) oxidation and increased fat accumulation.22,23 Unlike the compensatory glycolysis observed in myocardial ischemia-induced heart failure, aging hearts do not experience a similar shift in energy metabolism to offset decreased glucose oxidation and FA utilization. Consequently, the synergistic effects of anaerobic glycolysis and impaired FA consumption lead to dysfunctional heart contractions and an irreversible energy deficit.

Additionally, the enhanced pentose phosphate pathway (PPP) activity in the aging heart further complicates glucose metabolism.24 Activating this pathway can exacerbate cardio-lipotoxicity by impairing FA oxidation and promoting lipofuscin accumulation in cardiomyocytes.25 However, the exact molecular mechanisms underlying this process remain unclear. The increased glycolytic flux observed in aging hearts may partially be explained by the carboxylation of pyruvate to malate. This process does not involve acetyl-CoA synthesis.26,27 Although this pathway generates less energy than the complete Krebs cycle, it may help mitigate the consequences of defective pyruvate oxidation by acting as an anaplerotic reaction.28 In response to inadequate fuel availability, these anaplerotic processes may alleviate pyruvate accumulation within the heart.

A growing body of evidence connects epigenetic processes to aging, derived from diverse sources such as tissues, in vitro systems, invertebrates, and vertebrates. With advancing age, mammals undergo local and global alterations in DNA methylation throughout their genomes. All aging models exhibit this characteristic alongside histone depletion and global chromatin remodeling. Cellular senescence also depends on posttranscriptional mechanisms, crucial for RNA modification and non-coding RNA control.29 Researchers must comprehend how epigenetic processes govern individual aging to identify methods for decelerating and rejuvenating ancient species Fig. 2.

DNA methylation at cytosines within CpG dinucleotides produces 5-methylcytosine (5-mC), with 60–90 % of CpG sites in the mammalian genome methylated Fig. 3. Genomes frequently undergo hypomethylation with advancing age.30,31 Following this, genes associated with energy metabolism and oxidative stress tolerance are overexpressed in the skeletal muscles of elderly adults. Three DNA methyltransferases (DNMTs)—DNMT1, DNMT3A, and DNMT3B—silence genes by adding methyl groups to nucleotides. DNA methylation levels diminish with aging due to reduced DNMT1 expression.32,33 DNMT1 mutants, which cannot bind to heterochromatin and lead to the degeneration of specific central and peripheral neurons, can translocate to the cytoplasm and form aggresomal. De novo methylation of CpG islands is facilitated by DNMT3A and DNMT3B, whose expression escalates with age in mammalian cells.34,35

Heart failure is a clinical condition characterized by specific symptoms and signs resulting from structural and/or functional cardiac abnormalities, leading to reduced cardiac output and/or increased intracardiac pressure, both at rest and during exertion. The underlying causes of heart failure include intrinsic cardiac dysfunction, such as myocardial infarction (MI), valvular abnormalities, arrhythmias, and disorders affecting the endocardium or pericardium. Heart failure can manifest in different forms, including mid-range ejection fraction (HFmrEF; EF 40–50 %), preserved ejection fraction (HFpEF; EF > 50 %), or reduced left ventricular ejection fraction (HFrEF; EF < 40 %). In HFpEF, structural remodeling results in impaired left ventricular relaxation due to intracellular fibrosis and cardiomyocyte hypertrophy.4,36,37, 38, 39, 40 Conversely, in HFrEF, the deterioration of ventricular contraction is attributed to cardiomyocyte loss caused by myocardial infarction or volume overload. This overload increases cardiac pressure and volume, leading to structural and functional alterations that create a detrimental cycle, progressively worsening cardiac function over time.

This cycle involves releasing vasoactive peptides, activating the renin-angiotensin-aldosterone system, and stimulating the sympathoadrenergic system, which can further compromise heart function.41 Prolonged stimulation leads to maladaptive mechanisms, including desensitization of the β-adrenergic system, alterations in intracellular calcium handling, and a shift in the Frank-Starling curve toward a negative force-frequency relationship. Furthermore, cardiac stresses in the adult heart may reactivate the fetal gene program associated with myocyte hypertrophy and heart failure, resulting in early epigenetic changes that underlie the morphological and functional alterations leading to heart failure in Fig. 4.42

In recent years, there has been an increasing focus on the role of DNA methylation in the pathogenesis of heart failure Fig. 5. The most recognized form of genomic DNA methylation involves the addition of a methyl group to the 5′ position of cytosine (5mC) by de novo methyltransferases (DNMTs), primarily occurring in the context of cytosine-phosphate-guanine (CpG) dinucleotides. Historically, DNA methylation has been associated with gene silencing, either by preventing transcription factors from binding to DNA or by facilitating the binding of methyl-binding proteins (MBPs), which promote gene repression through interactions with co-repressor complexes.

