Promises and challenges of senolytics in skin regeneration, pathology and ageing.

The research of the last two decades has defined a crucial role of cellular senescence in both the physiology and pathology of skin, and senescent cells have been detected in conditions including development, regeneration, aging, and disease. The pathophysiology of cellular senescence in skin is complex as the phenotype of senescence pertains to several different cell types including fibroblasts, keratinocytes and melanocytes, among others. Paradoxically, the transient presence of senescent cells is believed to be beneficial in the context of development and wound healing, while the chronic presence of senescent cells is detrimental in the context of aging, diseases, and chronic wounds, which afflict predominantly the elderly.

The role of lipid-based signalling in wound healing and senescence.

Lipid-based signalling modulates several cellular processes and intercellular communication during wound healing and tissue regeneration. Bioactive lipids include but are not limited to the diverse group of eicosanoids, phospholipids, and extracellular vesicles and mediate the attraction of immune cells, initiation of inflammatory responses, and their resolution. In aged individuals, wound healing and tissue regeneration are greatly impaired, resulting in a delayed healing process and non-healing wounds.

Epilipidomics of Senescent Dermal Fibroblasts Identify Lysophosphatidylcholines as Pleiotropic Senescence-Associated Secretory Phenotype (SASP) Factors.

During aging, skin accumulates senescent cells. The transient presence of senescent cells, followed by their clearance by the immune system, is important in tissue repair and homeostasis. The persistence of senescent cells that evade clearance contributes to the age-related deterioration of the skin.

Extracellular Vesicles in Human Skin: Cross-Talk from Senescent Fibroblasts to Keratinocytes by miRNAs.

Extracellular vesicles (EVs) and their miRNA cargo are intercellular communicators transmitting their pleiotropic messages between different cell types, tissues, and body fluids. Recently, they have been reported to contribute to skin homeostasis and were identified as members of the senescence-associated secretory phenotype of human dermal fibroblasts. However, the role of EV-miRNAs in paracrine signaling during skin aging is yet unclear.

Small extracellular vesicles and their miRNA cargo are anti-apoptotic members of the senescence-associated secretory phenotype.

Loss of functionality during aging of cells and organisms is caused and accompanied by altered cell-to-cell communication and signalling. One factor thereby is the chronic accumulation of senescent cells and the concomitant senescence-associated secretory phenotype (SASP) that contributes to microenvironment remodelling and a pro-inflammatory status. While protein based SASP factors have been well characterized, little is known about small extracellular vesicles (sEVs) and their miRNA cargo.