The role of melanocyte senescence in skin ageing

Abstract

Cellular senescence is a stable cell cycle arrest associated with the secretion of pro-inflammatory factors, also known as the senescence-associated secretory phenotype (SASP), which can act in a paracrine manner and induce senescence in neighbouring cells. Accumulation of senescent cells has been shown to contribute to age-associated tissue dysfunction. Melanocytes positive for senescence markers have been shown in the skin of middle-aged human donors, however, very little is known about the mechanisms underlying melanocyte senescence, and their contribution to skin ageing. In this study, I aimed to investigate whether telomere dysfunction is a driver of melanocyte senescence, and whether senescent melanocytes contribute to skin ageing phenotypes by affecting surrounding cells in a paracrine manner. I found that melanocytes bearing dysfunctional telomeres accumulate in human skin with age. Importantly, I found that telomere dysfunction occurred independently of telomere length and could be induced in vitro as a result of exposure to different stressors. Furthermore, in human skin in vivo, I observed that telomeric damage was significantly higher in keratinocytes surrounding melanocytes with higher numbers of dysfunctional telomeres, suggesting that senescent melanocytes exert a bystander effect in vivo. Consistent with this, I found that senescent melanocytes secrete soluble factors which induce telomere dysfunction and repress proliferation of dermal fibroblasts in culture. Importantly, I identified that CXCR3, a cell-surface receptor for the cytokine IP-10, is involved in bystander telomere damage induction. Finally, I have shown in three-dimensional human epidermal equivalents that senescent melanocytes can induce paracrine telomere damage and senescence in surrounding keratinocytes, thereby contributing to epidermal thinning, a characteristic of ageing skin. Overall, this study provides evidence that length-independent telomere dysfunction plays a role in melanocyte senescence both in vivo and in vitro. Moreover, senescent melanocytes induce paracrine DNA damage and senescence in neighbouring cells, and consequently contribute to age-associated epidermal changes.