Senescent macrophages accumulating within atherosclerotic plaques deploy a senescence-associated secretory phenotype (SASP) that simultaneously fuels chronic NF-κB-mediated inflammation and impairs efferocytosis — the clearance of apoptotic debris — while overlapping programmed cell death (PCD) pathways including necroptosis, pyroptosis, and ferroptosis independently accelerate necrotic core expansion. Shared molecular governors — NF-κB, mTOR, and p53 — create a cross-talk axis where senescence and PCD amplify one another, creating a feed-forward loop of arterial pathology. Pharmacological candidates reviewed include quercetin (via p38 MAPK inhibition), melatonin (Nrf2 activation), NLRP3 inhibitors, and established senolytics.
This is a review, not primary data, which limits causal inference — yet its mechanistic framing is timely and practically significant. Atherosclerosis remains the dominant cause of global mortality, and the senescence-PCD axis represents an underexplored therapeutic lever beyond LDL-lowering. The identification of quercetin and melatonin as accessible, pleiotropic modulators aligns with emerging nutraceutical research, though human cardiovascular endpoint trials remain sparse. The necroptosis-pyroptosis distinction matters clinically: pyroptosis releases IL-1β and IL-18, directly activating NLRP3 inflammasome cascades already validated in the CANTOS trial framework. Crucially, all cited therapeutic strategies rely on preclinical models; translational failures in this space are common. The dual-targeting concept — hitting senescence and PCD simultaneously — is conceptually compelling but raises polypharmacy and tissue-specificity concerns that the review acknowledges only partially. Incremental rather than paradigm-shifting, but a useful mechanistic roadmap for cardiovascular aging researchers.