Conversely, the ten-eleven translocation (TET) protein family plays a role in oxidizing 5mC to 5-hydroxymethylcytosine (5hmC), a modification linked to transcriptional activation. DNA methylation enzymes can be categorized into writers, erasers, and readers. DNMT1 is an example of a writing enzyme that uses methylating cytosine residues to replicate the initial DNA methylation pattern before replication. In contrast, the de novo methyltransferases DNMT3a and DNMT3b introduce methyl groups to unprotected DNA, generating unique methylation patterns. Eraser enzymes remove methyl groups while reading enzymes such as MBPs, UHRF proteins, and zinc finger domain proteins recognize methyl groups and influence transcription factor binding, potentially leading to gene activation or repression.43

Histone is a general term for essential proteins in eukaryotic cell chromatin that bind to DNA. The octamer structure composed of double copies of histone H2A, H2B, H3, and H4 forms the core particle of the nucleosome. In contrast, the N-terminal residues at the free end of the histone can undergo various types of histone modifications under the action of related enzymes, thus affecting chromatin structure and gene expression activity.44 Under physiological conditions, histone modification mainly repairs DNA damage by reshaping chromatin structure, regulating the transcriptional activity of key genes, and maintaining genome stability. Extensive changes in histone modification patterns are important molecular biological characteristics and pathological basis leading to cell senescence.45 On the other hand, the characteristics of histone modification itself, such as reversible regulation and no change in genetic information, also make the intervention strategy based on the former one of the research hotspots in related fields.46

In aging, histone modification represents a significant epigenetic alteration characterized by the loss of histone proteins alongside profound shifts in histone modification profiles, including methylation, acetylation, and phosphorylation. These changes significantly impact genome stability and the transcriptional regulation of key aging-associated genes.47 Numerous studies have established a marked correlation between aberrant histone modifications and the pathophysiological changes associated with age-related cardiac remodeling and the progressive decline in cardiac function, highlighting the potential of histone modification as a pivotal mechanism governing the pathological alterations seen in cardiac aging.48,49

Epigenomic investigations have revealed that the alterations in histone modifications associated with cardiac aging predominantly manifest as increased markers of transcriptional activation alongside a reduction in those indicative of transcriptional repression.50 However, the specific modifications and their regulatory effects concerning cardiac aging vary significantly under diverse stimuli. For instance, in models of cardiac hypertrophy induced by transverse aortic coarctation, histone modifications induced by pressure signaling were characterized by a loss of transcriptional activation markers and a concomitant increase in inhibitory markers.51 Specifically, localized transcriptional repression was associated with a reduction in the abundance of H3K9ac, an active marker, and a rise in the levels of repressive markers, namely H3K9me3 and H3K27me3. Conversely, localized transcriptional activation involved suppression of H3K9me3 and depletion of H3K27me3. In this context, genes such as Rgs2, Tcap, Bmp2, and Tgfbr1, which are linked to cardiomyopathic hypertrophy, were identified as significantly up-regulated, with Bmp2 and Tgfbr1 playing crucial roles in processes related to cardiac aging.52 Bmp2 is instrumental in mediating transforming growth factor-β (TGF-β)/Smad signaling during aging-related aortic calcification, while Tgfbr1 is closely associated with age-related ventricular muscle fibrosis.53

In models of chronic heart failure resulting from a high-salt diet, stress signaling predominantly drives the accumulation of H3K9me3 within myocardial chromatin, leading to the transcriptional repression of mitochondria-associated proteins such as Pgc1α, thereby precipitating mitochondrial dysfunction typically associated with aging.54 Furthermore, histone modifications significantly influence various cellular processes relevant to cardiac aging, including DNA damage, inflammation, apoptosis, and fibrosis.55 Notably, these processes are intricately linked to changes in histone modifications affecting genes such as IκBα, Bcl, and Tgf-β.56,57

