Cardiovascular ageing: hallmarks, signaling pathways, diseases and therapeutic targets.

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Learn more: PMC Disclaimer | PMC Copyright Notice Signal Transduct Target Ther . 2026 Apr 21;11:142. doi: 10.1038/s41392-026-02630-7 Search in PMC Search in PubMed View in NLM Catalog Add to search Cardiovascular ageing: hallmarks, signaling pathways, diseases and therapeutic targets Pingjing Zheng Pingjing Zheng 1 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China 2 National Clinical Research Center for Interventional Medicine, Shanghai, China 3 State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China 4 NHC Key Laboratory of Ischemic Heart Diseases, Shanghai, China 5 Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China Find articles by Pingjing Zheng 1, 2, 3, 4, 5, # , Wendi Yan Wendi Yan 1 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China 2 National Clinical Research Center for Interventional Medicine, Shanghai, China 3 State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China 4 NHC Key Laboratory of Ischemic Heart Diseases, Shanghai, China 5 Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China Find articles by Wendi Yan 1, 2, 3, 4, 5, # , Yangnan Ding Yangnan Ding 6 Department of Laboratory Medicine, Zhengzhou Key Laboratory for In Vitro Diagnosis of Hypertensive Disorders of Pregnancy, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China Find articles by Yangnan Ding 6, # , Yang Zhang Yang Zhang 1 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China 2 National Clinical Research Center for Interventional Medicine, Shanghai, China 3 State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China 4 NHC Key Laboratory of Ischemic Heart Diseases, Shanghai, China 5 Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China Find articles by Yang Zhang 1, 2, 3, 4, 5, ✉ , Zhangwei Chen Zhangwei Chen 1 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China 2 National Clinical Research Center for Interventional Medicine, Shanghai, China 3 State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China 4 NHC Key Laboratory of Ischemic Heart Diseases, Shanghai, China 5 Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China Find articles by Zhangwei Chen 1, 2, 3, 4, 5 , Juying Qian Juying Qian 1 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China 2 National Clinical Research Center for Interventional Medicine, Shanghai, China 3 State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China 4 NHC Key Laboratory of Ischemic Heart Diseases, Shanghai, China 5 Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China Find articles by Juying Qian 1, 2, 3, 4, 5, ✉ , Junbo Ge Junbo Ge 1 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China 2 National Clinical Research Center for Interventional Medicine, Shanghai, China 3 State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China 4 NHC Key Laboratory of Ischemic Heart Diseases, Shanghai, China 5 Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China Find articles by Junbo Ge 1, 2, 3, 4, 5, ✉ Author information Article notes Copyright and License information 1 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China 2 National Clinical Research Center for Interventional Medicine, Shanghai, China 3 State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China 4 NHC Key Laboratory of Ischemic Heart Diseases, Shanghai, China 5 Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China 6 Department of Laboratory Medicine, Zhengzhou Key Laboratory for In Vitro Diagnosis of Hypertensive Disorders of Pregnancy, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China ✉ Corresponding author. # Contributed equally. Received 2025 Mar 5; Revised 2025 Sep 15; Accepted 2026 Jan 23; Collection date 2026. © The Author(s) 2026 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . PMC Copyright notice PMCID: PMC13096361  PMID: 42010239 Abstract Cardiovascular disease (CVD) predominantly affects elderly individuals and is the leading cause of morbidity, disability, and mortality worldwide. Systemic ageing, especially cardiovascular ageing, contributes to the development of CVD phenotypes and outcomes. Therefore, in this review, we innovatively summarize the five major etiologies and risk factors for cardiovascular ageing, including lifestyle and behavioral factors, metabolic disorders and physiological dysregulation, environmental exposures and physicochemical determinants, genetics and epigenetics, and host biology and sociodemographic determinants. Furthermore, we enumerate the structural and functional changes that occur in the cardiovascular ageing process. The twelve hallmarks of cardiovascular ageing, including genomic instability and epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, oxidative stress, and inflammation; cellular dysfunction; cellular senescence; stem cell exhaustion; metabolic changes; and the renin‒angiotensin‒aldosterone system, β-adrenergic signaling, growth signaling, and mechanosignaling, stratify across three dimensions: molecular, cellular, and systemic levels. Given the elucidated role of cardiovascular ageing in diverse pathologies, we propose specific rejuvenation strategies to mitigate residual cardiovascular risk in older adults: targeting senescent cells, adjusting energy sensor pathways, addressing central inflammatory pathways, modulating neurocardiological dynamics, adopting healthy lifestyles, and assessing and preventing the degree of ageing. We also list FDA-approved drugs and clinical trials targeting cardiovascular ageing, thus serving as a cutting-edge reference for developing intervention strategies. Subject terms: Cardiology, Molecular medicine, Therapeutics, Cardiovascular diseases Introduction Cardiovascular disease (CVD) is the leading cause of mortality and morbidity worldwide. Between 1990 and 2019, the global number of CVD patients nearly doubled, increasing from 271 million to 523 million, whereas related deaths increased from 12.1 million to 18.6 million. 1 It is not only the primary contributor to premature death but also imposes a continuously growing economic burden on healthcare systems. Even though the abundance of novel therapies has proven markedly efficient in reducing the cardiovascular mortality, the residual cardiovascular risk remains significantly high. Thus, there is an urgent need to increase CVD prevention and treatment efforts. 2 In general, CVD risk factors can be broadly categorized into modifiable and nonmodifiable factors. CVD is largely driven by a set of modifiable risk factors, including smoking, unhealthy diet, physical inactivity, excessive alcohol consumption, hypertension, dyslipidaemia, diabetes mellitus, obesity, and psychosocial stress. 1 In addition, nonmodifiable risk factors include age, sex, and genetics. 3 Indeed, advancing age is strongly associated with structural and functional decline of the heart and vasculature. Cardiac ageing involves structural changes such as fibrosis and reduced functional reserve. 4 – 6 Vascular ageing is characterized by endothelial dysfunction, arterial stiffness and chronic inflammation. 7 – 9 Together, they impair cardiovascular adaptability and heighten disease risk. Consequently, older adults bear the greatest burden of CVD, including heart failure, atrial fibrillation, and atherosclerotic complications. 10 Although the increase in age is irreversible, recent studies challenge the conventional view of ageing as an inevitable consequence of time accumulation, demonstrating that the pace of ageing differs across species, individuals, and even specific organs. 11 , 12 These variations are driven by a complex interplay of factors, including lifestyle behaviors, metabolic disorders, environmental exposures, and genetic–epigenetic determinants, which collectively accelerate cardiovascular functional decline. Interventions such as lifestyle modifications, pharmacological treatments, and targeted therapies aimed at ageing-related pathways have been shown to effectively modulate the cardiac ageing process. 13 – 15 This emerging perspective views ageing as a modifiable condition driven by multiple pathological factors, suggesting that delaying or even reversing age-related CVD through targeted intervention may be possible. 16 Cardiovascular ageing has been subjected to rigorous scientific investigation for over a century, yielding substantial pathophysiological insights, as summarized in Fig. 1 . Early observations by William Osler that “a man is as old as his arteries” underscored the centrality of vascular health in organismal ageing. The mid-20th century established key theories linking ageing to cardiac function and oxidative stress. While the late 20th century identified pivotal mechanisms such as endothelial nitric oxide synthesis. The early 21st century marked a turning point with the discoveries of cellular senescence in plaques, the senescence-associated secretory phenotype, and the development of epigenetic clocks. Since around 2015, the field has accelerated toward translation, exemplified by the advent of senolytics, the launch of human clinical trials, and the systematic definition of cardiovascular ageing hallmarks and biomarkers. Recent breakthroughs in molecular gerontology and targeted anti-ageing therapies have stimulated transformative research into age-related cardiovascular disorders. Therefore, a systematic discussion of the related advances and challenges is urgently needed. Fig. 1. Open in a new tab Timelines of key discoveries in cardiovascular ageing research. Since 1892, when William Osler proposed that “a man is only as old as his arteries,” research on cardiovascular ageing formally commenced. Prior to the 21st century, investigations were largely confined to tissue-level changes. The landmark discovery of the senescence-associated secretory phenotype (SASP) in 2008 marked a paradigm shift, demonstrating that ageing research extends beyond senescent cells themselves. Following the 2015 conceptualization of senolytics, targeted therapeutics advanced progressively, culminating in the first published human clinical trials in 2019. China’s 2022 establishment of the ageing Biomarker Consortium (ABC) yielded its foundational consensus document, Biomarkers of ageing. Subsequent to the 2023 proposal of the eight hallmarks of cardiovascular ageing, ABC released two additional frameworks elucidating cardiovascular senescence. The 2024 Wiggers-Bernard Conference on In Vivo Senescence produced widely endorsed guidelines coauthored by field leaders, whereas the NIH-funded SenNet Consortium concurrently proposed standardized protocols for detecting senescent cells across tissues. Created in BioRender (2025) https://BioRender.com/y4u6ysw This review synthesizes current knowledge on cardiovascular ageing, emphasizing that its progression is accelerated not merely by time but by a complex network of etiologies and risk factors, which is a comprehensive integration not previously consolidated. A key contribution is the novel stratification of established hallmarks into three interconnected tiers: molecular, cellular, and systemic. This framework clarifies their roles while highlighting their essential crosstalk. Furthermore, the mechanistic links between these ageing hallmarks and diverse age-related diseases are elucidated, providing a foundation for targeted clinical translation. While promising therapeutic strategies are emerging, their potential side effects warrant careful consideration. For instance, senolytic agents that clear senescent cells may carry risks such as impaired tissue repair. 17 Elucidating the processes of cellular senescence, along with their associated hallmarks and signaling pathways, offers new insights into ageing biology and opens promising avenues for addressing CVD in an integrated, system-level framework. Ultimately, advancing cardiovascular health in ageing populations will require strategies that effectively target core ageing mechanisms while diligently managing treatment-related risks. The etiology and risk factors for cardiovascular ageing Cardiovascular ageing is a biological process resulting from the progressive accumulation of cellular, tissue, and organ damage over time, leading to functional and structural decline. With increasing age, the accumulation of molecular damage progressively increases. For example, arteries and the myocardium exhibit progressive stiffening and enhanced fibrotic remodeling, 18 , 19 , whereas the maximal heart rate decreases linearly with age. 4 Moreover, in addition to chronological ageing itself, specific factors may contribute to or accelerate cardiovascular ageing, as shown in Fig. 2 . Fig. 2. Open in a new tab The etiology and risk factors for cardiovascular ageing. The etiological framework of cardiovascular ageing encompasses five principal categories: lifestyle and behavioral factors, metabolic disorders and physiological dysregulation, environmental exposures and physicochemical determinants, genetics and epigenetics, and host biology and sociodemographic determinants. Each category includes multiple specific risk factors. All etiology and risk factors form a highly intricate and interconnected complex network. They may work synergistically or antagonistically, exerting cumulative and sometimes even multiplicative effects. Created in BioRender (2025) https://BioRender.com/1w0a7po Lifestyle and behavioral factors Lifestyle and behavioral factors constitute significant contributors to the pathogenesis of cardiovascular ageing. As shown in Fig. 2 , chronic exposure to unhealthy lifestyle patterns (including excessive caloric intake, suboptimal nutritional status, physical inactivity, psychological stress, and tobacco use) accelerates the deterioration of cardiovascular function. Tobacco smoking is a well-established risk factor for accelerated vascular ageing, demonstrating associations with both clinical manifestations of premature cardiovascular senescence and protein-based biomarkers. 20 Comparative analyses indicate that smokers present significantly greater proportions of senescent and dysfunctional endothelial progenitor cells (EPCs) than nonsmokers do. 21 Additionally, their endothelial cells show heightened susceptibility to stress-induced premature senescence. 22 With respect to exercise interventions, long-term physical training has demonstrated substantial efficacy in attenuating age-related cardiovascular functional decline. 23 Conversely, sedentary behavior in otherwise healthy adults correlates with accelerated cardiovascular ageing trajectories, manifested through increased arterial stiffness, impaired endothelial function, and elevated mortality risk. 24 Being overweight itself significantly accelerates cardiovascular ageing. 25 At the dietary level, higher dietary quality indices and adherence to Mediterranean dietary patterns are associated with favorable vascular ageing risk profiles. 26 Both Mediterranean diets and omega-3-enriched nutritional regimens exert protective effects against vascular ageing. 27 , 28 Caloric restriction strategies have the potential for optimizing vascular architecture and function. 29 Furthermore, lifestyle modifications, including increased physical activity, reduced sedentary behavior, and body weight management, effectively ameliorate vascular ageing phenotypes. 30 Psychological determinants warrant equal consideration. For example, incarceration-related stress in familial/social networks correlates with validated vascular ageing biomarkers. 31 Clinical depression elevates coronary artery disease risk, 32 whereas anxiety disorders are associated with increased cardiac mortality. 33 Nevertheless, the relationships between psychological factors (including depression, anxiety disorders, and chronic stress) and cardiovascular ageing require further investigation. Metabolic disorders and physiological dysregulation In one cross-sectional study, investigators employed machine learning algorithms to quantify cardiovascular age in 39,559 participants from the UK Biobank, revealing that cardiometabolic risk factors (hypertension, diabetes, and dyslipidemia) collectively accelerate cardiovascular ageing trajectories. 34 Further observational studies have established causal relationships between vascular ageing and hypertension. Advanced-age populations exhibit hallmark pathological features, including oxidative stress, chronic low-grade inflammation, vascular dysfunction, vasoconstrictive phenotypes, and increased endothelial permeability. 35 The diabetic microenvironment potentiates vasculature susceptibility to ageing processes, 36 primarily through dysregulation of the growth hormone/insulin-like growth factor-I (GH/IGF-I) axis and the SIRT1/dimethylarginine dimethylaminohydrolase/asymmetric dimethylarginine (SIRT1/DDAH/ADMA) pathway. These mechanisms systematically impair endothelial cells, vascular smooth muscle cells (VSMCs), and EPCs, thereby driving coordinated vascular senescence. 