12 Hallmarks of Cardiovascular Aging Mapped With Targets for Reversal

Cardiovascular disease (CVD) is the leading cause of death globally, and aging is its single greatest nonmodifiable risk factor. Between 1990 and 2019, the global CVD patient population nearly doubled from 271 million to 523 million, while related deaths rose from 12.1 million to 18.6 million. Yet even as novel therapies have cut cardiovascular mortality, residual risk in older adults remains unacceptably high. This landmark review from Zhongshan Hospital, Fudan University — published in Signal Transduction and Targeted Therapy — attempts to consolidate the field's understanding of why and how hearts and vessels age, and what can realistically be done about it.

The authors open by cataloging five major etiology categories that accelerate cardiovascular aging beyond chronological time. Lifestyle factors include tobacco use, physical inactivity, poor diet, obesity, and psychological stress — each linked to accelerated biomarker aging, increased endothelial progenitor cell senescence, and elevated arterial stiffness. Metabolic disorders (hypertension, diabetes, dyslipidemia, metabolic syndrome, and chronic kidney disease) compound these effects. A machine-learning analysis of 39,559 UK Biobank participants demonstrated that cardiometabolic risk factors collectively and measurably advance a person's cardiovascular age beyond their chronological age. Environmental exposures, genetic and epigenetic factors, and sociodemographic variables complete the etiology framework, underscoring that cardiovascular aging is as much a product of lived experience as of biology.

The review's central intellectual contribution is a novel 12-hallmark framework stratified across three tiers. At the molecular level: genomic instability and epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, oxidative stress, and inflammation. At the cellular level: cellular dysfunction, cellular senescence (marked by the senescence-associated secretory phenotype, SASP), and stem cell exhaustion. At the systemic level: metabolic reprogramming, renin-angiotensin-aldosterone system (RAAS) dysregulation, β-adrenergic signaling alterations, growth signaling changes, and mechanosignaling disruptions. This tiered structure clarifies not only the individual roles of each hallmark but also how they interact — cellular senescence, for instance, amplifies systemic inflammation through SASP, while mitochondrial dysfunction feeds back into oxidative stress and genomic damage.

The structural and functional changes cataloged include progressive arterial stiffening, myocardial fibrosis, reduced maximal heart rate (which declines linearly with age), endothelial dysfunction, and impaired vascular repair capacity. Hyperglycemia exacerbates endothelial aging via the apoptosis signal-regulating kinase 1 (ASK1) pathway and upregulation of plasminogen activator inhibitor-1 (PAI-1), identifying ASK1 as a specific therapeutic target. Hyperhomocysteinemia elevates VSMC senescence markers including SA-β-galactosidase, p53/p21, and p16, while also inactivating telomerase in endothelial cells and progenitor cells — compounding vascular senescence through multiple parallel mechanisms.

On the therapeutic side, the review maps six rejuvenation strategy classes to the hallmarks: targeting senescent cells (senolytics and senomorphics), adjusting energy sensor pathways (AMPK, mTOR, sirtuins), addressing central inflammatory pathways (targeting SASP and inflammasome components), modulating neurocardiological dynamics (RAAS and adrenergic axis interventions), adopting healthy lifestyles, and assessing and preventing the pace of aging using validated biomarkers including epigenetic clocks. The authors catalog FDA-approved drugs and active clinical trials relevant to each approach, providing a reference map for clinical translation. Importantly, they caution that senolytic agents — while promising — may impair tissue repair, and that the selective removal of senescent cells carries risks that must be weighed carefully in older or frail patients.