Beyond cardiomyocytes, histone modifications' dysregulation in other cardiovascular system cellular components often reflects similar abnormalities. It influences the pathological changes that mediate the heart’s aging and associated organs. For example, in cardiac fibroblasts, hypoxic and stress signals activate lysine demethylase 5B, which mediates the demethylation of H3K4me2/3 at the ATF3 promoter, correlating with transcriptional repression of the antifibrotic factor ATF3 and adverse cardiac remodeling.58 In aging aortic tissues, a significant downregulation of protein arginine methyltransferase 1 contributes to decreased histone activation marker abundance (H3K9ac and H4R3me2a) while increasing levels of the repressive marker H3K27me3 within the promoter region of genes coding for cardiac myosin, culminating in reduced aortic contractility and vascular dysfunction.59 Cardiac tissue-derived stem cells (CSCs), a newly identified subgroup of cardiac stem cells, exhibit notable alterations in their metabolic and epigenetic characteristics as they transition from a neonatal to a senescent state. Compared to neonatal counterparts, CSCs sourced from senescent myocardium display reduced ratios of histone acetylation and diminished activity in enzymes linked to the cytoplasmic acetyl-CoA synthesis pathway, including adenosine citrate triphosphate lyase and cytoplasmic acetyl-CoA synthetase. This observation implies a potential interplay between histone acetylation modifications and the metabolic landscape of aging cardiac tissue.60

Histone methylation primarily occurs at arginine and lysine residues on histones H3 and H4, regulated by histone methylases and demethylases.61 In the cardiac milieu, the modulation of histone methylation significantly influences mitochondrial dysfunction, DNA repair mechanisms, myocardial hypertrophy, and fibrosis. In a model involving a high-salt diet and coupling factor 6 overexpression, they demonstrated that sustained intracellular acidosis triggers a premature aging phenotype in mice.62 Specifically, they observed increased trimethylated H3K4 and H4K20 levels, with a concurrent decrease in trimethylated H3K9 and H3K27. However, the underlying mechanisms by which abnormal histone methylation contributes to cardiac aging remain inadequately explored in this research.

Long-term chronic stress in the heart has been evidenced to elevate H3K4me3 and H3K9me3 abundances, leading to heterochromatin formation in genomic repeat elements and mitochondrial dysfunction, ultimately resulting in ventricular remodeling and chronic heart failure.63 Inhibitors targeting the H3K9 trimethylation modification enzyme effectively ameliorated these deleterious outcomes. Gene ontology analyses have elucidated that mitochondrial-related genes impacted by H3K9 trimethylation include Pgc1α, Acadm, and Ndufs4. Moreover, losses associated with aging-related histone methylation also play a critical role in DNA damage repair processes. Research by Liu et al. [16] indicates that the aberrant accumulation of miR‑29a/b, driven by the TGF-β signaling pathway, inhibits H4K20 tri methylase Suv4-20 h, resulting in the depletion of H4K20me3. This depletion directly obstructs DNA damage repair mechanisms, subsequently inducing senescence in isolated cardiomyocytes and declining cardiac function in murine models. Additionally, protein arginine methyltransferase five is identified as a crucial gene modulating rational hypertrophy in aging cardiomyopathy, with its expression significantly diminished in aging myocardium.64 Further investigations reveal that the absence of symmetric dimethylation at histone lysine H3R4, mediated by protein arginine methyltransferase 5, disrupts β-catenin degradation via interactions with filament protein A interacting protein-1-like a pathway, leading to its accumulation in cardiomyocytes-and subsequent cardiac hypertrophy.65 Notably, the progressive accumulation of abnormal histone methylation in cardiomyocytes with age often leads to chromosomal heterochromatin formation and impaired DNA repair capabilities. Overall, histone methylation modifications in aging myocardium typically increase transcriptional activation markers, such as H3K4me3, while exhibiting a decrease in the repressive markers H3K9me3 and H3K27me3. However, variations in modification site-specific changes have been observed, underscoring that the unique responses of histone methylation modifications can differ based on the context and model examined. Thus, elucidating the mechanisms by which histone methylation affects target-specific genes is vital for understanding its precise role in cardiac aging.