37 , 38 Hyperglycemia exacerbates endothelial ageing through apoptosis signal-regulating kinase 1 (ASK1) signaling pathway activation and the upregulation of plasminogen activator inhibitor-1 (PAI-1) expression. Consequently, ASK1 represents a novel therapeutic target for preventing diabetic vascular ageing. 36 Murine models of diet-induced hypercholesterolemia exhibit accelerated cellular senescence and vascular dysfunction signatures, characterized by telomere shortening, elevated p16 and p21 mRNA expression, and diminished proliferative and reparative capacities in endothelial cells, EPCs, and hematopoietic stem cells. 39 , 40 Hyperhomocysteinemia emerges as another critical determinant of vascular ageing. In rats, a methionine-rich diet-induced hyperhomocysteinemia elevates VSMC senescence markers (SA-β-galactosidase, p53/p21, p16), augments pulse pressure, and promotes collagen deposition. 41 This condition additionally inactivates telomerase activity in endothelial cells and EPCs, thereby accelerating their senescence. 42 Metabolic syndrome (MetS) exacerbates the risk of type 2 diabetes and cardiovascular events. Inflammation-dependent accelerated cardiovascular ageing represents a core pathophysiological feature that increases the cardiovascular risk burden in MetS patients. 43 The uremic milieu in chronic kidney disease is correlated with premature ageing phenotypes, 44 which clinically manifest as low-grade inflammation, sarcopenia, osteoporosis, frailty, and disproportionately elevated cardiovascular mortality. 45 , 46 Specific uremic toxins (e.g., IL-6, IL-1β, CXCL8, and leptin) are associated with profound VSMC alterations and other pathological changes that drive vascular calcification and early vascular ageing (EVA). 47 Furthermore, cumulative uremic toxin exposure induces allostatic overload (cumulative physiological wear from chronic stress), thereby accelerating senescence and promoting EVA development. 48 Environmental exposures and physicochemical determinants CVD is the leading cause of morbidity and mortality worldwide, with urban environmental risk factors substantially contributing to the CVD burden. Urbanization exacerbates vascular ageing through increased exposure to air pollutants. 49 Furthermore, analysis of 3772 participants from the National Health and Nutrition Examination Survey (NHANES, 2005–2016) demonstrated that chronic exposure to metallic elements—including cadmium (Cd), cesium (Cs), cobalt (Co), and lead (Pb)—exhibited significant dose-dependent associations with accelerated vascular ageing biomarkers. 50 Chronic low-dose radiation exposure induces persistent cardiac proteomic remodeling, which disrupts myocardial energy metabolism, extracellular matrix homeostasis, oxidative stress regulation, and senescence-associated signaling pathways. These molecular perturbations recapitulate hallmarks of age-related cardiac pathology, thereby increasing susceptibility to cardiovascular injury. Notably, bioengineered human cardiac tissues subjected to one-month spaceflight conditions displayed reduced contractile force, arrhythmic beating patterns, and molecular/genetic signatures consistent with accelerated ageing phenotypes. 51 Pharmacological agents further modulate cardiovascular ageing trajectories. 34 A 2008 Japanese study revealed that doxorubicin-treated cardiomyocytes acquire morphological and functional characteristics analogous to those of senescent cardiomyocytes in aged rodents, implicating premature cellular senescence as a mechanism underlying anthracycline-induced cardiotoxicity. 52 Systematic reviews confirm that anthracycline-driven cardiac ageing underlies persistent chemotherapy-associated cardiovascular complications, particularly progressive myocardial dysfunction. 53 Cross-sectional analyses identify opioid dependence as an independent accelerator of arterial stiffness and vascular senescence, with stronger dose‒response correlations in female cohorts than in male cohorts. 54 Longitudinal evidence further links chronic opioid use to elevated vascular stiffness and senescence biomarker profiles, indicative of accelerated systemic biological ageing. 55 Human immunodeficiency virus (HIV) management studies have demonstrated comparable vascular ageing indices (e.g., Framingham risk scores) between early antiretroviral therapy initiation and chronic infection groups at the six-year follow-up. Paradoxically, higher CD4 + T-cell counts are correlated with poorer vascular health metrics. 56 Emerging research highlights hydrogen sulfide (H 2 S) as a gaseous mediator that influences senescence-associated molecular mechanisms, positioning H2S as a promising therapeutic target for mitigating age-related cardiovascular pathologies. 57 Genetics and epigenetics Human ageing is strongly associated with an increased risk of CVD. Cardiac ageing studies in Drosophila have identified critical gene networks governing cardiac senescence, involving nutrient-sensing pathways, ion channel regulation, and sarcomere-related genes. These evolutionarily conserved mechanisms operate similarly in mammalian cardiac ageing. 58 UK Biobank analyses demonstrated that cardiovascular ageing is significantly associated with common/rare variants in genes regulating sarcomeric homeostasis, myocardial immune modulation, and tissue responses to biophysical stress. 34 Artificial intelligence-driven electrocardiogram analysis for cardiovascular age prediction reveals that delta age (the difference between predicted and chronological age) is associated with all-cause mortality and comorbidities. Genome-wide association studies have further revealed that its genetic architecture predominantly involves cardiovascular system-related genes. Senescence- and longevity-associated genes modulate cardiovascular function through downstream pathways involving inflammatory cascades and oxidative stress, representing therapeutic targets for preventing age-related cardiovascular dysfunction. 59 Neuregulin-1 (NRG-1), an epidermal growth factor with cardioprotective and antiatherogenic properties, significantly suppresses stress-induced premature senescence in diabetic murine aortae in in vitro and in vivo models. Conversely, ErbB4 receptor deficiency induces cellular senescence across experimental systems. 60 Klotho may exert cardioprotective effects against ageing through autophagy activation and apoptosis suppression. 61 The cardiovascular system critically affects physiological health. Age-related epigenetic modifications influence gene expression patterns, cellular differentiation, and disease pathogenesis. Biological age, which is distinct from chronological age, reflects systemic health status. Accelerated vascular ageing lowers disease thresholds, whereas modifiable lifestyle factors (nutrition, exercise) interact with epigenetic clocks to synergistically increase cardiovascular health, suggesting that epigenetic interventions are viable strategies for achieving healthy ageing. 62 Smooth muscle cell-mineralocorticoid receptor (SMC-MR) signaling promotes vascular stiffness and senescence through EZH2-mediated H3K27me3 epigenetic regulation. 63 Noncoding RNAs (ncRNAs) serve as master regulators of ageing-associated biological processes, 64 with established roles in cardiovascular pathophysiology. 65 Among these, microRNAs (miRNAs) represent the most extensively characterized class, modulating cardiovascular function through cell differentiation, proliferation, apoptosis, angiogenesis, and contractility regulation. 1 For example, miR-34a overexpression in aged hearts promotes cardiomyocyte apoptosis and fibrosis by targeting PNUTS, contributing to functional decline. Pharmacological inhibition of miR-34a attenuates age-related cardiomyocyte death and postinfarction fibrosis, enhancing functional recovery. 66 Long noncoding RNAs (lncRNAs), although less evolutionarily conserved than miRNAs, play emerging roles in cardiac ageing through senescence pathway modulation. 67 Circular RNAs, first identified in the early 1990s, are increasingly implicated in cardiovascular cellular senescence and ageing-related pathologies. However, their mechanistic roles remain incompletely understood. 68 Host biology and sociodemographic determinants The role of the gut microbiota and its metabolites in cardiovascular pathologies is gaining increasing recognition. A Spanish cross-sectional study revealed significant associations between EVA and an elevated abundance of Bilophila in the gut microbiome. 69 The gut microbial composition may mitigate age-related diseases through systemic immune modulation and increased infection resistance. 70 Compared with noncentenarians, centenarians exhibit distinct gut microbiota profiles, 71 with emerging evidence suggesting that altered gut microbiome composition or function contributes to age-dependent vascular dysfunction and cardiovascular pathogenesis. 72 The gut microbiota critically regulates host metabolism, immune responses, and inflammatory pathways—all of which are mechanistically linked to vascular ageing processes. 73 – 76 Virus-associated progeroid phenotypes have been observed in patients with chronic viral infections, including HIV, hepatitis B/C/D viruses (HBV/HCV/HDV), Epstein–Barr virus, human herpesviruses, human papillomavirus, and SARS-CoV-2. 77 – 79 HIV-infected individuals exhibit premature senescence in stem cells, endothelial cells, and leukocytes. SARS-CoV-2 infection accelerates endothelial senescence and induces the release of the senescence-associated secretory phenotype (SASP). 78 Centenarians typically exhibit immune profiles optimized for controlling low-grade inflammation while maintaining antimicrobial defense capacity. Antimicrobial peptides (AMPs) may confer protection by directly neutralizing pathogens and preventing infections that could otherwise accelerate senescence or trigger systemic inflammation. This resilience is partially attributed to their unique immune signatures 80 and preserved adaptive immunity. 81 Preterm birth is correlated with myocardial remodeling and accelerated cardiovascular ageing later in life. Echocardiographic analyses revealed abnormal left ventricular function in very preterm infants at six months post-natally. 82 Sex-specific cardiovascular ageing trajectories emerge early in life. Age-dependent sexual dimorphism in vascular structure/function contributes to differential coronary artery disease manifestations. Hormonal and nonhormonal factors jointly mediate sex disparities in cardiovascular ageing and age-related disease progression. 83 Females generally exhibit lower CVD susceptibility and more robust immune responses, 84 whereas males exhibit earlier vascular ageing phenotypes. However, these sex differences attenuate in elderly populations, 85 potentially reflecting menopausal transitions in middle-aged females. 86 A study revealed that elevated prolactin levels in healthy postmenopausal women are associated with endothelial dysfunction and blood pressure alterations, particularly in the prediction of accelerated arterial stiffening in younger cohorts. 87 A cross-sectional study of Gujarati Asian Indians revealed significantly greater vascular versus chronological age (6.54 ± 9.5 years), indicating premature vascular ageing in this population. The key risk factors included hypertension, dyslipidemia, and tobacco use. 88 An ongoing clinical trial further demonstrated that sub-Saharan Black individuals exhibit worse cardiovascular risk profiles and vascular ageing indices despite being younger, 89 highlighting ethnic disparities in cardiovascular ageing trajectories. Pathophysiological changes associated with cardiovascular ageing Heart ageing As depicted in Fig. 3a , as the heart ages, it undergoes structural changes, such as myocardial fibrosis 5 and cardiac amyloidosis, 18 , 19 which increase its functional demands. Concurrently, left atrial (LA) dilation and left ventricular (LV) hypertrophy occur. 6 The compensatory mechanisms developed by the heart at rest to accommodate these changes often lead to functional impairments. Progressive deterioration of LV diastolic function 90 is accompanied by reduced left ventricular ejection fraction (LVEF), 6 collectively indicating diminished cardiac pumping capacity. Concurrently, systemic physical activity levels decrease, 6 potentially reflecting compromised cardiac functional status. Both heart rate reserve 4 and cardiac reserve capacity exhibit age-dependent reductions, impairing the compensatory responses of the heart to external stimuli and increasing hemodynamic stress. Furthermore, intracardiac electrophysiological alterations emerge during ageing. 91 These alterations collectively contribute to an ageing cardiac phenotype characterized by progressive functional deterioration, impaired rhythm regulation, and diminished adaptive capacity. ageing is also associated with progressive panmyocardial impairment of coronary vasodilatory capacity due to an increase in minimal microvascular resistance. 92 These impairments reduce the heart’s capacity to respond to disease or injury, eventually contributing to an increased incidence of CVD, such as atrial fibrillation. 10 Fig. 3. Open in a new tab Changes in cardiovascular ageing. a Aged hearts undergo myocardial fibrosis, cardiac amyloidosis, LA dilation and LV hypertrophy. These structural changes lead to functional impairments, such as decreases in LV diastolic function and LVEF. These impairments reduce the heart’s capacity to respond to disease or injury, eventually contributing to an increased incidence of CVD, such as AF. b Aged vessels undergo vascular dyshomeostasis and remodeling, such as luminal dilation, intima‒medial thickness, chronic inflammation, vascular calcification, arterial stiffening and decreased elasticity. A range of changes in senescent ECs and VSMCs exacerbate the onset and outcome of vascular dysfunction, which is intrinsically linked to vascular ageing and related diseases. Abbreviations : LV, left ventricle; LA, left atrium; LVEF, left ventricular ejection fraction; AF, atrial fibrillation; ECs, endothelial cells; VSMCs, vascular smooth muscle cells; SASP, senescence-associated secretory phenotype. Created in BioRender (2025) https://BioRender.com/2x6apnt In addition, the coronary microvasculature undergoes significant structural remodeling, characterized by increased vascular stiffness, progressive thickening of the intimal layer, 6 and reduced capillary density. 93 Structural microcirculatory remodeling is reflected in backward expansion wave intensity and diastolic microvascular conductance measurements. 94 Functionally, these structural alterations contribute to endothelial dysfunction, 10 which is characterized by diminished nitric oxide (NO) bioavailability and heightened oxidative stress, disrupting the balance of vasoactive signaling. 95 Simultaneously, dysregulation of vascular tone emerges, alongside a lowered threshold for cellular Ca 2+ overload that exacerbates ischemic injury. 10 These changes collectively lead to tissue perfusion deficiency, compromising oxygen and nutrient delivery to cardiomyocytes. Furthermore, age-related increases in vascular permeability and lymphatic dysfunction 96 and reductions in baseline coronary blood flow and coronary reserve capacity, such as coronary flow reserve (CFR), further impair myocardial perfusion. 97 Heart ageing is associated with widespread deterioration of both the structure and function of the microvasculature, which accelerates cardiac remodeling and ultimately disrupts the coupling between the microcirculation and the heart (Fig. 3a ), fostering the development and progression of CVD. 6 This deterioration extends beyond the heart, affecting other critical organs, such as the brain, kidneys, skeletal muscle, and eyes, thereby accelerating the ageing process. This systemic decline disrupts tissue oxygenation, waste elimination, and the efficient transport and distribution of nutrients, hormones, growth factors, and metabolites throughout the body, significantly increasing the risk of chronic diseases. 98 Vascular ageing As a famous 19th-century doctor, William Osler proposed, “A man is as old as his arteries”. Vascular ageing is considered the most important risk factor for high CVD mortality. It is a progressive process that involves structural and functional changes in the vasculature during the ageing process and is characterized mainly by vascular cell dysfunction and senescence, vascular dyshomeostasis and remodeling (Fig. 3b ), such as luminal dilation, intima‒medial thickness, chronic inflammation, vascular calcification, arterial stiffening and decreased elasticity. 