Even when LDL cholesterol is well-controlled, older adults with cardiovascular disease often keep experiencing plaque progression — a phenomenon driven not by lipids but by smoldering vascular inflammation. This residual inflammatory risk has long lacked a targeted pharmacological answer, and emerging evidence now points to cellular senescence as a central, underappreciated driver.
This review, published in Naunyn-Schmiedeberg's Archives of Pharmacology, synthesizes preclinical and early translational evidence for two complementary drug classes aimed at the senescence-associated secretory phenotype (SASP) in atherosclerosis. Senescent endothelial cells, vascular smooth muscle cells, and lipid-laden foam cells accumulate within arterial plaques and continuously release pro-inflammatory cytokines — specifically IL-1α, IL-6, and MCP-1 — alongside matrix metalloproteinases that erode plaque structural integrity. The review evaluates senolytics (dasatinib plus quercetin, fisetin, and lanatoside C), which selectively eliminate senescent cells by blocking anti-apoptotic survival pathways including BCL-2, PI3K/AKT, and HSP90, and senomorphics (rapamycin, metformin, JAK/STAT inhibitors, and NF-κB modulators), which suppress SASP output without killing senescent cells by dampening mTOR, NF-κB, and JAK/STAT signaling. Preclinical models show senolytics reduce plaque burden and necrotic core expansion while improving plaque stability; senomorphics offer parallel benefits with potentially more favorable chronic tolerability.
The SASP-atherosclerosis axis slots into a rapidly maturing field: senolytic trials such as AFFIRM-NASH and early cardiovascular pilot studies have begun generating human data, yet adequately powered, cardiovascular-endpoint randomized controlled trials remain absent. The review's most clinically relevant contribution is framing SASP suppression not as an alternative to lipid-lowering but as a mechanistically distinct complement — particularly relevant for the large fraction of statin-treated patients who still progress. Key limitations include the predominance of murine atherosclerosis models, uncertain optimal dosing intervals for senolytics in aged vasculature, and the challenge of achieving tissue-selective senolysis without impairing tissue-repair senescence. The field is at an inflection point: incremental evidence is accumulating rapidly, but the translation from mouse plaques to human outcomes remains the critical unproven step.