Histone acetylation, impacting lysine residues on the N-terminal of histone proteins, comprises a dynamic and reversible process orchestrated by histone acetylases and histone deacetylases (HDACs). This modification predominantly influences DNA damage repair and the transcriptional regulation of aging-related genes. Observations in aging myocardium generally reveal an elevated abundance of histone acetylation alongside an upregulation in transcriptional activities and the exacerbation of DNA damage. They established a link between dihydrosphingosine levels and histone acetylation, highlighting its correlation with aging-associated cardiac dysfunction.66 Specifically, sphingosine 1-phosphate, a phosphorylated dihydrosphingosine product and recognized cardiac aging marker, directly inhibits HDAC1/2 activity. Consequently, this modulation increases acetylation levels of histones H4K16, H3K27, and H3K56, aggravating DNA damage and compromising genomic integrity, thereby promoting the senescence phenotype in cardiomyocytes and contributing to cardiac dysfunction.

Curcumin, an inhibitor of histone acetylation, has been shown to reverse the cardiomyocyte aging effects induced by dihydrosphingosine accumulation partially. These findings imply that HDACs and histone acetylases regulate cardiac aging. Yet, a prevailing body of evidence supports that deleting HDACs predominantly drives the aging-related pathological mechanisms within cardiac tissues. For instance, the anti-aging activities attributed to Sirt6, a member of the nicotinamide adenine dinucleotide-dependent HDAC family (sirtuins, Sirt), demonstrate multifaceted effects across various pathological processes. In the context of myocardial fibrosis, Sirt6 inhibits the activity of Smad3 by facilitating its deacetylation, thereby obstructing its binding to promoter regions of TGF-β. Simultaneously, Sirt6 directly attenuates the transcriptional activity of TGF-β by reducing the levels of H3K9ac and H3K5ac within its promoter region, collaboratively exerting inhibitory effects on the TGF-β/Smad3 pathway linked to myocardial fibrosis.67 Additionally, under conditions where self-deacetylation activity is inhibited by the transcription factor GATA4, Sirt6 recruits the histone acetylase TIP‑60 within the promoter region of Bcl, enhancing GATA4 activity and augmenting the abundance of H3K9ac protein. This process fortifies the expression of Bcl and other anti-apoptotic genes, subsequently protecting cardiomyocytes from apoptosis. Sirt6 further enhances the expression of the IκBα gene by mediating the monoubiquitination of H3K9Me3-specific histone methyltransferase Suv39h1, consequently promoting the acetylation of H3K9 within the IκBα activator region marked by H3K9me3 and mitigating inflammatory responses regulated by nuclear factor kappa B.68,69

Moreover, other HDACs, including Sirt1, Sirt3, Sirt7, HDAC2, and HDAC3, have also been implicated in regulating cardiac aging. However, current literature lacks a comprehensive examination of the specific molecular mechanisms through which these enzymes influence cardiac aging, leaving it unclear whether their anti-aging effects rely extensively on histone acetylation activities and modifications at pertinent sites.70,71 Throughout the aging process, characterized by global transcriptional activation, histone acetylation trends suggest an increase in overall acetylation levels alongside a decrease in localized acetylation markers. The transcriptional regulation linked to histone acetylation, however, is recognized for its complexity, frequently involving cooperative interactions with other epigenetic modifications such as histone methylation, DNA methylation, and a variety of post-translational modifications, contributing to the functional diversity of HDACs in their regulatory roles.

In addition to the well-established histone modifications of methylation and acetylation, histone phosphorylation emerges as a critical epigenetic mechanism influencing cardiac aging. Research has elucidated that the phosphorylation of Ser‑139 residues in the variant histone H2AX is a vital early event indicative of DNA double-strand break responses, with significant elevation observed in the levels of γ‑H2AX protein within the cardiac tissue of mice deficient in telomere-associated Rap1.72,73 The primary modification sites for histone phosphorylation include serine, threonine, and tyrosine residues on histone H3, where phosphorylation is crucial in modulating the biological and qualitative changes associated with cardiac aging correlates.

Calcium/calmodulin-dependent kinase II (CaMKII) is a pivotal enzyme mediating histone H3 phosphorylation, influencing various cardiac pathologies. they demonstrated that both CaMKII isoforms, CamKⅡδ and CaMKⅡα, can directly facilitate the phosphorylation of histone H3 at the S10 position in cardiomyocytes, albeit with differing functional outcomes.74 Specifically, hyperphosphorylation of histone H3 mediated by CaMKIIδ is primarily associated with pathological manifestations such as cardiac hypertrophy and fibrosis. In contrast, CaMKIIα localized in the nucleus enhances the expression of cardioprotective proteins, including heat shock proteins and Bcl-2, thereby exerting a protective effect under conditions of cellular stress.