8 , 9 The arterial wall is composed of three anatomical layers: a single layer of endothelial cells (the tunica intima), multiple layers of vascular smooth muscle cells and elastic fiber layers between VSMC layers (the tunica media), and the tunica adventitia, which contains adipocytes, fibrous connective tissue, and ECM. ECs and VSMCs, which form the intima and media layers of the vessel wall, respectively, are closely associated with normal vascular function. The accumulation of senescent ECs and VSMCs in the culprit lesions of the cardiovascular system exacerbates the onset and outcome of vascular dysfunction, which is intrinsically linked to vascular ageing and related diseases. For example, senescent ECs lose their balance in the production of vasodilatory and vasoconstrictive agents, characterized by decreased vasodilatory signals and increased vasoconstrictive signals. This reduced endothelium-dependent vasodilation is consistently observed in the ageing vascular wall of human and animal models. 7 Furthermore, senescent ECs undergo phenotypic changes (Fig. 3b ) that alter the pattern of expressed proteins, lose their ability to proliferate, become flattened and enlarged in shape and size, exhibit increased polyploidy and SASP, and are accompanied by increased oxidative stress and a decrease in proteostasis. 99 In addition, endothelial senescence reduces vascular density, increases intima‒media layer thickness and collagen deposition, reduces elastin deposition, and induces vascular lumen dilation, which occurs in multiple organ systems. More importantly, endothelial barrier function is disrupted, facilitating the circulation of harmful substances that affect VSMCs in the tunica media. Emerging evidence has shown that the quantity of VSMCs in the tunica media decreases in ageing blood vessels, and a number of VSMCs show features of phenotype switching that involve a decrease in the expression of contractile proteins and an increase in the expression of pro-proliferative and migratory substances, contributing to increased aortic stiffness and calcification. 100 Furthermore, the metabolism of VSMCs is also correlated with phenotype switching and the progression of vascular ageing. Recent research has further demonstrated that Sox9 promotes compositional and structural ECM changes that regulate VSMC senescence and mimic features of vascular ageing. Healthy VSMCs exposed to Sox9-modified ECM exhibit accelerated senescence, whereas senescent cells are partially rejuvenated when exposed to Sox9-depleted ECM. 101 Cell senescence has received potential attention as a promising target for preventing vascular ageing and related diseases. The hallmarks of cardiovascular ageing Molecular level Genomic instability and epigenetic alterations Genomic instability is a critical pathogenic factor in vascular ageing (Fig. 4 ). Studies in mice have demonstrated that local endothelial genomic instability can recapitulate key features of vascular ageing, such as increased vascular stiffness, vascular hypertrophic remodeling, loss of endothelium-dependent vasodilation, increased vascular leakage, and differential vulnerability of various arteries. 102 These characteristics are also observed in humans. 103 , 104 The accumulation of damaged DNA is recognized as one of the primary drivers of ageing and involves multiple processes. 105 , 106 Cells with unrepaired DNA damage may either undergo apoptosis or enter senescence. Apoptosis leads to cellular or tissue atrophy and a decline in organ function, whereas senescent cells adopt a SASP, which impacts neighboring cells and induces age-related phenotypic changes. 107 Additionally, the continuous accumulation of DNA damage can activate a “survival response”, shifting the physiology of organisms from growth promotion to maintaining cellular homeostasis and function. 108 In endothelial cells, selective defects in DNA repair can result in age-related endothelial dysfunction, primarily due to the reduced bioavailability of endothelial-derived NO. Increased production of superoxide radicals can further impair the perfusion of vital organs. 102 In humans, genetic and environmental variability contributes to differences in ageing rates among individuals and even among different organs within the same individual. This variability has also been observed in mouse models of premature ageing phenotypes due to defects in DNA repair. 108 A growing body of evidence suggests that the DNA damage response plays a central role in vascular ageing, 109 where ageing can be driven by genomic instability and persistent DNA damage in a cell-autonomous manner across various organs and tissues. 110 – 113 In addition, DNA damage at the ends of chromosomes (telomeres) contributes to ageing and age-related diseases. DNA damage at telomeres is a recognized contributor to ageing and age-related diseases. 114 Furthermore, radiation studies in humans and mice have demonstrated that such damage accelerates ageing within the carotid and cerebral vasculature, implicating telomere attrition and cellular senescence as key underlying mechanisms. 103 , 104 , 115 Fig. 4. Open in a new tab The hallmarks of cardiovascular ageing. This figure categorizes the hallmarks of cardiovascular ageing into three interconnected tiers: the molecular level, encompassing genomic instability and epigenetic alterations, loss of proteostasis, mitochondrial dysfunction and oxidative stress, and inflammation; the cellular level, comprising cellular dysfunction, cellular senescence, stem cell exhaustion, and metabolic changes; and the systemic level, involving signaling pathways, including the renin‒angiotensin‒aldosterone system (RAAS), β-adrenergic signaling, growth signaling, and mechanosignaling. Created in BioRender (2025) https://BioRender.com/zasg1s1 In addition to DNA mutations, gene expression levels in the cardiovascular system are modulated by a variety of epigenetic factors, including DNA methylation, histone modifications, and ncRNAs. 116 In failing human hearts, alterations in DNA methylation patterns have been identified, 117 and these patterns are increasingly being utilized as markers to estimate the rate of cardiovascular ageing. 118 , 119 However, further research is needed to elucidate the significance and mechanisms of reduced DNA methylation in vascular ageing. Additionally, histone loss and tissue-specific changes in posttranslational histone modifications, such as those involving the SIRT family, are closely associated with ageing. Sirtuins (SIRT1--7), a family of NAD-dependent histone deacetylases, are of particular interest. Since NAD levels decrease with age, NAD supplementation is considered a promising strategy for reversing age-related phenotypes, 120 despite its uneven distribution in cells as well as subcells. 121 We have established that SIRTs are activated by NAD 122 and play important roles in ageing and capillarization. 123 For example, endothelial cell (EC)-specific Sirt1 knockout mice exhibit reduced cardiac capillarization and diastolic dysfunction, 124 whereas EC-specific SIRT3 depletion plays the same role. 125 Notably, the SIRT1 activator resveratrol has broad biological activities that ameliorate the aforementioned ageing-related deficits, establishing this compound as a promising antiageing therapeutic. 126 Angiotensin II-induced fibrosis reduces vascular density in the heart, and this effect is exacerbated by SIRT3 depletion. Our research also revealed that SIRT2 deficiency exacerbates age-related arterial stiffness and systolic-diastolic dysfunction, accompanied by aortic remodeling. SIRT2 can repress p66Shc to reduce mROS generation. Either p66Shc silencing or MnTBAP treatment could block the inhibitory effects of SIRT2 deficiency on the expression of MMP2 and MMP9, which contribute to vascular remodeling and dysfunction. 127 The role of other SIRTs in cardiac capillarization remains to be fully explored. Among ncRNAs, circular RNAs, miRNAs, and lncRNAs have emerged as significant epigenetic regulators with roles in cardiovascular ageing. 65 For example, the lncRNA Sarrah is downregulated in aged mouse hearts and in rodent models of ischemic cardiomyopathy and heart failure with preserved ejection fraction (HFpEF). In contrast, the overexpression of Sarrah enhances cardiomyocyte survival, promotes endothelial cell proliferation, and improves functional recovery from myocardial ischemia while reducing cardiac apoptosis in aged mice. 67 However, most studies to date have focused on miRNAs, and the role of other ncRNAs remains controversial, with ongoing debates about the extent to which they may arise from transcriptional noise, necessitating further research. 128 Loss of proteostasis Proteostasis, defined as the balance between protein synthesis, folding, and degradation, is critical for preserving cellular health and enabling cells to respond effectively to stress. 129 , 130 Disruptions in proteostasis prompt compensatory cellular adaptations. Cells have developed several mechanisms to minimize protein misfolding and eliminate misfolded proteins, 129 one of which involves molecular chaperones. These chaperones bind to incomplete polypeptide chains, preventing premature folding and facilitating correct protein folding. Chaperones also mitigate protein denaturation during cellular stress, such as heat shock, which is why they are commonly referred to as heat shock proteins (HSPs). 131 – 133 When chaperones and other molecular helpers cannot refold dysfunctional proteins, these proteins are marked for degradation via the ubiquitin‒proteasome system or through chaperone-mediated autophagy (CMA). 134 As organisms age, the proteostasis network becomes less efficient, resulting in the accumulation of misfolded and damaged proteins, which can aggregate into intracellular inclusions or extracellular amyloid plaques. 129 , 135 While the accumulation of toxic protein aggregates is most prominent in neurodegenerative diseases, it is also a characteristic of various age-related CVDs, including atherosclerosis, AF, heart failure, and hypertrophic, ischemic, and dilated cardiomyopathies 136 – 139 (Fig. 4 ). In the vascular system, CMA activity significantly decreases with age. 140 In lysosome-associated membrane protein type 2A (LAMP-2A)-null mice, the inhibition of CMA accelerates atherosclerotic plaque formation by promoting dyslipidemia, vascular smooth muscle cell dedifferentiation, and proinflammatory macrophage activation. In contrast, systemic activation of CMA in mice overexpressing human LAMP-2A attenuates atherosclerosis severity and slows its progression when induced by a proatherosclerotic diet. 141 Data from the single-cell human transcriptome atlas (Tabula sapiens) indicate that the expression of CMA-related genes decreases with age, especially in aortic macrophages and smooth muscle cells. 142 In addition, caloric restriction exerts beneficial effects on cardiovascular ageing by reinforcing proteostasis. 143 Experimental studies have demonstrated this mechanism through two distinct manifestations: the upregulation of HSP70 in the rodent myocardium 144 and the activation of protein folding-related transcripts in human skeletal muscle. 145 Experimental evidence strongly supports the causal role of proteostasis dysregulation in cardiovascular ageing. Studies have shown that inducing (or preventing) the breakdown of proteostasis within the cardiovascular system accelerates (or delays) cardiovascular ageing. 141 , 146 – 149 Thus, the loss of proteostasis is closely linked to age-associated declines in cardiovascular function, suggesting that genetic, dietary or pharmacological strategies to maintain proteostasis may hold promise for delaying cardiovascular ageing. Mitochondrial dysfunction and oxidative stress Oxidative stress is recognized as a biological process of ageing, 95 and its effects on age-related cardiovascular dysfunction may be more pronounced than those of other established mechanisms 150 (Fig. 4 ). There is growing evidence that mitochondria serve as the central organelles linking vascular ageing and oROSxidative stress, driving interest in the pathways that regulate mitochondrial reactive oxygen species (ROS), which may influence the progression of ageing. 151 Among these regulators, the p66Shc protein and its transcriptional regulator, deacetylase SIRT1, have received substantial attention in the last decade. 152 – 155 Mitochondria are essential for energy metabolism in eukaryotic cells, and through the coordinated action of the respiratory chain, they produce the necessary energy substrates. As a result, age-related deterioration in energy metabolism is closely tied to specific changes in mitochondrial function and dynamics. Impaired electron transport within the mitochondrial respiratory chain leads to increased ROS production and reduced ATP synthesis, which is considered a key driver of the ageing process. 156 , 157 Vascular endothelial cells largely rely on glycolysis, yet pharmacological inhibition of mitochondrial respiratory chain complexes disrupts ex vivo vascular tone control. 158 , 159 Notably, altered mitochondrial redox status has been mechanistically linked to impaired coronary arteriolar flow regulation, suggesting that targeted restoration of mitochondrial bioenergetics may improve clinical indices of coronary function, including the CFR and FFR. 160 Furthermore, mitochondrial dysfunction is also linked to disrupted calcium signaling due to alterations in the type 2 ryanodine receptor (RyR2) and the sarcoplasmic reticulum Ca 2+ ATPase pump. 161 Cardiovascular ageing promotes oxidative stress alongside chronic inflammation. NADPH oxidase, a major source of ROS, is upregulated during vascular ageing, intensifying oxidative stress and activating proinflammatory pathways, particularly the NF-κB pathway. 162 Excess ROS not only act as common damaging agents in various inflammatory pathways but also contribute to chronic, low-grade inflammation, which is characteristic of ageing. The most significant impact of ROS on endothelial dysfunction stems from the degradation of endothelial-derived NO. Reduced endothelial NO synthase (eNOS) activity leads to lower NO bioavailability, 163 a hallmark of age-related endothelial dysfunction, which results in vasoconstriction and impaired tissue perfusion. 109 This, in turn, contributes to cardiovascular remodeling and triggers adaptive metabolic changes in peripheral tissues. Reduced NO levels may also impair cardiomyocyte contractility, leading to decreased LV diastolic compliance via a PKG-dependent pathway. 164 In conclusion, the cardiovascular system is highly reliant on mitochondrial metabolism and signaling, and mitochondrial dysfunction due to ageing has a particularly profound impact on cardiovascular function, 165 making it a central pathogenic factor in many CVDs. 166 , 167 Inflammation A chronic proinflammatory state is a hallmark of ageing (Fig. 4 ). This persistent, low-grade inflammation, which occurs without an obvious infection, is termed “inflammageing” 168 and is a major risk factor for morbidity and mortality in the elderly. 169 Potential mechanisms of “inflammageing” include genetic predisposition, central obesity, increased gut permeability, changes in the microbiome, cellular senescence, activation of the NLRP3 inflammasome, oxidative stress due to mitochondrial dysfunction, chronic infections, and immune cell dysregulation. 170 Circulating inflammatory biomarkers can predict the progression of atherosclerosis and its cardiovascular complications, whereas inflammatory processes further drive secondary events that indicate disease progression. Inflammation also plays a crucial role in disrupting cardiovascular homeostasis. 171 Dysregulation of immune‒inflammatory pathways during ageing results in elevated levels of circulating cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6), which are located primarily in the “central pathway“. 172 , 173 Studies have demonstrated that interventions aimed at the pathogenic pathway effectively attenuate chronic inflammatory states, consequently slowing the progression of cardiovascular ageing. 174 , 175 Moreover, our research has shown that the chemokine CCL17 can regulate the reprogramming of Th cells in the immune microenvironment, acting as a coordinator of vascular ageing. Targeting CCL17 represents a promising new anti-inflammatory approach to prevent cardiovascular ageing. Cook et al. 176 reported that IL-11 plays a central role in fibrosis across the cardiovascular system and multiple organs and that inhibiting IL-11 may extend lifespan. Additionally, the persistent low-grade inflammatory environment produces advanced glycation end products (AGEs) and matrix metalloproteinases and, combined with increased vascular permeability, promotes the local accumulation of inflammatory cells. 109 These inflammatory cells and cytokines not only directly damage the vascular wall but also increase ROS production, further compromising the vascular structure, inducing arteriolar remodeling, and triggering compensatory responses such as angiogenesis. 177 These compensatory mechanisms aim to restore or maintain cardiovascular balance but place sustained stress on endothelial cells, leading to their premature senescence. In turn, senescent immune-inflammatory cells acquire a proinflammatory phenotype when dysfunctional, perpetuating the inflammatory response and creating a vicious cycle. 