Prostaglandin Biosynthesis Reinforces Cellular Senescence Through a RAS/p53 Feedback Loop and Allows Detection of Senolysis

Abstract

SummaryCellular senescence is a stress or damage response that results in a permanent proliferative arrest and secretion of numerous factors with potent biological activities. This senescence-associated secretory phenotype (SASP) has been characterized largely for secreted proteins that participate in embryogenesis, wound healing, inflammation and many age-related pathologies. By contrast, lipid components of the SASP have been understudied. We show that senescent cells activate the biosynthesis of several eicosanoids that promote segments of the SASP and reinforce the proliferative arrest. Notably, senescent cells synthesize an unstudied intracellular prostaglandin, 1a,1b-dihomo-15-deoxy-delta-12,14-prostaglandin J2, which, together with other prostaglandin D2 derivatives, promote the senescence arrest and SASP by activating RAS signaling. Further, 15-deoxy-delta-12,14-prostaglandin J2 is a biomarker of senolysis in culture and in vivo. These data identify an important new aspect of cellular senescence and a novel method to detect senolysis.