Cardiac remodeling is frequently regarded as a pivotal factor influencing the clinical progression of HF. Cardiac remodeling is defined as changes in genomic expression leading to molecular, cellular and interstitial modifications, clinically evident as an increase in cardiac volume due to hemodynamic overload or injury, and a transformation in cardiac shape from elliptical to spherical, resulting in alterations in ventricular dimensions and both systolic and diastolic dysfunction (14, 19, 20). Cardiac remodeling is influenced by hemodynamic stress, neurohormonal activation and additional mechanisms now under investigation. The key steps leading to cardiac remodeling include cardiac hypertrophy, cardiomyocyte loss and interstitial fibrosis. During this remodeling, fibroblasts differentiate into myofibroblasts, activating their secretory functions and producing large amounts of extracellular matrix proteins. This results in scar tissue formation, which impedes the normal contractile function of cardiomyocytes, ultimately contributing to the development of HF in the long term (21, 22). Additional components involved include the interstitium, collagen and the coronary vascular system, with associated processes including ischaemia, cell necrosis and apoptosis. Patients with severe remodeling show progressive deterioration of cardiac function, with severe cases progressing to HF stages. Nonetheless, factors beyond remodeling can also influence the course of heart disease, and disease progression may occur in other ways in the absence of cardiac remodeling (19).

As a result of reduced cardiac output several neuroendocrine systems are activated, including the renin-angiotensin-aldosterone system (RAAS), arginine vasopressin system (AVPS) and the sympathetic nervous system (SNS). The persistent neurohormonal activation of the RAAS, AVPS and SNS plays a key role in the progression of HF. Extended activation of these systems leads to tachycardia, increased systemic vascular resistance, vasoconstriction, sodium and water retention, which in turn increases cardiac load and exacerbates HF. In addition, it leads to polyadrenergic receptor desensitization, cardiomyocyte hypertrophy, necrosis, cellular dysmorphism, myocardial fibrosis, renal arteriolar and venous vasoconstriction, diminished response to natriuretic peptides (NPs), peripheral vasoconstriction and vascular hypertrophy, and cardiac arrhythmia et al. (20, 23).

HF is characterized by pathological hemodynamic disturbances, including elevated cardiac filling pressures, which is associated with reduced cardiac output. The hemodynamic abnormalities in HF are not only influenced by cardiomyocytes, but also include important processes such as pericardial restriction, ventricular interactions and altered venous volumes (24). As the failing heart attempts to maintain adequate function, several compensatory mechanisms occur to ensure relatively normal cardiac output and maintain adequate cardiac function, including increased cardiac output and ventricular end-diastolic volume via the Frank-Starling mechanism, which increases cardiac output and cardiac workload, escalated ventricular volume and wall thickness via ventricular remodeling and maintained tissue perfusion by activating the neurohormonal system to increase mean arterial pressure, leading to increased myocardial contractility and sodium and water retention (25). The initial augmentation of ventricular wall thickness compensates for the heightened workload. However, it progressively diminishes cardiac diastolic function and leads to HF (16). These compensatory mechanisms, while initially beneficial in the early stages of HF, eventually lead to a vicious cycle of worsening HF (25). In addition, cardiac remodeling-induced cardiac changes can impair systolic function and reduce stroke volume output (26). Additionally, myocardial fibrosis, valve dysfunction and arrhythmias can also compromise systolic and diastolic function, thereby affecting cardiac output (16).

Decreased and impaired function of cardiomyocytes, including altered calcium handling and energy production (14), leads to impaired cardiac contractile function, cardiomyocyte apoptosis, myocardial ischemia and myocardial fibrosis. Among them, myocardial fibrosis destroys myocardial structure and leads to myocardial disorders, affecting the systolic and diastolic functions of the heart, leading to structural changes and inducing arrhythmias (27). Moreover, myocardial infarction significantly contributes to ventricular remodeling and the subsequent development of HF (28). Damage to cardiomyocytes involving inflammation, oxidative stress and impaired myocardial energy metabolism, they also are important causes of HF (14). Inflammation contributes to the pathogenesis and progression of HF through different mechanistic pathways. The HF state is characterized by an imbalance between pro-inflammatory and anti-inflammatory cytokines (29). The pro-inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) both induce systolic and diastolic dysfunction, and the latter also promotes adverse cardiac remodeling (30). Oxidative stress characterized by the generation of reactive oxygen species (ROS) and intrinsic energy metabolism. The generation of ROS and endogenous antioxidant defense systems are significant factors in the pathogenesis of cardiac remodeling and HF (31). When existing at low concentrations, ROS exert a pivotal function in maintaining cellular homeostasis. Nevertheless, an excess of ROS can lead to cellular dysregulation, lipid peroxidation, cellular injury and apoptosis. Ultimately, through the induction of cardiac fibroblast proliferation and the activation of matrix metalloproteinases, it triggers extracellular matrix remodeling, displaying profibrogenic properties. This process significantly influences the onset and progression of HF, contributing to the exacerbation of the pathological state (32). Van Bilsen et al. proposed the concept of myocardial metabolic remodeling in the context of myocardial energy metabolism disorders. They posited that HF induces a disturbance in the metabolism of carbohydrates and fats within myocardial cells, leading to alterations in the cardiac energy metabolic pathway and resulting in the abnormal structure and function of myocardial cells (33). There is increasing evidence that impaired myocardial energy metabolism can be one of the causes of HF, and HF can also exacerbate impaired myocardial energy metabolism. Therefore, reducing excessive myocardial energy expenditure and improving myocardial energy metabolism can improve the prognosis of HF (34).