171 Cellular level Cell dysfunction This review examines cell dysfunction through two distinct dimensions: the specific functional impairments affecting cells and the particular cell types manifesting these dysfunctions. Specifically, it focuses on macroautophagy impairment and immune cell dysfunction, both of which contribute significantly to cardiovascular ageing (Fig. 4 ). Macroautophagy serves as a critical cellular quality control mechanism responsible for degrading and recycling dysfunctional cytoplasmic components. This process begins with the encapsulation of toxic protein aggregates and aged organelles within double-membraned vesicles called autophagosomes. These vesicles subsequently merge with lysosomes, where the enzymatic breakdown of their contents generates metabolites essential for energy production and biosynthesis. 178 In cardiomyocytes, macroautophagy extends to a specialized process termed heterophagy, wherein damaged mitochondria are packaged into extracellular vesicles (exospheres) and expelled into the extracellular space. Here, cardiac macrophages degrade cellular debris, further underscoring the role of autophagy in maintaining cellular homeostasis. 179 , 180 Owing to its vital contributions to cellular longevity, macroautophagy is a key determinant of healthspan and lifespan across eukaryotic cells, particularly within the cardiovascular system. 170 , 181 , 182 However, autophagy efficiency decreases with organismal ageing, 183 – 185 a phenomenon linked to the onset of age-related chronic diseases. In the cardiovascular context, studies in aged mice and humans have revealed diminished autophagic activity in vascular tissues. 186 Advanced methodologies to assess autophagic flux in model organisms (e.g., flies and rodents) have conclusively demonstrated age-dependent impairment in autophagy within both the heart and vasculature. 187 – 189 Such deficits—observed in cardiomyocytes, VSMCs and ECs—result in structural and functional abnormalities characteristic of cardiovascular ageing. 190 The age-related decline in autophagy arises through multiple interconnected mechanisms. Central to this process is the hyperacetylation of autophagy-related proteins, a consequence of reduced SIRT deacetylase activity and decreased NAD + levels in the ageing cardiovascular system. 191 , 192 Nutrient excess—particularly prevalent in visceral obesity and metabolic syndrome—further suppresses autophagy by increasing acetyl-CoA availability (promoting protein acetylation) and hyperactivating the insulin-IGF1-mTOR (mammalian target of rapamycin) signaling axis. Calcium signaling, which is altered during cardiovascular ageing, 193 also impairs autophagic flux, especially in ECs and cardiomyocytes. 194 , 195 Additionally, diminished levels of the polyamine spermidine 196 , 197 disrupt the hypusination-dependent synthesis of autophagy machinery components. 198 Human studies corroborate this link, demonstrating a progressive age-dependent decline in cardiac spermidine. Conversely, spermidine supplementation in aged mice restores autophagy in both cardiac and vascular tissues, 199 , 200 highlighting its therapeutic potential. Immune cells play a pivotal role in cardiovascular ageing, with their functional dysregulation driving and amplifying age-related pathologies. 201 – 203 Emerging evidence suggests that macrophages are critical modulators of cardiac senescence. 204 In addition, CD28 − T cells play a pivotal role in age-related cardiovascular diseases. 205 CD57 + T cells exhibit reduced proliferative capacity and increased secretion of proinflammatory cytokines during ageing. In humans, both CD28 - and CD57 + T cells are considered replicatively senescent T-cell subsets, and their frequencies in peripheral blood increase with increasing age. 206 However, key knowledge gaps persist. The functional trajectories of immune cells (e.g., shifts in proinflammatory cytokine secretion, phagocytic capacity, and antigen presentation) during cardiovascular ageing remain poorly characterized. Delineating how age-altered immune crosstalk exacerbates endothelial dysfunction, myocardial fibrosis, and vascular stiffness will be essential for developing immunomodulatory therapies to decelerate cardiovascular decline. Cell senescence Cellular senescence is typically defined as a state of permanent cell cycle arrest characterized by the irreversible loss of replicative capacity. It results in the loss of specific cellular functions and the acquisition of a proinflammatory secretory and metabolic phenotype in both cardiomyocytes and nonmyocyte cardiac cells. 207 , 208 In postmitotic cardiomyocytes, chronic stressors such as oxidative damage and inflammation drive telomere attrition, DNA damage accumulation, functional decline, and polyploidization—hallmark features of cellular senescence. 209 – 211 These senescent cardiomyocytes exhibit impaired contractility, cellular hypertrophy, mitochondrial dysfunction, and shortened telomeres, all of which collectively undermine myocardial performance. 212 , 213 The age-dependent accumulation of these dysfunctional cells disrupts intercellular communication, impairing tissue homeostasis and propagating chronic inflammation through the SASP, ultimately culminating in cardiomyocyte loss. 212 , 213 Thus, targeting cardiomyocyte senescence has emerged as a central therapeutic strategy to mitigate age-related structural and functional cardiac deterioration. 214 – 216 Concurrently, vascular and interstitial cardiac cells (e.g., fibroblasts and progenitor cells) undergo senescence characterized by cell cycle arrest, heightened inflammatory signaling, and the upregulation of senescence markers (e.g., p16INK4A). 217 Senescent endothelial cells produce an increased number of functional small extracellular vesicles (EVs), which may play a role in vascular physiology and disease. 218 VSMCs are the principal cell type in the vascular wall and maintain vascular tone. EVA-related phenotypic switching of VSMCs contributes to cardiovascular ageing. 219 Senescent cardiac fibroblasts exacerbate maladaptive remodeling in aged hearts by secreting matrix-degrading enzymes and profibrotic factors. 217 Age-related telomere shortening and dysregulated cell division also impair the self-renewal capacity of cardiac progenitor cells (CPCs), further accelerating global cardiac ageing. 220 – 222 Notably, hematopoietic stem cells with telomerase deficiency exhibit a reduced replicative lifespan during serial transplantation, 223 whereas bone marrow-derived monocytes from ischemic heart disease patients display telomere erosion, impaired differentiation, and elevated p21/p16INK4A expression. 224 These observations underscore a critical barrier in regenerative medicine: autologous stem/progenitor cell therapies often rely on aged, functionally compromised cells from CVD patients. Reprogramming aged somatic cells into induced pluripotent stem cells (iPSCs) offers molecular insights into rejuvenation mechanisms, although translational challenges persist for cardiac applications. Overall, restoring functional competence in aged stem cells represents a pivotal bottleneck for developing effective personalized regenerative therapies. Historically, the most prominent feature of cellular senescence has been stable proliferative arrest, which is mediated by the activation of the tumor suppressors TP53 and CDKN2A/p16, along with their downstream effectors CDKN1A/p21 and retinoblastoma-1 family proteins. Together, these proteins inhibit cell cycle progression by suppressing cyclin-dependent kinases (CDKs) and E2F family transcription factors. 225 In mouse models of pressure overload, increased p53 expression, which induces cellular senescence, exacerbates cardiac dysfunction. p53 promotes cardiac hypoxia and remodeling by inhibiting hypoxia-inducible factor 1α (HIF-1α) and VEGF, thereby suppressing cardiac angiogenesis. 226 Increased p53 signaling in endothelial cells leads to capillary rarefaction in cardiac tissue, whereas depletion of endothelial p53 improves capillary density and cardiac function and suppresses cardiac fibrosis. 227 Furthermore, p53 activation in cardiac endothelial cells and bone marrow cells promotes cardiac inflammation by increasing the expression of adhesion molecules to attract inflammatory cells. Deletion of the p53 gene downregulates these molecules, suppresses inflammation, and improves cardiac function. Conversely, the overexpression of p53 in bone marrow cells worsens cardiac inflammation and dysfunction. 228 The protein p21, encoded by the cyclin-dependent kinase inhibitor 1a (Cdkn1a) gene, is a cell cycle regulator downstream of p53. 229 The activation of p21 triggers cellular senescence and apoptosis. 230 Compared with 4-month-old mice, 24-month-old C57BL/6 mice presented higher levels of p21 in cardiac tissue. 231 Additionally, systemic depletion of p21 reduces capillary density and impairs cardiac contractile function. 232 The role of p21 in capillary formation may be context dependent, varying across organs, cell types, and diseases. p16INK4a, a cell cycle regulator encoded by Cdkn2a, is widely used as a marker of senescent cells and has been reported to increase with age in cardiomyocytes, 207 endothelial cells, 233 and cardiac progenitor cells. 234 The levels of p16 increase in the hearts of aged mice. 231 In humans, protein levels of p53, p21, and p16 increase in the endothelial cells of older individuals (~60 years old), whereas these levels are reduced in physically active older adults (~57 years old). 233 The functional diversity of p16 Ink4a+ senescent cells has led researchers to develop a genetic toolset comprising three p16Ink4a-related systems for tracking, ablating, and manipulating p16 Ink4a+ cells in vivo. This toolset lays the foundation for developing future cell type-specific senolytic therapies. 235 However, further studies are needed to elucidate the role of p16 in cardiac capillarization and explore more specific senescence markers. Stem cell exhaustion Cardiomyocytes undergo renewal with age, with the highest renewal rate occurring during the first two decades of life. At the age of 20, the cardiomyocyte renewal rate is ~1% per year, but this rate decreases to less than 0.5% per year with increasing age. 236 In contrast, endothelial cells have a high renewal rate throughout life (greater than 15% annually), whereas mesenchymal stem cells have a more limited renewal rate (less than 4% per year in adulthood). 237 CD133 + endothelial progenitor cells not only restore neovascularization but also improve longevity in progeroid and naturally aged murine models. 238 Arterial Sca1 vascular stem cells generate functional smooth muscle cells for vascular repair and regeneration. 239 Stem cell-derived extracellular vesicles mitigate age-related arterial stiffening and hypertension. 240 Mounting evidence confirms the multifaceted roles of stem cells in vascular repair: restoring endothelial integrity, promoting angiogenesis, and modulating inflammatory pathways to attenuate atherogenesis. 241 , 242 Pericytes, which are mesenchymal stem cells associated with capillaries, play a critical role in maintaining vascular homeostasis. They are key regulators of angiogenesis, vascular permeability, barrier function, and extracellular matrix (ECM) formation. 243 As mechanical support for blood vessels, 244 pericytes possess regenerative potential. 245 The evidence also suggests that the pericyte secretome plays an important role in controlling and altering the local cardiac environment. Regulator of G-protein signaling 5 (RGS5) belongs to a family of proteins that act as GTPase-activating proteins, regulating G-protein-coupled receptor (GPCR) signaling pathways by inhibiting the Gq protein alpha subunit (Gαq) and Gi protein alpha subunit (Gαi). In smooth muscle cells, RGS5 has been shown to regulate both proliferation 246 and contraction. 247 A decrease in RGS5 expression in pericytes is a marker of cardiac ageing. RGS5 is crucial for maintaining pericyte function and preventing the activation of profibrotic gene expression in the heart. The loss of RGS5 in pericytes drives these mural cells into an entropic state characterized by morphological changes, excessive ECM deposition, and the secretion of harmful profibrotic growth factors in the heart. 248 Ageing is associated with reduced tissue renewal under homeostatic conditions and impaired tissue repair following injury, with each organ employing its own strategies for renewal and repair. 249 In fact, tissue repair is thought to rely heavily on injury-induced dedifferentiation and cellular plasticity. Injury-induced plasticity (and its progressive loss with ageing) may be more relevant to ageing than the plasticity of resident stem cells under normal homeostatic conditions. Both stem cells and progenitor cells experience the same ageing hallmarks as cells without stem cell potential. 12 During embryonic development, very small embryonic-like stem cells, which act as mobile reservoirs of circulating pluripotent stem cells (PSCs), are deposited in adult tissues. However, the number of these cells decreases with age. 250 Thus, age-dependent exhaustion of the PSC pool in adult tissues may contribute to the ageing process to some extent. Cellular reprogramming is a commonly used strategy to combat the decline in stem cell function with ageing. Reprogramming toward pluripotency involves the transduction of four external transcription factors—OCT4, SOX2, KLF4, and MYC (collectively known as OSKM)—which convert somatic cells into embryonic-like pluripotent stem cells, referred to as iPSCs. 251 Short-term cyclic expression of OSKM ameliorated the cellular and physiological hallmarks of ageing and extended lifespan in a premature ageing mouse model. Additionally, in vivo OSKM expression enhances recovery from metabolic disease and muscle injury in aged wild-type mice. 252 In addition, transient reprogramming restores the regenerative capacity of aged tissues, enabling them to repair injuries as effectively as young individuals do. This enhanced repair capacity has been demonstrated in models of cardiac tissue injury. 253 Metabolic changes Metabolic alterations within tissues and intercellular metabolite trafficking represent emerging frontiers in cardiovascular ageing research (Fig. 4 ). Accumulating evidence underscores that metabolic reprogramming is essential in senescent cells to redirect substantial energy toward senescence-specific functions, notably the SASP and the modulation of immune responses within the tissue microenvironment. Despite their diminished proliferative capacity, senescent cells exhibit heightened metabolic activity. A hallmark of this state is a pronounced shift toward glycolysis, persisting under normoxic conditions—a Warburg-like effect analogous to that observed in cancer cells. This bioenergetic reprogramming involves shunting pyruvate, the end-product of glycolysis, away from oxidative phosphorylation. The resulting altered metabolic state may constitute an adaptive response to elevated oxidative stress driven by dysfunctional mitochondrial accumulation. 254 Recent findings highlight the significance of EC senescence: impaired glucose transport is associated with cardiac EC senescence 255 ; a glycolytic shift promotes vascular senescence, an effect reversible by senolytics 256 ; and evidence suggests reduced lactate production in senescent ECs. Conversely, studies have reported increased fatty acid oxidation activity and increased intracellular ATP content in senescent human umbilical vein endothelial cells. 257 Collectively, these findings reveal a complex and sometimes seemingly contradictory metabolic landscape within senescent ECs. Despite unresolved discrepancies, interest in senescent cell metabolism is rapidly increasing, warranting dedicated attention as a key area for elucidating the mechanisms of cardiovascular ageing and identifying therapeutic targets. Systemic level Systemic and local signaling pathway dysregulation, including the renin‒angiotensin‒aldosterone system (RAAS), β-adrenergic signaling, growth signaling, and mechanosignaling, results in chronic activation during ageing, leading to cardiovascular dysfunction (Fig. 4 ). RAAS Chronic activation of the RAAS is closely associated with age-related CVD, including hypertension, atherosclerosis, coronary artery disease, AF, and heart failure. 258 Although the RAAS has adaptive functions in the early stage of CVD, its long-term activation triggers adverse cardiovascular effects through various mechanisms, including disruption of sodium homeostasis; dysregulation of vascular tone and blood volume; and abnormal cell proliferation and growth, oxidative stress, inflammation, and fibrotic remodeling in the cardiovascular system. 