Notably, they reported a significant increase in the phosphorylation levels at histone H3S28 in myocardial tissues from patients suffering from end-stage heart failure, with a subsequent reduction in phosphorylation levels following β-receptor blocker administration.75 This suggests that phosphorylation at the histone H3S28 site may be linked to the detrimental effects of chronic β-adrenergic receptor activation. Their findings further confirmed that CaMKII is a major mediator of histone H3S28 phosphorylation in response to β-adrenergic stimulation, enhancing phosphorylation levels under catecholamine-induced pressure. Nonetheless, the precise mechanisms through which H3S28 phosphorylation contributes to myocardial hypertrophy and the progressive decline of cardiac function remain fully elucidated. They recently shed light on the hypertrophic impact of histone H3S28 phosphorylation, which is mediated by mitogen-activated protein kinases (MAPKs).76 Under stress conditions, signaling pathways activate MAPKs, facilitating early gene responses and promoting cardiomyopathic hypertrophy through increased histone H3S28 phosphorylation. Additionally, drug toxicity has emerged as a significant contributor to elevated phosphorylation levels of histones associated with myocardial hypertrophy. They conducted toxicology studies on primary rat cardiomyocytes, revealing a marked increase in the phosphorylation levels of histone H3S10 following a 72-hour exposure to rosiglitazone.77 This was accompanied by chromatin remodeling and the activation of genes related to hypertrophic responses. The mechanisms governing histone phosphorylation in cardiac tissues are relatively straightforward. They typically serve as stress responses activated by various stressors or toxic stimuli. However, prolonged elevations in histone phosphorylation levels resulting from chronic stress are crucial in mediating rational remodeling associated with heart disease. Targeted interventions to modulate histone phosphorylation may present practical strategies for managing aging-related cardiac hypertrophy.

Interventions targeting mitochondrial dysfunction linked to aging focus on optimizing electron transport, enhancing mitophagy, and mitigating reactive oxygen species (ROS) generation and mutations in mitochondrial DNA (mtDNA). The reduction of ROS formation within mitochondria has been a longstanding concern, and significant progress has been made in managing ROS concentrations over recent decades.

Ferulic acid, a naturally occurring compound recognized for its antioxidant properties, acts as a free radical scavenger by inhibiting ROS accumulation, thereby contributing to longevity and resilience against stress. Furthermore, to address aging-related declines in oxidative phosphorylation (OXPHOS), acetylcarnitine—a metabolite indicative of acetyl-CoA—promotes the transcription of mitochondrial DNA associated with electron transport chain (ETC) subunits. metformin (Glucophage) has also emerged as a significant agent in enhancing mitochondrial respiration and is correlated with increased longevity in patients. Notably, it was the first medication to have its effects on aging, and it was rigorously tested in a pivotal clinical trial known as TAME. Retrospective analyses of diabetic patients treated with metformin (Glucophage) have indicated a longer lifespan compared to non-diabetic individuals. Coenzyme Q (CoQ) plays an essential role in the mitochondrial respiratory chain by functioning as an electron acceptor, capturing electrons from ROS. Moreover, CoQ serves as a necessary cofactor for OXPHOS. However, CoQ levels tend to diminish with age, and patients with heart failure exhibit significantly reduced plasma CoQ concentrations. Research from the Q-SYMBIO study suggests that administering Coenzyme Q10 may help alleviate symptoms in heart failure patients, reduce the risk of major adverse cardiovascular events (MACEs), and potentially assist in managing chronic heart failure. Numerous preclinical studies have consistently demonstrated that CoQ can reduce oxidative stress within the heart, thus improving aging-associated mitochondrial dysfunction. Clinical trials in cardiovascular disease contexts have further shown that CoQ supplementation can mitigate fibrosis and the effects of aging in cardiac tissue. An improved formulation, Mitoquinol mesylate (MitoQ), is synthesized by conjugating CoQ with the lipophilic cation TPP+, which enhances its absorption by mitochondria. Animal studies have validated MitoQ’s anti-heart failure and anti-aging properties. Nevertheless, further research is needed to elucidate the specific roles of MitoQ and CoQ in cardiac aging, as there is limited evidence regarding their clinical application in human patients in Fig. 6.

Another promising potential strategy for influencing ROS levels in cardiac aging involves the activity of specific cytokines, microRNAs (miRNAs), and exosomes derived from the heart or other distant organs.