Cardiovascular ageing is now a central framework for understanding late-life heart disease
Cardiovascular disease remains the leading cause of morbidity, disability, and mortality worldwide, and the burden falls disproportionately on older adults. This review places cardiovascular ageing at the center of that pattern, arguing that age-related biological change is not just background noise but a driver of distinct disease phenotypes and worse outcomes. The framing matters because ageing in the heart and vasculature is not limited to chronological age; it reflects a layered process shaped by lifestyle, metabolism, environmental exposure, genetics, epigenetics, and host biology. In practical terms, residual cardiovascular risk in older adults cannot be understood fully without accounting for the ageing programs acting inside vessels, myocardium, and regulatory signaling networks.
Five broad etiologic domains organize the discussion: lifestyle and behavioral factors, metabolic disorders and physiological dysregulation, environmental exposures and physicochemical determinants, genetics and epigenetics, and host biology and sociodemographic determinants. Each domain can accelerate structural decline and functional loss across the cardiovascular system. Sedentary behavior, poor diet, dysregulated metabolism, and chronic environmental stressors do not simply coexist with ageing; they help drive it. Genetic susceptibility and epigenetic drift can further amplify vulnerability, setting the stage for hypertension, atherosclerosis, heart failure, arrhythmia, and other age-linked cardiovascular phenotypes.
One sentence captures the clinical stakes: ageing biology and cardiovascular disease are deeply intertwined.
Twelve hallmarks connect molecular injury to organ-level decline
The review organizes cardiovascular ageing across three levels: molecular, cellular, and systemic. At the molecular level, the hallmarks include genomic instability, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, oxidative stress, and inflammation. These are not isolated abnormalities. They interact in feedback loops that erode cellular repair, impair energy production, and expose the cardiovascular system to persistent injury. Oxidative stress and inflammation can reinforce one another, while mitochondrial dysfunction weakens the energetic reserve needed for contractility, vascular tone, and adaptive repair.
Cellular dysfunction and cellular senescence sit at the next layer. Senescent cells stop dividing yet remain metabolically active, often releasing inflammatory mediators and other factors that can spread dysfunction to neighboring tissue. In the heart and vasculature, this creates a permissive environment for fibrosis, endothelial impairment, and reduced regenerative capacity. Stem cell exhaustion follows a similar logic. When the pools responsible for tissue renewal diminish, the organ loses resilience after hemodynamic stress, ischemia, or mechanical injury.
Metabolic changes complete the framework. Ageing shifts the biochemical balance needed to maintain vascular integrity and myocardial performance. The review also identifies major signaling axes involved in cardiovascular ageing, including the renin-angiotensin-aldosterone system, beta-adrenergic signaling, growth signaling, and mechanosignaling. These pathways govern blood pressure, neurohormonal stress responses, hypertrophic adaptation, and the tissue response to stretch and flow. Their dysregulation helps explain why ageing hearts and vessels often become less adaptable and more injury-prone.
Ageing in this context is not a single event. It is a progressive reprogramming of repair, stress response, and signaling fidelity.
Therapeutic targets now extend from senescent cells to neurocardiological regulation
The most clinically relevant part of the review is its therapeutic orientation. It proposes several rejuvenation strategies aimed at reducing residual cardiovascular risk in older adults. These include 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. The list reflects a shift in strategy: instead of treating only the downstream disease state, the field is moving toward interventions that address the biology generating that disease state.
Senescent-cell targeting stands out because it addresses one of the core sources of persistent inflammatory signaling. If senescent cells drive tissue-level dysfunction through pro-inflammatory secretory activity, then removing or modifying them could reduce the biological pressure that pushes the cardiovascular system toward failure. Energy sensor pathways represent another rational target because ageing alters how cells detect nutrient availability and energy stress. Restoring balance in those pathways may help preserve mitochondrial function and cellular adaptation.
Central inflammatory pathways remain a major mechanistic focus. Chronic inflammation can accelerate vascular damage, destabilize plaques, and impair myocardial remodeling. Modulating that inflammatory burden may be especially relevant in older adults, where traditional risk factor control does not always eliminate event risk. Neurocardiological dynamics are also included, reflecting the role of autonomic and neurohormonal regulation in blood pressure control, rhythm stability, and cardiac workload. Healthy lifestyle measures remain part of the strategy set, not as an afterthought but because they influence multiple ageing pathways at once, from metabolism to inflammation to vascular function.
FDA-approved drugs and trial activity point to a field moving toward translation
The review also lists FDA-approved drugs and clinical trials that target cardiovascular ageing, which gives the framework translational weight. Even without treating ageing as a standalone diagnosis in routine practice, clinicians already influence many of its pathways through established therapies. The inclusion of approved agents and ongoing trials suggests that the field is moving from conceptual mapping toward intervention design, with ageing biology increasingly treated as a modifiable substrate rather than an unavoidable background process.
This approach may be especially relevant for older adults who remain at risk despite standard secondary prevention. In those patients, the problem is often not a single missed target but a layered biological state in which inflammation, mitochondrial decline, neurohormonal activation, and senescence all contribute to persistent vulnerability. A pathway-based framework can help explain why some patients continue to experience cardiovascular events even after conventional risk factors are treated.
The review’s strongest contribution is its integration of systems biology with bedside relevance. By classifying cardiovascular ageing across etiologic domains, hallmarks, signaling pathways, and therapeutic strategies, it offers a language for understanding why age-related cardiovascular disease behaves the way it does. It also gives researchers a structured menu of targets for future intervention studies.
What remains unresolved is how best to measure ageing burden in routine care and which combination of interventions will prove most effective across different cardiovascular phenotypes. The review itself points to that gap by emphasizing the need to assess and prevent the degree of ageing, rather than treating age as a fixed number on the calendar.