Do chronic inflammatory signaling and pro-inflammatory lipid mediators promote cellular senescence and SASP?

As biological systems age, chronic low-grade systemic inflammation becomes a major driver of tissue degeneration. Accumulating evidence confirms that this persistent inflammatory state directly initiates and stabilizes cellular senescence.

Inflammatory signaling and the senescent state

• Chronic inflammatory signaling, largely mediated by the master transcription factor NF-κB, acts as a primary upstream stimulus that forces proliferating cells into stable cell-cycle arrest.
• This process contributes to a progressive accumulation of senescent cells in aging tissues, compromising local tissue regeneration and homeostasis.

Mechanistic role of lipid mediators

• Pro-inflammatory lipid mediators, particularly arachidonic acid-derived eicosanoids such as prostaglandin E2 (PGE2), PGD2, dihomo-15d-PGJ2, and leukotriene D4 (LTD4), serve as direct regulators of this transition.
• PGE2 actively induces and maintains the senescent state in fibroblasts and keratinocytes by signaling through its cognate EP receptors.
• Senescent cells actively upregulate cyclooxygenase-2 (COX-2), leading to elevated synthesis and secretion of PGE2. This establishes a self-reinforcing autocrine and paracrine feedback loop that sustains senescence in the local microenvironment.

Development of the SASP

• Established cellular senescence directly results in the assembly and release of a complex senescence-associated secretory phenotype (SASP), transcriptionally orchestrated by NF-κB.
• The SASP contains a potent mixture of pro-inflammatory cytokines, chemokines, and a specialized "lipid SASP" rich in PGE2 and other bioactive eicosanoids, which propagates inflammatory signaling to surrounding healthy cells.

Bottom line

• Chronic inflammatory signaling and bioactive lipid mediators like PGE2 act as both upstream triggers and downstream products of cellular senescence, forming a self-sustaining feedback loop that drives tissue aging.