Senolytics—transgenic, and pharmacological interventions that selectively kill senescent cells—are currently in clinical trials aiming to treat age-related degenerative pathologies. Here, Wiley et al. discover that senescent cells produce multiple signaling lipids known as oxylipins. One oxylipin, dihomo-15d-PGJ2, promotes features of senescence by activating RAS and is released from cells during senolysis, serving as the first biomarker of the process in culture and in vivo.
- Senescent cells make several oxylipins, dihomo-prostaglandins, and leukotrienes
- Dihomo-15d-PGJ2 is intracellular during senescence and released during senolysis
- Dihomo-15d-PGJ2 activates RAS, promoting senescence and the SASP
- Positive feedback between prostaglandins, RAS, and p53 maintains senescence
Cellular senescence is a stress or damage response that causes 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 are understudied.
We 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, 1a,1b-dihomo-15-deoxy-delta-12,14-prostaglandin J2. Released 15-deoxy-delta-12,14-prostaglandin J2 is a biomarker of senolysis in culture and in vivo. This and other prostaglandin D2-related lipids promote the senescence arrest and SASP by activating RAS signaling.
These data identify an important aspect of cellular senescence and a method to detect senolysis.
[Keywords: cellular senescence, senescence, aging, lipids, metabolomics, eicosanoid, SASP, prostaglandin, dihomo-prostaglandin, biomarker, mass spectrometry, 15d-PGJ2, oxylipin, RAS]
[A universal biomarker measurable in blood for senolytics: “This biomarker is a unique signaling lipid metabolite, normally exclusively intracellular, but is released when senescent cells are forced to die.”]