259 , 260 Studies have shown that circulating levels of renin and angiotensin II increase with age in healthy elderly mice. Additionally, in the hearts and vascular systems of older mice, there is a significant increase in the expression of angiotensin II mRNA and protein. 261 This process is accompanied by elevated vascular expression of ACE, collagen IV, fibronectin, and transforming growth factor-β (TGF-β), along with increased susceptibility to developing hypertension in response to low doses of angiotensin II. 262 These findings suggest that overactivation of the RAAS system is a key mechanism driving cardiovascular ageing, independent of common CVD. Additionally, the expression of mineralocorticoid receptors (MRs) in vascular smooth muscle cells gradually increases with age. 263 , 264 This enhanced expression leads to vasoconstriction, increased vascular tension, and exacerbated oxidative stress, which in turn results in elevated blood pressure and vascular stiffness. 265 As transcriptional regulators, smooth muscle cell-MRs promote vascular fibrosis by activating genes related to fibrosis, thereby reducing vascular elasticity and further worsening vascular stiffness. 266 , 267 Moreover, MR enhances the expression of target genes, including the L-type calcium channel (LTCC) subunit Cav1.2 and the angiotensin II type 1 receptor (Agtr1), by inhibiting the expression of miRNA-155. This contributes to age-related vasoconstriction and vascular oxidative stress. 264 Collectively, these changes accelerate the process of vascular ageing. These age-related vascular changes are further amplified through systemic neurohumoral networks. The heart‒brain axis (HBA), which functions via autonomic-RAAS-hypothalamic integrations, not only mediates cross-organ communication but also establishes feedback loops that exacerbate vascular stiffness. 268 In summary, the RAAS, particularly the MR, drives cardiovascular ageing by regulating vascular smooth muscle cell function, thereby increasing vascular stiffness and the risk of CVD. β-Adrenergic signaling As we age, circulating catecholamine levels gradually increase, leading to sustained stimulation and eventual desensitization of cardiac β-adrenergic receptors. 269 , 270 This phenomenon, observed in both elderly humans and rodents, results in impaired cardiac autonomic regulation, known as β-adrenergic desensitization, 271 which in turn leads to reduced cardiac reserve and decreased exercise tolerance. 272 , 273 While early activation of β-adrenergic signaling may transiently improve cardiac function, prolonged overactivation can trigger myocardial hypertrophy and fibrosis. 274 Continuous stimulation leads to β-receptor desensitization, gradually weakening the regulatory capacity of the heart. Intervention with β-blockers has been shown to slow progression, improve cardiac reserve, and prolong patient survival. 275 , 276 Thus, inhibiting β-adrenergic signaling is considered a protective mechanism, preventing excessive cardiac responses to long-term catecholamine stimulation. However, inhibition itself can also have negative effects, particularly by reducing cAMP production, which impairs vascular smooth muscle cell function, 277 thereby increasing the risk of atherosclerosis and other vascular diseases. 278 – 281 Additionally, β2-adrenergic receptors in EPCs promote angiogenesis through signaling with eNOS. 282 This ability diminishes with age. Notably, strategies aimed at restoring β2-adrenergic receptor signaling have been shown to effectively improve impaired angiogenesis. 283 Growth signaling The cardiovascular system is a key target of growth hormone (GH) and insulin-like growth factor-1 (IGF-1). Evidence suggests that cardiomyocytes, vascular endothelial cells, and smooth muscle cells abundantly express IGF1-R, which is more sensitive to IGF-1 than to insulin. 284 – 286 On the basis of the temporal decline in circulating IGF-1 levels and the development of cardiovascular dysfunction with ageing, a causal relationship has been proposed between reduced IGF-1 levels and the onset of cardiac and vascular ageing phenotypes. 287 Both circulating and locally produced IGF-1 help maintain the integrity of cardiovascular function and structure by increasing NO bioavailability, reducing ROS production, and exerting anti-inflammatory, antiapoptotic, and proangiogenic effects. 288 Recent studies have shown that GH supplementation, which significantly elevates circulating IGF-1 levels, substantially increases cortical vascular density in aged rats 289 while also improving cognitive function. 287 , 290 – 294 IGF-1 infusion has also been shown to increase brain microvascular density in adult mice by ~40%. 295 Research has indicated that ageing is associated with microvascular rarefaction in the rat heart, and GH treatment has been shown to increase myocardial blood flow and capillary density in aged rats. 296 During embryonic development, vascular endothelial growth factor (VEGF) is the primary regulator of neovascularization, stimulating the sprouting of new blood vessels from the existing vasculature. Hypoxic regions in tissues create VEGF gradients, prompting endothelial cells to differentiate into tip cells that guide capillary formation. 297 Together, angiogenesis and vasculogenesis establish a mature, well-perfused microvascular network. However, as ageing progresses, the ability to repair blood vessels and form new ones decreases, partly due to reduced VEGF production. 298 Impaired angiogenesis hinders the formation of new blood vessels, contributing to vascular ageing. 299 Reduced expression of proangiogenic factors such as VEGF limits endothelial cell proliferation and blood vessel formation. 300 In patients with chronic heart failure, insufficient angiogenesis hampers the ability of the heart to adapt to changing demands, resulting in inadequate blood supply. 301 Transgenic overexpression of VEGF prevents the natural age-related decline in VEGF signaling; reduces endothelial cell senescence, inflammation and mitochondrial dysfunction; promotes blood perfusion of various tissues; and extends healthspan and lifespan. 302 Mechanosignaling Dysregulation of mechanotransduction coactivators, such as Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), occurs in response to mechanical stress. Inhibition of YAP/TAZ blocks JNK signaling and downregulates proinflammatory gene expression, thereby reducing monocyte adhesion and infiltration. Endothelial-specific overexpression of YAP in vivo exacerbates, whereas CRISPR/Cas9-mediated knockdown of YAP in endothelial cells delays, plaque formation in ApoE-/- mice. 303 Moreover, maintaining YAP function can rejuvenate senescent cells and prevent the onset of ageing features by regulating cGAS-STING signaling. In contrast, genetic inactivation of YAP/TAZ in stromal cells accelerates ageing. 304 YAP/TAZ play crucial roles in arterial stiffening during cardiovascular ageing. As summarized in Table 1 , ageing disrupts critical signaling pathways, each contributing uniquely to cardiovascular dysfunction. Targeted modulation of these pathways—such as MR antagonism, β-blockers, or low-dose GH therapy—may mitigate age-related vascular and cardiac decline (Table 2 ). Table 1. Dysregulation of signaling pathways Signaling Pathway Key Mechanisms Age-Related Changes Cardiovascular Impact RAAS Disruption of sodium homeostasis, Dysregulation of vascular tone and blood volume, Abnormal cell proliferation and growth, Oxidative stress, Inflammation, Fibrotic remodeling. ↑ Renin, Angiotensin II, ACE, Collagen IV, Fibronectin, TGF-β, MRs, LTCC , Agtr1 ↓ miRNA-155 Hypertension, Atherosclerosis, Coronary artery disease, AF, Heart failure. β-Adrenergic signaling β-adrenergic desensitization, Impaired angiogenesis ↑ Circulating catecholamines, ↓ β-receptor sensitivity, ↓ β 2 -adrenergic receptor signaling Reduced cardiac reserve, Decreased exercise tolerance, Myocardial hypertrophy and fibrosis. Growth signaling Disruption of the integrity of microvascular function and structure ↓GH/IGF-1 levels Microvascular rarefaction, Impaired tissue perfusion. Impaired angiogenesis and vasculogenesis. ↓VEGF production Mechanosignaling Dysregulation of mechanotransduction coactivators. ↑YAP/TAZ activation, ↑Proinflammatory gene expression, ↓Monocyte adhesion and infiltration. Plaque formation, Arterial stiffening. Open in a new tab RAAS renin‒angiotensin‒aldosterone system; ACE angiotensin converting enzyme; TGF-β transforming growth factor-β; MRs mineralocorticoid receptors; LTCC L-type calcium channel; Agtr1 angiotensin II type 1 receptor; AF atrial fibrillation; GH/IGF-1 growth hormone/insulin-like growth factor-1; VEGF vascular endothelial growth factor; YAP/TAZ Yes-associated protein/transcriptional coactivator with PDZ-binding motif Table 2. FDA-approved drugs targeting cardiovascular ageing Drugs Mechanism Metformin Activate AMPK pathway and regulate metabolism. Rapamycin Inhibit mTOR. SGLT2 inhibitors Reduce oxidative stress, inhibit inflammation and improve vascular function. GLP-1 receptor agonizts Regulate insulin and glucagon secretion, delay gastric emptying and increase satiety. ACEI Increase NO production, improve cardiac function, metabolism and endothelia function. ARB Reduce peripheral vascular resistance and aldosterone secretion, lower blood pressure. Aspirin Decrease expression of iNOS and Cox-2 Statins Reduce in ROS levels, increase NO synthesis and neoangiogenesis. β-blockers Reduce cardiac output, blood pressure and myocardial oxygen consumption PCSK9 inhibitors Lower LDL levels, regulate inflammation and immunity, improve endothelial function Acarbose Stop postprandial blood sugar spikes. N-acetylcysteine Antioxidant, anti-inflammatory and immunomodulatory. sGC Agonizts Activate cGMP pathway and promote vasodilation. CCBs Reduce vascular resistance associated with ageing. DPP-4 inhibitors Mitigate age-related glucose intolerance. Open in a new tab AMPK AMP-activated protein kinase, mTOR mammalian target of rapamycin, SGLT-2 sodium-glucose cotransporter 2, GLP-1 glucagon-like peptide-1, ACEI angiotensin-converting enzyme inhibitor, NO nitric oxide, ARB angiotensin II receptor blocker, iNOS inducible nitric oxide synthase, Cox-2 cyclooxygenase-2, ROS reactive oxygen species, PCSK9 Proprotein Convertase Subtilisin/Kexin Type 9, LDL low-density lipoprotein, sGC soluble guanylate cyclase, cGMP cyclic guanosine monophosphate, CCBs calcium channel blockers, DPP-4 dipeptidyl peptidase-4 Crosstalk among cardiovascular ageing hallmarks The hallmarks of cardiovascular ageing exhibit profound interconnectivity, wherein experimental amplification or suppression of a single hallmark invariably cascades to influence the majority, if not all, of the remaining features. For example, senescent cells secrete a range of proinflammatory cytokines and chemokines, growth factors, and matrix metalloproteinases, collectively known as the SASP, which can induce “secondary” or “paracrine” senescence in neighboring nonsenescent cells. 305 Mechanistically, inflammation and cellular senescence are closely linked through the SASP. The innate immune cGAS‒STING pathway senses cytosolic DNA and promotes downstream activation of interferon-dependent inflammatory pathways, which are essential for the acquisition of cellular senescence and the SASP. 306 Moreover, the SASP drives inflammation, primarily through the accumulation of senescent cells and the buildup of extracellular debris and infectious pathogens that cannot be cleared due to senescence. 307 Therefore, targeting excess senescent cells represents a promising strategy for delaying vascular ageing. In conclusion, inflammatory processes contribute to cardiac and vascular ageing, and anti-inflammatory interventions targeting key nodes of the SASP may delay or halt this process. Additionally, leveraging lineage tracing and functional studies of senescent cells in vivo to develop cell type-specific senolytic and rejuvenation strategies offers new tools and directions for advancing senescent cell clearance therapies. 235 In addition, genomic instability can directly promote inflammation through clonal hematopoiesis of indeterminate potential (CHIP). 308 Moreover, epigenetic alterations not only affect gene expression but also induce cellular senescence and disrupt neurohormonal signaling pathways in the ageing cardiovascular system. 190 , 309 This interdependence is further reflected in experimental anti-ageing interventions, which frequently engage multiple hallmarks simultaneously through their mechanisms of action. For example, SIRT activators, such as NAD + precursors, counteract multiple hallmarks of cardiovascular ageing. 310 They mitigate genomic instability via enhanced DNA repair, reverse epigenetic alterations through histone deacetylation, restore proteostasis by promoting the clearance of protein aggregates, and ameliorate mitochondrial dysfunction by augmenting mitophagy-mediated quality control. However, metformin has pleiotropic effects, including activation of AMPK (a nutrient scarcity sensor), inhibition of mitochondrial respiration, attenuation of adipocyte senescence, suppression of proinflammatory pathways, and modulation of the gut microbiota toward a metabolically favorable composition. 311 These interactions increase the complexity of cardiovascular ageing, indicating that abnormalities in a single mechanism may trigger widespread biological cascades. Therefore, future research on mechanisms should not focus solely on amplifying the effects of a specific hallmark but should consider the systemic interactions between these hallmarks, providing a theoretical basis for the development of multitargeted therapeutic strategies. The role of cardiovascular ageing in ageing-related diseases Cardiovascular diseases Heart failure Heart failure (HF) is a clinical syndrome that usually occurs in elderly individuals. Each HF phenotype is determined by the patient’s risk factors, comorbidities, and disease modifiers superimposed on the cardiovascular ageing process, which act as a scaffold. 312 Current theories of ageing mechanisms identify the progressive dysregulation of cellular protein homeostasis (proteostasis) and loss of protein quality control as central determinants of senescence, a phenomenon now termed “loss of proteostasis”. Proteostasis collapse has been mechanistically linked to HF development following myocardial infarction or valvulopathy. As evidenced in genetic forms of cardiomyopathy, disrupted proteostasis is recognized as a critical contributor to acquired cardiomyopathy pathogenesis. 313 , 314 While the presence of autophagosomes does not invariably indicate increased autophagic protein degradation (i.e., increased autophagic flux), ultrastructural evidence demonstrating autophagosome-associated sarcomere degradation suggests that activated autophagic proteolysis accelerates protein turnover, thereby potentiating cardiac remodeling and disease progression in patients with cardiac hypertrophy or mitral regurgitation. Experimental studies in mice with pressure overload-induced cardiac hypertrophy demonstrated the tripartite interplay of proteotoxic stress, the induction of autophagic degradation, and the formation of protein aggregates/aggregate-like structures. 315 These aggregates emerge when proteolytic systems become impaired, overwhelmed, or pharmacologically inhibited. 315 Notably, cardiomyocytes from HF patients with ischemic or valvular etiologies exhibit increased autophagic proteolysis. This maladaptive response may drive excessive sarcomeric degradation, contractile dysfunction, and pathological disease progression. Crucially, the dual role of autophagy—as both a quality control mechanism and a potential contributor to proteostatic imbalance—highlights the context-dependent nature of proteostasis regulation in HFs. Apart from the loss of proteostasis, mitochondrial and oxidative stress are considered important factors in cardiac ageing and in the development of cardiac diseases such as heart failure, cardiac hypertrophy, and diabetic cardiomyopathy. As we age, cellular processes associated with mitochondrial function, such as bioenergetic metabolism, apoptosis, and inflammatory responses, change, leading to cardiac dysfunction. An in-depth understanding of the mitochondrial mechanisms associated with the ageing process will provide new strategies to ameliorate this process, particularly in heart failure. 316 Notably, CPCs and CMs develop senescent phenotypes with increasing age. This cellular senescence suggests that senolytic approaches may provide therapeutic benefits for age-related cardiac deterioration and restore regenerative capacity in the ageing heart. 207 , 234 In addition, cardiovascular ageing may ultimately trigger heart failure by causing impaired cardiac function, fibrosis, and associated changes in genetic and biological processes. In particular, in the Tgαq*44 mouse model, these changes are observed in the early stages of heart failure and persist as heart failure progresses. 