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

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.