Epilipidomics of senescent dermal fibroblasts identify lysophosphatidylcholines as pleiotropic SASP factors

During aging, skin accumulates senescent cells. Transient presence of senescent cells, followed by their clearance by the immune system is important in tissue repair and homeostasis. Persistence of senescent cells that evaded clearance contributes to the age-related deterioration of the skin. The senescence associated secretory phenotype (SASP) these cells contains immunomodulatory molecules which facilitate clearance, but also promote chronic damage. We here investigated the epilipidome - the oxidative modifications of phospholipids - of senescent dermal fibroblasts, as these molecules are among the bioactive lipids which were recently identified as SASP factors. Using replicative- and stress- induced senescence protocols we identified lysophosphatidylcholines as universally elevated in senescent fibroblasts, while other oxidized lipids displayed a pattern that was characteristic for the used senescence protocol. When we tested the lysophosphatidylcholines for SASP activity, we found that they elicit chemokine release in non-senescent FB but also interfere with TLR2/6/CD36 signaling and phagocytic capacity in macrophages. Using MALDI-FTICR-mass spectrometric imaging we localized two lysoPC species in aged skin. This suggests that the lysophospholipids may facilitate immune evasion and low grade chronic inflammation in skin aging.