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

Figures

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  Fig. 1. 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.…

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  Fig. 2. 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

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  Fig. 3. 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

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  Fig. 4. 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

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  Fig. 5. 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…

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  Fig. 6. 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