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Lipid Biomarker Discovery in Senescent Cells

Cellular senescence is a stress response that results in 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 wound healing, inflammation and many age-related pathologies. Models that allow elimination of senescent cells, or senolysis, protect against pathology by preventing secretion of SASP factors. In contrast to proteins, lipid components of the SASP are understudied.

We used lipid profiling to show that senescent cells activate the biosynthesis of several oxylipins that promote segments of the SASP and reinforce the proliferative arrest. Notably, senescent cells synthesize and accumulate an unstudied intracellular prostaglandin, dihomo-15d-PGJ2. This and other prostaglandin D2-related lipids promote the senescence arrest and SASP by activating RAS signaling. Dihomo-15d-PGJ2 is also released during induced apoptosis of senescent cells in culture and in vivo, acting as the first biomarker of senolysis. These data identify an important aspect of cellular senescence and a novel method to detect senolysis.