317 In senescence-accelerated mice, endothelial senescence contributes to HFpEF. The addition of a high-salt, high-fat diet accelerated endothelial senescence and promoted endothelial inflammation. This coincides with the hemodynamic and structural changes typical of HFpEF. 318 Overall, cardiovascular ageing manifests as a decline in function and structure leading to heart failure, and targeting this process may lead to new options for the treatment and management of heart failure (Fig. 5a ). Fig. 5. Open in a new tab Disease-specific mechanisms linked to cardiovascular ageing. a Cell senescence and dysfunction, loss of proteostasis, mitochondrial dysfunction and oxidative stress all contribute to heart failure. Among these mechanisms, the loss of proteostasis plays a central role. Different senescent cells play important roles in atherosclerosis. Aortic dissection and aortic aneurysm are partly caused by cell senescence and epigenetic alterations. These factors are all hallmarks of cardiovascular ageing. b Blood‒brain barrier breakdown and impaired fluid flow dynamics collectively exacerbate neurodegenerative disorders associated with ageing. The latter encompasses three interdependent components: vascular dynamics, maintenance of perivascular spaces, and meningeal lymphatic drainage. Additionally, T and B lymphocyte expansion alongside elevated proinflammatory cytokines contribute to the pathogenesis of these age-related neurodegenerative conditions. c Circulating biochemical factors and hemodynamic forces drive cellular senescence in endothelial cells, which compromises their regenerative and angiogenic potential, thereby exacerbating the pathogenesis and progression of diabetes. This impairment can be reversed by MSC-sEVs carrying miR-146a-5p. Conversely, hyperglycemia accelerates EC senescence through ASK1 activation, thereby promoting cardiovascular ageing. Consequently, diabetes and cardiovascular ageing establish a vicious cycle. Whether obesity and hyperlipidemia—established risk factors for cardiovascular ageing—form analogous pathological circuits remains unclear. HF heart failure, CPCs cardiac progenitor cells, CMs cardiomyocytes, AS atherosclerosis, AD aortic dissection, AA aortic aneurysm, NDAs neurodegenerative disorders of ageing, MetS metabolic disorders, SASP senescence-associated secretory phenotype, ECs endothelial cells, VSMCs vascular smooth muscle cells, BBB blood‒brain barrier, PBM parenchymal border macrophage, CBF cerebral blood flow, CSF cerebrospinal fluid, NVC neurovascular coupling, MSC‒sEVs mesenchymal stem cell-derived small extracellular vesicles. Created in BioRender (2025) https://BioRender.com/fozj7xk Atherosclerosis Atherosclerosis is characterized by the accumulation of fibrofatty lesions in the intima and is one of the most common underlying causes of cardiovascular disease. The key factors involved in the development of atherosclerosis include endothelial dysfunction, leukocyte adhesion, foam macrophage formation, and VSMC phenotypic transition. 319 Endothelial dysfunction is considered the initial step in atherosclerosis, and VSMCs are the major cellular origin of atherosclerotic lesions. Notably, a growing body of evidence indicates that senescent ECs are frequently found in atherosclerosis. 320 These senescent ECs increase the secretion of SASP factors and promote the activation of monocytes and their infiltration into the subendothelial region. In addition, senescent ECs compromise endothelium integrity and permeability, facilitating the accumulation of oxidized low-density lipoprotein (LDL), which further contributes to atherosclerosis. 321 , 322 Elimination of endothelial senescent cells by angptl2 knockdown could promote endothelium repair and limit the progression of atherosclerotic lesions in the aortic wall. 323 Senescent VSMCs are considered to be a driving force of atherosclerosis, promoting plaque instability by producing inflammatory adhesion molecules, matrix metalloproteinases and metabolic abnormalities. 324 SIRT6 has been demonstrated to delay VSMC senescence by preserving telomere integrity, thereby reducing atherosclerotic plaque burden and preserving plaque stability. 325 An ageing-associated metabolic regulator, TRAP1, can mediate metabolic reprogramming to increase lactate-dependent H4K12la via HDAC3, promoting SASP expression and offering a new therapeutic direction for VSMC senescence and atherosclerosis. 326 Macrophages infiltrate the arterial wall, take up lipids/cholesterol and convert into foam cells. A high accumulation of senescent foamy macrophages occurs in fatty-streaked lesions, and these cells can express VCAM1 and MCP1 to recruit circulating monocytes and further promote the development of senescent cells. This results in the production of multiple inflammatory cytokines and MMPs. 327 In addition, the senescence of T cells, B cells, and dendritic cells significantly contributes to vascular ageing and atherosclerosis. 328 Aortic dissection (AD) and aortic aneurysm (AA) Aortic aneurysm (AA) occurs when the progressive weakening of the aortic wall causes the aorta to enlarge, whereas aortic dissection (AD) occurs when a tear forms within the aortic wall and causes blood to flow between the laminar layers of the media, thereby separating them and creating a false lumen with a severely weakened outer aortic wall. 329 Recent studies have demonstrated that vascular ageing affects AA/AD formation. According to the proteomics results, approximately 2/3 of the proteins differentially expressed in aged vs young aortic tissue were also differentially expressed in patients with thoracic AA (TAA) compared with healthy aortic tissue. 330 In addition, ageing induces miR-1204, which inhibits myosin light chain kinase, facilitating the acquisition of the SASP and the loss of the contractile phenotype in VSMCs. aggravates abdominal AD via the miR-1204-MYLK signaling axis. 331 VSMC senescence has been observed in mouse and human AAA and TAA samples. Senescent VSMCs release a variety of proinflammatory cytokines and matrix-related molecules, which are correlated with AA progression. The age-related sirtuin members SIIRT1 and SIRT6 were decreased in human AAA samples. VSMC-specific Sirt1 knockout and transgenic mice have consistently shown that SIRT1 significantly attenuates AAA formation via inhibition of the p21 and nuclear factor kappa B pathways in angiotensin II and CaCl2 aortic aneurysm mouse models. 332 The overexpression of SIRT6 significantly prevents AAA formation in an Ang II infusion model and attenuates premature senescence, the inflammatory response and neoangiogenesis in VSMCs under Ang II stimulation. 333 SIRT6 has also been demonstrated to protect against TAA by epigenetically inhibiting vascular inflammation and senescence. The VSMC senescence/proinflammatory phenotype in AAA is partly mediated by MLK1, and MLK1 deficiency abolishes p38MAPK activity and is accompanied by reduced senescence/proinflammation in the vessel wall and cultured VSMCs. 334 Stress-induced premature senescence (SIPS) was detected in AAAs from patients and mouse models, and SIPS promoted the transformation of VSMCs from a contractile phenotype to a synthetic phenotype, whereas inhibition of SIPS by the senolytic agent ABT263 suppressed VSMC phenotype switching. 335 On the basis of these related studies, great progress may be made in AAA treatment by interfering with VSMC senescence. Neurodegenerative disorders Neurodegenerative disorders of ageing (NDAs), such as Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, Huntington’s disease and amyotrophic lateral sclerosis, are characterized by progressive neuronal dysfunction and cognitive decline. They represent a major socioeconomic challenge in view of their high prevalence yet poor treatment. 336 Traditionally, ageing in the healthy brain is characterized by a low-grade, chronic and sterile inflammatory process called neuroinflammation. This condition is characterized primarily by the upregulation of inflammatory responses at the brain level, contributing to the development of age-related neurodegenerative disorders. 337 However, few studies have explored the effects of ageing on neurodegenerative disorders at the cardiovascular level. The blood‒brain barrier (BBB) is highly specialized to protect the brain from harmful circulating factors in the blood and maintain homeostasis in the brain. 338 , 339 A hallmark pathological feature of NDAs is BBB breakdown (Fig. 5b ), which is observed in nearly all neurodegenerative disorders. 340 Researchers have reported breakdown of the BBB in both rodent models and humans, which begins as early as middle age and progresses to the end of the life span. 341 The brain endothelial glycocalyx, a key structural component of the BBB, 342 may strongly contribute to NDAs during ageing. 343 BBB disruption in Alzheimer’s disease (AD) has been confirmed through multiple independent postmortem human studies. 344 Recent neuroimaging investigations revealed BBB compromise in patients with mild cognitive impairment (MCI) and early-stage AD, preceding measurable cognitive decline and other cerebral pathologies. 345 MRI studies further demonstrated increased cerebral microbleeds—reflecting cerebrovascular integrity loss—in 25% of MCI patients and 45–78% of early AD patients during predementia stages. 346 – 348 These findings suggest that BBB dysfunction is not merely a consequence but also a causative contributor to AD pathogenesis. 349 , 350 Vascular cognitive impairment (VCI), defined as cognitive deficits linked to cerebrovascular disease, represents another prevalent dementia subtype. 351 Like AD, BBB disruption is closely associated with VCI. For example, serum-derived proteins have been detected in the brain tissues of VCI patients, 352 , 353 whereas elevated cerebrospinal fluid (CSF) levels of albumin and laminin have been detected in this population. 352 , 354 MRI analyses additionally revealed enhanced BBB leakage in VCI patients, 355 , 356 collectively implicating BBB breakdown as a critical driver of VCI pathogenesis. BBB impairment has also been documented in Parkinson’s disease (PD) animal models. 357 , 358 Postmortem studies revealed increased BBB permeability in the posterior commissural putamen of PD patients. 359 Positron emission tomography imaging has demonstrated dysfunction of the BBB transporter system in PD, 360 and dynamic contrast-enhanced MRI has revealed increased BBB leakage, 361 underscoring the pivotal role of BBB integrity in PD pathophysiology. In amyotrophic lateral sclerosis (ALS), blood–central nervous system barrier (BCNSB) disruption has been reported. Rodent ALS models exhibit blood‒spinal cord barrier (BSCB) rupture preceding motor neuron degeneration and neuroinflammation, with progressive deterioration during the disease course 362 , 363 —although one human study revealed no correlation between BSCB leakage and motor neuron pathology. 364 Postmortem analyses revealed structural and functional impairments in BSCB-associated microvasculature within the gray and white matter of the medulla and spinal cord tissues of ALS patients. 363 , 365 Emerging neuroimaging studies have further revealed early-stage BSCB dysfunction in ALS patients, 366 , 367 suggesting that barrier disruption contributes to ALS pathogenesis. Within the CNS, the vasculature resides in the meningeal (dura/leptomeninges) and parenchymal compartments. Meningeal vessels exhibit location-dependent specialization: dural vessels are fenestrated and lack tight junctions, permitting macromolecule and immune cell trafficking from the blood into the dura. 368 , 369 However, the precise alterations in the meningeal vasculature during ageing and neurodegeneration remain uncharacterized, representing an intriguing area for future investigations. In addition to the structural breakdown of the BBB, changes in cerebral vascular dynamics with ageing contribute to the onset and progression of neurodegenerative disorders. Brain health is intimately connected to fluid flow dynamics that cleanse the brain of potentially harmful waste material. This system is regulated by vascular dynamics, the maintenance of perivascular spaces and lymphatic drainage in the meningeal layers. However, ageing can impinge on each of these layers of regulation, leading to impaired brain cleansing and the emergence of various age-associated neurological disorders, including Alzheimer’s and Parkinson’s diseases. 337 Age profoundly impacts cerebrovascular dynamics. With advancing age, increased arterial tortuosity alters cerebral blood flow (CBF) patterns, 370 whereas progressive arterial stiffening—closely associated with perivascular ECM deposition—becomes evident. 371 During ageing, the resting luminal diameter of cerebral vessels expands, impairing vascular tone regulation. This results in reduced baseline CBF and diminished neurovascular coupling (NVC) efficiency. 372 Concurrently, BBB permeability and CSF dynamics undergo age-dependent modifications, disrupting molecular and fluid exchange between the brain and periphery. 373 , 374 Notably, modifiable age-related risk factors (e.g., hypertension) exacerbate vascular dysfunction and increase cerebrovascular disease susceptibility. 375 , 376 In aged murine models, NVC impairment predominantly localizes to precapillary sphincters, potentially obstructing CSF transport and cerebral waste clearance—mechanistic perturbations implicated in cognitive decline and neurodegenerative pathogenesis. 372 , 377 Parenchymal border macrophages (PBMs), comprising perivascular macrophages (PVMs) and leptomeningeal macrophages, critically regulate CSF flow dynamics. First characterized by Pío del Río-Hortega in the 1920s, PVMs were later identified as a distinct myeloid lineage. 378 PBMs originate from embryonic yolk sac progenitors, migrate to perivascular niches, and maintain population stability throughout adulthood. 379 – 381 Residing in perivascular spaces (excluding capillaries), PBM modulates CSF hydrodynamics and participates in cerebral homeostasis through ROS signaling, β-amyloid, autoimmunity and hypertension. 382 , 383 ageing is correlated with PBM dysfunction: single-cell RNA sequencing reveals an age-associated shift toward proinflammatory phenotypes marked by upregulated MHC class II gene expression. 384 – 386 Functionally, aged PBM exhibit diminished phagocytic capacity, 385 , 387 which is correlated with impaired CSF dynamics. Furthermore, PBM interacts with perivascular fibroblasts—primary ECM producers—to regulate vascular compliance. PBM depletion drives ECM accumulation and arterial stiffening, exacerbating vasomotor dysfunction 385 and establishing a vicious cycle. These observations align with histopathological findings in aged human brains, 386 underscoring the role of PBM in maintaining cerebral waste clearance. ageing also induces structural remodeling of meningeal lymphatic vessels, 388 , 389 characterized by reduced diameter, coverage, and branching of initial lymphatics, 374 increased endothelial permeability, 374 and atrophy of downstream cervical lymph nodes. 390 , 391 Paradoxically, basal meningeal lymphatics display hyperplastic phenotypes. 389 These architectural changes impair meningolymphatic function, diminishing CSF and waste efflux capacity 374 , 389 , 392 and exacerbating age-related declines in cerebral clearance efficiency. 390 , 393 Consequently, cognitive impairment and neurodegenerative risk increase. 374 , 394 In combination with these effects, ageing promotes a proinflammatory meningeal milieu characterized by T/B lymphocyte expansion, 395 – 397 elevated proinflammatory cytokines, 391 and loss of lymphatic integrity. These inflammatory perturbations further reduce CSF drainage efficacy, aggravating toxic metabolite accumulation. 391 Therapeutic strategies targeting VEGFR3 signaling to enhance meningolymphatic function have shown promise in restoring cerebral waste clearance. 374 However, more research focusing on the impact of the ageing cardiovascular system on neurodegenerative disorders is still needed to fill the knowledge gap in this area and address age-related declines in neurologic function. Metabolic disorders Diabetes Age-related vascular dysfunction plays a pivotal role in the pathogenesis of multiple age-associated disorders, including impaired wound healing, heart failure, diabetes mellitus, Alzheimer’s disease, and renal diseases. 109 The cellular senescence of endothelial cells represents a central mechanism underlying this process. ECs are persistently exposed to both circulating biochemical factors and hemodynamic forces. These factors include oxygen, nutrients (such as glucose, amino acids, and lipids), hormones (such as insulin, angiotensin II, and endothelin-1), and cytotoxic agents (including chemotherapeutic drugs). 398 Senescent ECs exhibit significant alterations in gene expression, replicative capacity, and morphology, compromising vascular endothelial integrity by impairing regenerative/angiogenic potential and promoting pathogenic progression—ultimately driving vascular ageing pathologies such as diabetes. 