Pharmacological targeting of the senescence-associated secretory phenotype in atherosclerosis: therapeutic potential of senolytics and senomorphics.

Abstract

Despite optimal lipid-lowering treatment, numerous older adults with atherosclerotic cardiovascular disease continue to experience progression driven by inflammation, referred to as residual inflammatory risk. Cellular senescence and the senescence-associated secretory phenotype (SASP) significantly contribute to vascular inflammaging; however, pharmacological interventions in aging populations are still inadequately investigated. This review synthesizes evidence regarding the role of SASP in atherosclerosis and critically evaluates senotherapeutic strategies, emphasizing mechanisms, preclinical efficacy, and translational potential. Senescent endothelial cells, vascular smooth muscle cells, and foam cells aggregate in plaques, secreting pro-inflammatory cytokines (IL-1α, IL-6, MCP-1) and matrix metalloproteinases that enhance plaque susceptibility. Two complementary pharmacological strategies have emerged. Senolytics (dasatinib combined with quercetin, fisetin, and lanatoside C) specifically eradicate senescent cells by inhibiting anti-apoptotic pathways (BCL-2, PI3K/AKT, and HSP90). Senomorphics (rapamycin, metformin, JAK/STAT inhibitors, NF-κB inhibitors) attenuate SASP expression through modulation of mTOR, NF-κB, and JAK/STAT pathways. Preclinical studies indicate that senolytics diminish the burden of senescent cells, reduce plaque area, and limit necrotic core expansion, while simultaneously improving plaque stability. Senomorphics provide comparable advantages with profiles appropriate for prolonged utilization. Targeting SASP constitutes a rational strategy to alleviate residual inflammatory risk. Nonetheless, significant knowledge deficiencies persist concerning patient selection, dosing protocols, drug-drug interactions with cardiovascular treatments, and long-term safety. Translation necessitates stringent clinical trials in geriatric cardiovascular patients. This review offers an extensive pharmacological framework for senotherapeutics in atherosclerosis.