Endothelial cells are a monolayer of cells that cover the inner surface of blood vessels and act as a functional and structural barrier between the blood and the vessel wall, preventing platelets and leukocytes from adhering and aggregating, controlling permeability to plasma constituents, and regulating blood flow (35). Endothelial dysfunction, characterized by an imbalance in nitric oxide (NO, be defined in subsequent use) production and an increase in endothelin-1, leads to a shift in endothelial function toward reduced vasodilation, a pro-inflammatory state and pro-thrombotic properties. This is also one of the early mechanisms determining the decrease in organ perfusion, intolerance to physical exertion and the progression of HF. Additionally, it is associated with cardiovascular diseases such as coronary artery disease, hypertension and chronic HF (36–38). It leads to impaired vasodilation and compromised coronary blood flow and increased vascular resistance. This endothelial dysfunction leads to increased afterload, which puts additional stress on the heart. Some studies have shown that inflammation also induces endothelial dysfunction (16).

Mitochondria are key double-membrane organelles for aerobic respiration in eukaryotic cells, mainly producing adenosine triphosphate (ATP) to provide energy for the organism, and participating in processes such as calcium homeostasis, lipid synthesis and regulation of apoptosis (39, 40). The heart, as the most metabolically active organ with the highest mitochondrial content, relies mainly on ATP generated by fatty acid oxidative metabolism to provide energy to maintain cardiac systolic and diastolic functions under physiological conditions. Bioenergetic homeostasis is accomplished almost exclusively through the “energy web” composed of the mitochondrial network and its associated phosphate transfer pairs (39). Common mitochondrial dysfunctions include decreased bioenergetics, increased oxidative stress, dysregulation of calcium homeostasis and altered mitochondrial dynamics (41). Mitochondrial dysfunction is thought to be one of the important pathogenetic mechanisms affecting cardiovascular diseases and is mainly associated with mitochondrial DNA (mtDNA) mutations, impaired mitochondrial autophagy, and elevated levels of mitochondria-derived ROS. Specifically, mitochondrial dysfunction has an important role in atherosclerosis, ischemic or reperfusion injury, calcium dyshomeostasis, neurodegenerative diseases, and cardiac systolic-diastolic dysfunction (41, 42).

Cardiac hypertrophy is the result of compensatory hypertrophy of myocardial tissue, which is divided into physiological hypertrophy and pathological hypertrophy. In physiological hypertrophy, the heart has normal or enhanced contractile function, reversible hypertrophy, and intact energy metabolism without causing HF. In pathological hypertrophy, the heart is associated with cardiomyocyte death, myocardial fibrosis, incomplete reversibility of hypertrophy, and metabolic remodeling of the myocardium, which ultimately leads to systolic dysfunction and HF (99). Francesco S Loffredo et al. demonstrated that heterochronic parabiosis is able to reverse age-related cardiac hypertrophy. Further screening studies showed that GDF11 is a mediator of systemic anti-hypertrophic activity in young mice and has powerful anti-hypertrophic properties (90). Ke Yang et al. found that Klotho is predominantly synthesized in the kidneys and subsequently released into the serum. It has antioxidant activity and can inhibit the cardiomyocyte hypertrophy induced by indoxyl sulfate (an important uremic solute) by blocking oxidative stress and inhibiting the signaling pathways of p38 and ERK1/2 (91). Myocardial fibrosis is a pathological process in which excessive deposition of fibrous connective tissue in myocardial tissue leads to structural and functional abnormalities of myocardial fibers, affecting cardiac diastolic function, leading to arrhythmias and increasing the risk of cardiovascular events. Yuliang Feng et al. demonstrated that exosomes secreted by mesenchymal stem cells after ischemic preconditioning contain miR-22 that targets Mecp2. Through this mechanism, these exosomes can significantly reduce apoptosis of ischemic cardiomyocytes and myocardial fibrosis (92). Kai Chen et al. proved that cardiac-specific overexpression of glutathione reductase (a flavoprotein oxidoreductase, GR) attenuates cardiac fibrosis in aged mice, and Klotho secreted by young mice largely ameliorated Klotho deficiency-induced and aging-associated cardiac diastolic dysfunction (71).