399 Critically, premature EC senescence contributes to diabetic microvascular complications, including retinopathy. Physiological angiogenesis supports wound healing through neovascularization. 400 However, this process becomes dysregulated with ageing, manifesting as delayed healing in elderly individuals compared with younger individuals. Diabetic conditions further impair angiogenesis, exacerbating wound healing deficits. 60 Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) enhance senescent EC recovery and accelerate wound closure in aged/diabetic murine models by augmenting angiogenesis, and miR-146a-5p serves as a key mediator. 401 Notably, the diabetes-vascular ageing relationship is bidirectional (as detailed in “Etiology and Risk Factors”). Dysglycemia independently predicts increased aortic stiffness over 5 years in elderly Black adults, 402 highlighting weight and glucose management as critical preventive measures against premature vascular ageing in African populations. Postprandial hyperglycemia—a hallmark of impaired glucose tolerance prevalent in ageing—represents a prediabetic state. Intermittent hyperglycemia accelerates endothelial senescence more potently than sustained hyperglycemia does, partially through superoxide overproduction, establishing a vicious cycle between diabetes and vascular ageing (Fig. 5c ). Breaking this pathological loop at any node may mitigate progressive deterioration. Yamagishi et al. demonstrated that hyperglycemia activates ASK1, accelerating EC senescence and upregulating PAI-1, thus identifying ASK1 as a therapeutic target for diabetic vascular ageing. 36 Recent evidence implicates NLRP3 inflammasome-mediated immunosenescence as both a precursor and a driver of diabetic vascular ageing. Senescent immune cells promote vascular dysfunction directly and indirectly via perivascular adipose tissue (PVAT) dysregulation—a unique modulator of vasomotor tone. Consequently, NLRP3 pathway inhibition may prevent early immunosenescence, alleviating diabetes-associated vascular injury, whereas senolytic T-cell-or PVAT-targeted strategies represent complementary therapeutic avenues. 403 Obesity and dyslipidemia As previously described, metabolic disorders, including obesity and dyslipidemia, constitute major contributors to cardiovascular ageing. 25 , 404 Nevertheless, few investigations have addressed the reciprocal impact of vascular ageing on metabolic pathophysiology—specifically, whether endothelial dysfunction arising from vascular senescence 405 modulates lipid metabolism. Analogous to the vicious cycle established between diabetes and cardiovascular ageing, the potential existence of similar feedback loops between vascular ageing and other metabolic diseases warrants rigorous exploration. Elucidating such bidirectional relationships may reveal novel therapeutic targets for metabolic disorders rooted in age-related vascular dysfunction. Turning back time with emerging rejuvenation strategies for cardiovascular ageing In Greek mythology, the Moirai (Fates)—Clotho, Lachesis, and Atropos—personify life’s temporal boundaries: Clotho spins the thread of life, Lachesis measures its length, and Atropos severs it with relentless shears, symbolizing the irrevocable nature of mortality. However, humanity’s quest to prolong life has persisted unabated across civilizations. From alchemical elixirs of immortality in antiquity to contemporary geroscience targeting fundamental ageing mechanisms, mankind has relentlessly sought to transcend these biological constraints encoded in our cellular machinery. This enduring endeavor reflects not merely a defiance of mythological predestination but also a scientific odyssey to decode the molecular signatures of senescence and reshape cardiovascular ageing trajectories through targeted interventions. The etiology, risk factors and hallmarks discussed above reveal the complex biological underpinnings of cardiovascular ageing. However, understanding these mechanisms alone is insufficient to effectively address cardiovascular ageing. On the basis of these findings, it is essential to explore specific management strategies aimed at the targeted prevention and treatment of age-related CVD (Fig. 6 ). Fig. 6. Open in a new tab Specific strategies for cardiovascular rejuvenation. Through health education and ageing evaluation, both doctors and patients can gain a clearer understanding of ageing and the extent of its progression. Lifestyle interventions such as exercise and dietary plans are adaptive strategies to counteract cardiovascular ageing. Furthermore, targeted therapeutics such as immunotherapy, clearance of senescent cells and stem cell replenishment are being tested to alleviate cardiovascular ageing. In addition, psycho-cardiological therapy may also be an effective strategy for age-related CVDs. Created in BioRender (2025) https://BioRender.com/e79x749 Targeting senescent cells Since the 1960s, when the cell biologist Leonard Hayflick proposed the “replicative senescence” theory, 406 senescent cells have been characterized by an irreversible cell cycle arrest state. Upon entering this terminally arrested phase, cells become trapped in a temporally constrained state, progressively advancing toward functional decline. Senescent cells typically exhibit upregulated expression of multiple cytokines and increased secretory capacity, a phenomenon termed the SASP. 407 This process exacerbates chronic sterile inflammation and tissue dysfunction. Consequently, cellular senescence is recognized as a critical driver of organismal ageing and age-related pathologies. Thus, targeting senescent cells has emerged as a viable anti-ageing strategy, primarily through three approaches: immunotherapy, gene delivery and immunological interventions. Three types of immunotherapies are used: enolytics (targeted elimination of senescent cells), senomorphics (suppression of the SASP), and the reverse (reversal of stress-induced cell cycle arrest). Among these, senolytics represent the most extensively investigated senotherapeutic approach and are currently used in clinical studies. 408 , 409 Notably, proof-of-concept studies in preclinical models have established that senolytic interventions not only treat but also prevent, delay, or ameliorate age-related disorders. A seminal study of senolytics, published in 2011, demonstrated that clearance of p16 + senescent cells delays age-related pathologies. 17 This was followed in 2015 by the first pharmacological validation of senolytic efficacy in aged mice. 410 Navitoclax—a senolytic agent—ameliorates age-related cardiac dysfunction in murine models, concurrently reducing CD8 + effector memory T-cell populations. 411 Senolytics have demonstrated therapeutic potential against various age-related pathologies and may synergize with conventional therapies in oncology. 412 Senomorphics—pharmacological agents that modulate critical senescence features (e.g., SASP) without eliminating SnCs—serve as alternative therapeutic candidates. 413 Although multiple signaling pathways contribute to the production of proinflammatory SASP factors, the most frequently studied pathways include the mTOR, p38 MAPK, and NF-κB pathways. 414 The miR-302b-mediated reverse strategy has shown precision in reversing senescence-associated proliferative arrest, significantly extending the organismal lifespan, ameliorating ageing phenotypes, and attenuating chronic inflammation without detectable safety concerns, thereby validating the feasibility of this approach both theoretically and practically. 415 The boundaries between senotherapeutic modalities remain fluid. For example, mTOR inhibitors may function as senolytics under specific conditions 416 or senomorphics 417 , 418 or delay senescence progression depending on context. 419 Similarly, the flavonoid procyanidin C1 exhibits dose-dependent dual functionality as either a senomorphic or a senolytic agent. 420 Despite their therapeutic promise, these strategies face inherent limitations. Although more than 20 clinical trials are currently ongoing and no major complications have been reported to date, senolytic therapies risk tissue damage when applied to environments with high senescent cell burdens, as evidenced by delayed wound healing—a primary adverse effect observed in INK-ATTAC mice. 17 Emerging concerns include hepatic fibrosis secondary to vascular leakage following elimination of senescent liver sinusoidal endothelial cells. 421 Compared with senolytics, senomorphics may require chronic administration rather than intermittent dosing, potentially increasing off-target toxicity risks. Furthermore, while effectively suppressing inflammation, senomorphics might compromise immune surveillance functions. In the opposite strategies, miR-302b successfully reverses stress-induced cell cycle arrest, yet its efficacy in postmitotic cells (e.g., neurons and cardiomyocytes) remains underexplored. In addition to immunotherapy, gene delivery-mediated targeted clearance of senescent cells has emerged as a highly promising therapeutic strategy. Therefore, selecting the appropriate target is critical. p16 is widely used as a marker of senescent cells. 207 p16 tdTom reporter mice, which use fluorescence to visualize senescent cells, allow for cell sorting and the study of senescence mechanisms, enabling targeted senescent cell clearance. 422 p16 3MR reporter mice have demonstrated that clearing senescent cells improves age-related diseases such as atherosclerosis. 423 However, a recent preprint raised concerns about the validity of p16 3MR mice, 424 necessitating further research to validate this model and studies built upon it. In the p16-INK-ATTAC transgenic murine model—engineered with a “suicide” transgene under the control of the p16 Ink4a promoter to enable senescent cell-specific apoptosis—pharmacologically mediated clearance of senescent cells significantly improves cardiovascular function. The core design principle of this INK-ATTAC system utilizes the p16 Ink4a promoter to drive inducible caspase-8 expression, thereby achieving targeted elimination of p16 Ink4a+ senescent cells. Studies have confirmed that transgene activation efficiently depletes senescent cell populations. Critically, eliminating these cells in aged subjects mitigates established age-related pathologies. In addition to p16, other markers of senescent cells can also serve as potential targets for gene delivery. Similar to the p16-INK-ATTAC model, the p21-ATTAC mouse model also enables efficient clearance of senescent cells and has demonstrated enhanced efficacy in certain disease contexts. 425 The development of the p21-Cre mouse model has facilitated in vivo monitoring, sorting, imaging, elimination, and manipulation of p21 high cells, providing a powerful tool for investigating the biology of senescent cells. 426 In p19-DTR mice, targeted removal of p19 ARF -expressing senescent cells in lung tissue prevents elastase-induced pulmonary dysfunction. 427 These findings substantiate that cellular senescence acts as a causal contributor to age-associated phenotypes, whereas senescent cell clearance prevents or delays tissue dysfunction and extends the healthspan. 17 , 428 Overall, the advantage of targeting senescent cells is that they promote tissue regeneration and repair, offering a promising approach to slow age-related cardiovascular decline. 307 However, in certain cases, senescent cells may have beneficial effects, 429 – 431 and excessive clearance of these cells could lead to the loss of cellular and tissue functions, potentially disrupting the balance and stability of the entire physiological system. 421 Therefore, carefully weighing the therapeutic benefits and potential side effects and identifying more precise methods to clear senescent cells are crucial. Bin Zhou et al., 235 on the basis of a dual-homologous recombinase system, established cell senescence lineage tracing techniques and developed four genetic strategies, laying the theoretical foundation for precision-targeted therapies. As therapies targeting stem cell exhaustion, such as replenishment, have already been summarized elsewhere, we do not discuss them further here. 432 Immunotherapy targeting SnCs represents an emerging therapeutic strategy that primarily functions by augmenting immune-mediated clearance of SnCs. These approaches leverage the intrinsic surveillance mechanisms of the immune system to eliminate SnCs through multiple modalities. Key immune effectors, including natural killer (NK) cells, macrophages, and T-cell subsets (CD8 + cytotoxic and CD4 + helper T cells), have been implicated in SnC surveillance and clearance. 433 – 435 However, SnCs may evade immune detection through the expression of inhibitory receptors and checkpoint proteins—such as programmed death-ligand 1/2 (PD-L1/PD-L2), CD80, and HLA-E—or via alternative mechanisms, including matrix metalloproteinase-mediated shedding of the NK cell costimulatory receptor NKG2D. 436 – 439 Owing to the clinical success of checkpoint inhibitors in oncology, 440 their repurposing to enhance immune-mediated SnC elimination has been actively explored. Additionally, immunotherapy targeting senescence-specific surface antigens—including dipeptidyl peptidase-4 (DPP4), urokinase-type plasminogen activator receptor (uPAR), β2-microglobulin (B2M), and glycoprotein nonmetastatic melanoma protein B (GPNMB)—is under development. 441 , 442 These antigens may be exploited through chimeric antigen receptor (CAR)-T-cell engineering, monoclonal antibodies, or vaccine-based strategies. Vaccination approaches to prime adaptive immunity against SnC-derived neoantigens are being investigated. The use of specific antibodies and antibody‒drug conjugates (ADCs) has further expanded the immunotherapeutic arsenal against SnCs. Collectively, these immune-focused modalities provide promising alternatives for senescent cell clearance, with potential applications in mitigating age-related pathologies and extending the healthspan. Adjusting energy sensor pathways In relation directly to the influence of diet, energy sensor pathways are important regulatory mechanisms controlling cardiac homeostasis. The mTOR pathway plays crucial roles in many physiological and pathological processes, particularly in ageing. Rapamycin, a well-known mTOR inhibitor, has been widely used in research and clinical antiageing therapies. 443 Manipulation of proline-rich AKT1 substrate 1 (PRAS40; also known as AKT1S1), an endogenous inhibitor of mTOR complex 1 (mTORC1) signaling, also confers cardioprotection after ischemic damage and prevents diabetic cardiomyopathy in obese mice. 444 However, the adverse effects of pharmacological mTOR inhibitors hinder their development as anti-ageing therapies. Low doses of one rapalogue have been demonstrated to safely enhance immune function in elderly patients. 445 Future research aimed at identifying mTOR inhibitors with lower toxicity and optimizing dosing regimens could uncover strategies to promote healthy cardiac phenotypes while mitigating adverse effects. SIRT1 is a family of redox-sensitive nicotinamide adenine dinucleotide-dependent deacetylases that catalyze the posttranslational modification of hundreds of proteins that are involved in metabolism and cellular homeostasis. More importantly, SIRT1 plays a role in ageing regulation by integrating multiple signaling pathways. Postnatally, SIRT1 expression decreases in most organs but remains elevated in healthy hearts unless myocardial ageing or cardiomyopathy manifests. 446 – 448 Mild to moderate SIRT1 upregulation exerts cardioprotective effects, 449 as demonstrated in multiple experimental models. 450 SIRT1 activation triggers antioxidant mechanisms to reduce oxidative stress and promote mitochondrial health and biogenesis while simultaneously suppressing proinflammatory pathways in cardiomyocytes, thereby increasing cellular survival. 451 , 452 Its activator, resveratrol, is considered an effective anti-ageing drug because its broad biological activities help mitigate the negative effects of ageing. 126 However, while most healthy subjects can tolerate doses of up to 2.5 g per day well, some may also experience reactions such as nausea, stomach pain, or headache as a result of ingesting high doses of resveratrol. 453 Owing to interindividual differences, it has not yet been possible to determine an optimal dosage for all people. In addition to these classic drugs, recent discoveries have shown that the ability to activate the AMP-activated protein kinase (AMPK) pathway decreases with age, impairing cellular homeostasis and accelerating the ageing process. Metformin, an AMPK activator, has been shown to slow ageing through various mechanisms. 