Intracranial aneurysms as a manifestation of premature vascular aging: Cellular senescence, inflammaging, and wall degeneration.

Aging is a major risk factor for the formation, growth, and rupture of intracranial aneurysms, but the underlying biological mechanisms remain incompletely understood. Beyond chronological aging, accumulating evidence suggests that vascular aging is driven by cellular senescence, chronic inflammation, and hemodynamic stress, which together contribute to aneurysm wall degeneration. In this review, we synthesize current evidence on the role of aging in intracranial aneurysm biology, with a particular focus on the interplay between senescent cells, inflammaging, and vascular remodeling. Senescent endothelial and smooth muscle cells exhibit a senescence-associated secretory phenotype (SASP), characterized by the release of pro-inflammatory cytokines, matrix-degrading enzymes, and oxidative stress mediators. These factors may contribute to extracellular matrix degradation, immune cell recruitment, and progressive weakening of the aneurysm wall. We also discuss the inconsistent association between age and aneurysm rupture across natural-history studies and the methodological factors that may contribute to this unresolved heterogeneity. Furthermore, we examine how aging-related alterations in vascular biology may modify the response to hemodynamic forces and therapeutic interventions. Finally, we explore emerging therapeutic strategies targeting aging pathways, including senolytics and senomorphics, as potential approaches for stabilizing aneurysms and preventing rupture. Understanding the mechanistic links between aging and aneurysm pathophysiology may open new avenues for risk stratification and disease-modifying treatments.