The decline in tissue regenerative capacity is a hallmark of aging and may be due to age-related changes in tissue-specific stem cells. Conboy et al. established paracrine pairs through heterochronic parabiosis and reveal that stem and progenitor cells retained their proliferative potential even in aging, and that serum from young animals reactivated the regeneration of senescent tissues (93). Shuai Ma et al. have found that hematopoietic stem and progenitor cells are sensitive to the environment of young blood by constructing an allogeneic symbiosis model and mapping the single-cell transcriptome, as well as the fact that young blood can induce changes in hematopoietic and immune systems by restoring the levels of key transcription factors, such as activating transcription factor (Atf)3, Atf4 and C-C motif chemokine ligand (CCL3), which promotes the activation of stem cells and systematic rejuvenation of senescent tissues (100). Manisha Sinha et al. demonstrated that supplementation of the body’s GDF11 levels through heterochronic symbiosis or systemic delivery of recombinant proteins reversed functional impairment and restored the integrity of gene organization in senescent muscle stem cells, suggesting an ameliorative effect of GDF11 on age-related skeletal muscle and stem cell dysfunction (76).

Declining mitochondrial bioenergetics is a characteristic feature of the aging process. Jenny L Gonzalez-Armenta et al. demonstrated that circulating factors themselves can mediate age-related structural and functional changes in mitochondria by using a heterochronic symbiosis model (101). Francisco Alejandro Lagunas-Rangely noted that heterochronic symbiosis of EV in young mice increased the expression of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) in older mice through its miRNA carriers. These miRNAs respectively target amyloid β precursor protein, poly [ADP-ribose] polymerase 2, and HIF-1α inhibitor, which enhances mitochondrial function and attenuating mitochondrial defects in aging tissues (94). In addition, Xiaorui Chen et al. showed that young EVs stimulate PGC-1α expression both in vitro and in vivo via their miRNA cargo, improving mitochondrial function and enhancing mitochondrial energy metabolism to ameliorate degenerative changes and age-related dysfunctions, including cardiac (48).

Vascular senescence is a degenerative change that occurs in the body with age and is manifested by thickening of the vascular wall, reduction of elastic fibers and dysfunction of endothelial cells. Endothelial cells are essential for vascular homeostasis, maintenance of blood flow, regulation of vascular tone, pro-inflammatory responses and neovascularization. Senescent endothelial cells display a flattened and enlarged morphology, reduced NO bioavailability, and increased secretion of various pro-inflammatory cytokines. The accumulation and deposition of which leads to vascular dysfunction and vascular senescence, and also promotes inflammation, thrombosis and atherosclerosis (102). Tamas Kiss et al. showed that, through a heterotopic symbiosis model, young blood can inhibit mammalian target of rapamycin (mTOR) signaling through activation of the PGC-1α and insulin-like growth factor 1 receptor (IGF1R) -mediated pathway and inhibiting mTOR signaling to promote vascular rejuvenation, improve NO-mediated endothelium-dependent vasodilation and attenuate vascular oxidative stress in aged mice (95). Plasma HDL content decreases with age. Ben J Wu et al. demonstrated that young plasma inhibits endothelial inflammation and decelerates vascular endothelial cell senescence through HDL-promoted 24-dehydrocholesterol reductase (DHCR24) expression, which in turn mediates PI3K/AKT/heme oxygenase-1 (HO-1) signaling pathway (96). In addition, Xiaorui Chen et al. demonstrated that young EVs not only improves cognitive function, counteracts mitochondrial defects, and enhances in vitro respiratory capacity by stimulating PGC-1α expression and enhancing mitochondrial energy metabolism, but also rejuvenates senescent tissues and inhibits cellular senescence, which is an indication of the ability of young EVs to ameliorate vascular endothelial cell aging (48).

Blood is a fluid tissue composed of plasma and blood cells, and plasma is the liquid component of blood, accounting for about 55% of the blood volume. Shiyao Wei et al. found that young plasma by decreasing the expression of pro-inflammatory chemokines in angiotensin II-stimulated pericytes which are located between the endothelial cells of capillaries and the basement membranes, and which have physiological functions such as regulating vascular function, participating in angiogenesis and immunomodulation), the pro-inflammatory and pro-fibrotic effects of angiotensin II on pericytes can be ameliorated (97), thus contributing to attenuating the effects of inflammation on the development and progression of HF. Kai Chen et al. found that exogenously secreted Klotho promotes the expression of GR through Nrf2 activation, and verified that cardiac-specific expression of GR can diminish oxidative stress and apoptosis in the hearts of aged mice, with a protective effect against age-related cardiac injury (71). Shaina Ailawadi et al. found that multiple sources of stem cells, stress preconditioned cells, and genetically modified cells can generate cardioprotective exosomes to mitigate inflammation and oxidative stress in the heart (98, 103).