311 Metformin has been extensively utilized as a first-line therapeutic for diabetes mellitus since the 1990s. Subsequent studies demonstrated its capacity to extend the healthspan in Caenorhabditis elegans and both the healthspan and lifespan in murine models, 454 , 455 although contradictory evidence revealed no lifespan extension in mice. 456 Metformin has been used in humans for more than six decades; it has a well-characterized safety profile and uniquely targets multiple pathways implicated in ageing and age-related pathologies. 457 Epidemiological analyses revealed geroprotective effects, including a reduced incidence of age-related comorbidities and attenuated all-cause mortality in diabetic and nondiabetic populations. 458 , 459 Nevertheless, this renowned therapeutic agent has inherent adverse effects, most notably gastrointestinal disturbances—such as abdominal pain, early satiety, appetite suppression, and diarrhea—which typically resolve within 1–2 weeks of treatment initiation. 460 Few patients may complain about anxiety, sleeplessness, fast breathing, and other symptoms soon after taking metformin and will usually stop the drugs on their own. Metformin increases lactate levels while maintaining the normal range, but it is possible that those with severe side effects, including MALA, may be more sensitive to the inhibition of mitochondrial complex I, which is attributable to genetic mechanisms. 311 Like many other biological processes, ageing is regulated by classical signaling pathways and transcription factors, and interventions targeting these pathways can alter the ageing process and delay disease onset. However, it remains unclear whether drugs such as rapamycin and metformin directly modulate the ageing process or act through indirect mechanisms. For example, rapamycin may exert its effects via immunosuppression, whereas metformin may function through glycemic control. Therefore, further exploration of classical ageing regulatory pathways may promote the development of specific therapeutic strategies for cardiovascular ageing. Addressing central inflammatory pathways As we reviewed before, in “inflammageing”, key players such as TNF-α, IL-1β, and IL-6 are central. 172 Targeting central inflammatory pathways, such as the use of the IL-1β antagonist canakinumab, has been shown to improve chronic inflammation in the microcirculation, thereby reducing cardiovascular ageing. 175 T-cell-specific deficiency in mitochondrial transcription factor A (TFAM) is sufficient to drive cardiovascular ageing, accompanied by increased circulating cytokines. The TNF-α inhibitor etanercept partially reverses this phenotype. 174 Additionally, chemokines play critical roles in inflammation and immunity, 461 and targeting chemokines is a promising therapeutic approach. 462 There is substantial evidence indicating that targeting central inflammatory pathways can improve cardiovascular ageing. However, a large phase III clinical trial involving aspirin in individuals over 70 years of age produced negative results, 463 leaving questions about which patient populations may benefit from anti-inflammatory interventions. In addition, targeting inflammation via TNF-α inhibitors such as etanercept ameliorates age-related cardiovascular dysfunction, yet concomitant immunosuppression may elicit adverse off-target effects. Kopp et al. demonstrated that patients with spondyloarthropathies (SpAs) receiving anti-TNFα therapy presented an elevated risk of noninfectious inflammatory events (NIEs) compared with untreated cohorts, 464 suggesting that systemic immunosuppression could counteract these benefits in ageing populations. As the inflammatory system is redundant, compensatory, and crucial for survival, evaluation of risks as well as benefits must drive the development of agents in this class. Modulating neurocardiology dynamics The physiological connection between the heart and the brain, known as HBA, operates through a complex network involving the autonomic nervous system, the RAAS, and the hypothalamic‒pituitary axis and plays a significant role in common diseases. 268 The influence of heart–brain interactions on cardiovascular health should not be underestimated. Sleep deprivation, a widespread phenomenon in modern society, has been shown to cause cardiac dysfunction, including increased heart rate variability, elevated blood pressure, and myocardial injury, thereby exacerbating the risk of CVD. 465 Cardiogenic regulation of sleep after heart injury, which restricts cardiac sympathetic input, limits inflammation and damage. 466 Depression, a common mental disorder, not only affects mood and cognitive function but is also closely associated with increased morbidity and mortality in patients following acute myocardial infarction, highlighting the potential threat that mental health issues pose to cardiovascular health. 32 , 467 We have shown that stress-related neural activity increases the risk of cardiovascular events by influencing the vulnerability of coronary artery plaques and promoting coronary inflammation, further highlighting the close connection between mental and cardiovascular health. 468 In addition, family or friend incarceration was strongly associated with indices of EVA. The mass incarceration of others may affect the physical health of African American women, which may contribute to CVD disparities. 31 This may represent a new therapeutic direction. In brief, psycho-cardiological therapy, which simultaneously addresses mental and cardiac health, may be an effective strategy for managing CVD driven by cardiovascular ageing. Adopting healthy lifestyles Smoking causes a decrease in life expectancy, premature biological ageing, and early onset of multiple diseases; thus, quitting smoking may be a good choice. 20 Maintaining healthy body weight throughout life is crucial for healthy ageing and longevity, reflecting the importance of caloric restriction (such as the Mediterranean diet 143 ) and alternative approaches, such as “lazy strategies” (e.g., GLP-1 receptor agonizts 469 , 470 ), which may benefit heart function. However, the use of GLP-1 receptor agonizts may lead to muscle mass reduction, 471 necessitating the development of therapies that specifically target fat tissue without influencing muscle. Given the importance of nutrition in ageing, dietary supplements offer a popular and convenient method for maintaining or restoring youthfulness in an ageing population. 472 For example, spermidine increases lifespan and improves cardiac function in aged mice and rats, which is correlated with a reduced incidence of CVD in humans. 199 While adhering to the core principles of a healthy diet, it is important to tailor dietary recommendations on the basis of individual preferences, culture, and the nutritional needs of the ageing population. 473 Additionally, exercise, a “medicine” available without prescription, plays an irreplaceable role in cardiovascular health. An appropriate exercise regimen not only slows cardiovascular ageing but also improves overall quality of life. 474 Embracing a healthy lifestyle can significantly delay or reverse the structural and functional changes caused by cardiac ageing and thus reduce the risk of age-related chronic diseases. 318 , 475 – 477 Assessing and preventing the degree of ageing Research efforts to identify biomarkers quantifying biological age—particularly multiomics-based biomarkers—have increased in recent years. These biomarkers not only predict ageing-related health outcomes but also serve as surrogate endpoints for evaluating interventions promoting healthy longevity. Comprehensive reviews have synthesized evidence on the predictive validity of omics biomarkers in population-based ageing studies. 478 Ageing clocks comprehensively monitor multiple dimensions of ageing, including hormonal signaling, lipid metabolism, chronic inflammation, and systemic manifestations. These clocks hold translational potential, enabling the identification of at-risk populations and guiding precision medicine. 479 Notably, DNA methylation (DNAm) in ageing clocks and their multimodal derivatives can effectively predict biological age and may provide further insights into factors influencing ageing rates. 480 However, while machine learning models that use DNAm data accurately predict biological age, they often lack causal insights. Epigenome-wide Mendelian randomization leveraging large-scale genetic data can identify CpG sites potentially causally linked to ageing phenotypes. By mapping CpG sites with putative causal relationships with lifespan and healthspan, this approach facilitates the development of ageing biomarkers, the evaluation of anti-ageing interventions and investigations into the reversibility of age-related changes. 481 Experimental validation confirmed the utility of a 3-CpG estimator for murine blood age prediction. A novel epigenetic age (EA) model was further developed for the mouse aorta, revealing significant correlations between epigenetic age acceleration (EAA) in blood/aortic samples and age-dependent endothelial dysfunction. 482 Additionally, large-scale plasma proteomics combined with machine learning can noninvasively assess organ health and ageing. 483 The SenMayo gene set enables the precise identification of senescent cells across different tissues and species, allowing the characterization of senescent cells at the single-cell level and the identification of key intercellular signaling pathways. 484 By employing a comprehensive assessment from the individual level to the cellular level and leveraging various technological approaches, these tools provide comprehensive frameworks for targeting cardiovascular ageing and related disorders, such as hypertension. 485 Conclusion and future perspectives With age, the cardiovascular system gradually degenerates, resulting in a series of pathophysiological changes. It may precede or even underlie body-wide, age-related health deterioration. In addition to the increase in time itself, we have innovatively summarized five major etiological factors as well as risk factors that have the potential to promote cardiovascular ageing (Fig. 2 ). On this basis, we propose several specific management strategies for cardiovascular ageing (Fig. 6 ). Tables 2 and 3 list FDA-approved drugs and clinical trials targeting cardiovascular ageing. However, it is important to note that categorization does not mean that the etiologies are independent of each other. A poor lifestyle (e.g., diet) can lead to obesity, 486 which, as a metabolic syndrome, can accelerate cardiovascular ageing. 25 Together, all the etiologies and risk factors form a complex ‘spider web’ of cardiovascular ageing. Obviously, focusing on only one aspect of the problem is limited and ineffective. Therefore, future research should take a holistic approach to propose a macroscopic framework for the etiology of cardiovascular ageing and corresponding therapeutic improvement methods. Table 3. Clinical trials targeting cardiovascular ageing NCT Number Study Title Study Status Interventions NCT01395277 Role of Flavanols In Cardiovascular Function in Healthy ageing COMPLETED DIETARY_SUPPLEMENT: High Flavanol first then Low Flavanol|DIETARY_SUPPLEMENT: Low Flavanol first then High Flavanol NCT05301192 Angiotensin-(1-7) Cardiovascular Effects in ageing RECRUITING DRUG: Angiotensin-(1-7) | DRUG: Saline NCT05235958 VascuFit: Exercise and Vascular ageing COMPLETED OTHER: nonlinear periodized exercise (NLPE) | OTHER: Exercise counseling NCT03535844 Cardio-vascular Protective Effects of Wolfberry in Middle-aged and Older Adults COMPLETED OTHER: Wolfberry|OTHER: Healthy diet NCT01883271 Effect of Aerobic Interval Training on Cardiovascular Function in ageing COMPLETED OTHER: High intensity aerobic interval training|OTHER: Continuous moderate intensity exercise NCT04344873 Impact of T Cells on Age-related Vascular Dysfunction: A Translational Approach NOT_YET_RECRUITING OTHER: Placebo|DRUG: Abatacept 10 mg/kg NCT01575288 Oral Trehalose Therapy to Reverse Arterial ageing in Middle-Aged and Older Adults COMPLETED DRUG: Placebo|DRUG: High-dose trehalose NCT01775865 Targeting Inflammation to Treat Cardiovascular ageing COMPLETED DRUG: Salsalate|DRUG: Placebo (for salsalate) NCT05872139 Role of Mitochondrial-derived Oxidative Stress to Promote Vascular Endothelial Dysfunction in Nonexercisers With ageing COMPLETED DIETARY_SUPPLEMENT: Placebo|DIETARY_SUPPLEMENT: Mitoquinone Mesylate NCT05598359 TA-65 and ageing Associated Microvascular Dysfunction NOT_YET_RECRUITING DIETARY_SUPPLEMENT: TA-65 | OTHER: Placebo NCT04530916 Wild Blueberries and Cardiovascular Health in Middle-aged/Older Men and Postmenopausal Women RECRUITING DIETARY_SUPPLEMENT: Blueberry Powder|DIETARY_SUPPLEMENT: Placebo Powder NCT01417663 Effects of Exercise Training and AGE-crosslink Breaker on Cardiovascular Structure and Function COMPLETED DRUG: Alt-711 | BEHAVIORAL: Physical exercise training NCT03476785 Prevention of Cardiovascular Stiffening with ageing and Hypertensive Heart Disease COMPLETED BEHAVIORAL: High intensity exercise|BEHAVIORAL: Yoga NCT01953705 n-3 PUFA for Vascular Cognitive ageing UNKNOWN DRUG: Omega 3 PUFA | DRUG: Placebo NCT01891513 ACE Inhibitors Combined with Exercise for Seniors - Pilot Study COMPLETED BEHAVIORAL: Exercise|DRUG: ACE inhibitor + exercise|DRUG: Thiazide diuretic + exercise|DRUG: Angiotensin receptor blocker + exercise NCT05706181 Heat Therapy, Functional Capacity, and Vascular Health in Older Adults RECRUITING OTHER: Home-based leg heat therapy|OTHER: Home-based sham therapy NCT04763291 Cardiovascular and Inflammageing Study RECRUITING DIETARY_SUPPLEMENT: Juice Plus+ Fruit, Vegetable and Berry blends|DIETARY_SUPPLEMENT: Juice Plus+ Omega blend NCT01842399 Resveratrol and Cardiovascular Health in the Elderly TERMINATED DIETARY_SUPPLEMENT: Resveratrol|DRUG: Placebo NCT03821623 Nicotinamide Riboside for Treating Elevated Systolic Blood Pressure and Arterial Stiffness in Middle-aged and Older Adults RECRUITING DRUG: Nicotinamide riboside|OTHER: Placebo NCT04588649 The ageing Brain and Cognition: Contribution of Vascular Injury, Amyloid Plaque and Tau Protein to Cognitive Dysfunction After Stroke COMPLETED DRUG: THK-5351 | DRUG: AV-45 NCT05433233 Effects of Lifestyle Walking on Blood Pressure in Older Adults with Hypertension COMPLETED BEHAVIORAL: Walking|OTHER: HAPA Behavior Change Counseling NCT03295734 ACES - ACE Inhibitors Combined with Exercise for Seniors with Hypertension COMPLETED BEHAVIORAL: Aerobic exercise|DRUG: Perindopril|DRUG: Losartan|DRUG: HCTZ NCT03370991 Blueberries for Improving Vascular Endothelial Function in Postmenopausal Women with Elevated Blood Pressure COMPLETED DIETARY_SUPPLEMENT: Blueberry Powder|DIETARY_SUPPLEMENT: Placebo Powder Open in a new tab ACE angiotensin-converting enzyme, ARB angiotensin II receptor blocker, HAPA health action process approach, HCTZ hydrochlorothiazide, NLPE nonlinear periodized exercise, PUFA polyunsaturated fatty acid(s), AGE advanced glycation end-product(s) For the first time, we have grouped the twelve hallmarks of cardiovascular ageing into three broad categories, from the micro- to the macrolevel, which are the molecular, cellular and systemic levels (Fig. 4 ). These findings collectively reveal that cardiovascular ageing is a complex process driven by the accumulation of multiple factors. Importantly, these hallmark features do not act independently but are intricately intertwined and synergistically interact, collectively exerting profound effects on ageing-related diseases (Fig. 5 ). However, many issues remain to be resolved. For example, the search for more specific ageing biomarkers than p16 remains an important direction for future research. In addition, different cardiac cells undergo senescence, either in naturally senescent or drug-induced senescent hearts. 487 It remains unknown whether they play the same role in cardiac function or in the development of CVD. 208 Whether reciprocal feedback loops exist between vascular ageing and nondiabetic metabolic disorders represents a compelling hypothesis that warrants further mechanistic investigation. In conclusion, the ageing process is central to the development of CVD. It is crucial to understand and intervene in this degeneration process. Future research should continue to focus on integrating mechanisms and therapeutic strategies to address the global challenges of ageing and the high incidence of CVD. Acknowledgements This study was supported by the National Key Research and Development Program of China (2023YFC3606500; 2023YFC2506500; 2023YFC2506505), the National Natural Science Foundation of China (82200437), and the Shanghai Clinical Research Center for Interventional Medicine (19MC1910300). Special Clinical Research Project of Shanghai Municipal Health Commission (20244Y0022), Shanghai “Rising Stars of Medical Talent” Youth Development Program [SHWSRS(2024)_070], and Shanghai Top Priority Research Center Construction Project (2022ZZ01010). We all thank Prof. Houzao Chen (Peking Union Medical College) and Prof. Xiaoqing Tang (Sichuan University) for their suggestions in the revision. 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