Usefulness of healthy aging models to study novel prevention strategies in the treatment of cardiac inflammation and atrial fibrillation: A narrative review

Healthy aging is defined as remarkable longevity (beyond 90 years of age) accompanied by preserved functional status and absence of major clinical conditions. Although the incidence of cardiac arrhythmias, including atrial fibrillation (AF), increases with age, epidemiological studies revealed a paradoxical reduction of AF prevalence in centenarians compared to octogenarians and nonagenarians. Emerging evidence indicates that the apparent cardioprotection in healthy aging may be related to specific molecular and cellular adaptations observed in long-lived individuals. These include reduced systemic inflammation (c-reactive protein, interleukin-6), attenuated oxidative stress (reactive oxygen species), improved mitochondrial function (PGC-1⍺), and preservation of atrial structural integrity with reduced fibrosis (TGFβ, ⍺-SMA). Together, these mechanisms may limit atrial remodeling and maintain more stable electrophysiological properties, thereby reducing susceptibility to AF. In this review, we first discuss the concept of healthy aging as a state of intrinsic cardioprotection, and its relevance to prevent age-related cardiovascular disease. We then examine how centenarian-associated protective mechanisms may mitigate atrial arrhythmogenic remodeling, with a particular focus on inflammation-driven pathways. In addition, we evaluate the contribution of experimental models of healthy aging in the understanding of cardiac electrophysiology and arrhythmia mechanisms. Finally, we summarize current therapeutic strategies for AF in elderly patients and highlight the complex necessity of considering underlying aging-related substrates. Overall, this review emphasizes that healthy aging phenotypes may harbor intrinsic anti-inflammatory and anti-fibrotic adaptations that protect against atrial arrhythmogenesis. Understanding these mechanisms may provide novel translational opportunities for the development of preventive and mechanism-based antiarrhythmic strategies in the aging population.