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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.

Cellular senescence irreversibly arrests cell proliferation, accompanied by a multi-component senescence-associated secretory phenotype (SASP) that participates in several age-related diseases. Using stable isotope labeling with amino acids in cell culture (SILAC), we identify 343 SASP proteins that senescent human fibroblasts secrete at 2-fold or higher levels compared to quiescent cell counterparts. Bioinformatic analysis revealed that 44 of these SASP factors are involved in hemostasis, a process not previously linked with cellular senescence. We validate the expression of some of these SASP factors in cell culture and in vivo. Mice treated with the chemotherapeutic agent doxorubicin, which induces widespread cellular senescence in vivo, show increased blood clotting. Conversely, use of a transgene that permits the selective removal of senescent cells shows that senescent cell clearance attenuates the increased clotting shown by doxorubicin-treated mice. Together, our study characterizes a SASP profile using SILAC, unveiling a novel function for cellular senescence in hemostasis.