Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction

Abstract

Cellular senescence has been shown to contribute to skin ageing. However, the role of melanocytes in the process is understudied. Our data show that melanocytes are the only epidermal cell type to express the senescence marker p16INK4A during human skin ageing. Aged melanocytes also display additional markers of senescence such as reduced HMGB1 and dysfunctional telomeres, without detectable telomere shortening. Additionally, senescent melanocyte SASP induces telomere dysfunction in paracrine manner and limits proliferation of surrounding cells via activation of CXCR3‐dependent mitochondrial ROS. Finally, senescent melanocytes impair basal keratinocyte proliferation and contribute to epidermal atrophy in vitro using 3D human epidermal equivalents. Crucially, clearance of senescent melanocytes using the senolytic drug ABT737 or treatment with mitochondria‐targeted antioxidant MitoQ suppressed this effect. In conclusion, our study provides proof‐of‐concept evidence that senescent melanocytes affect keratinocyte function and act as drivers of human skin ageing.

Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases

“…Poor physical function, vascular dysfunction, cardiac ageing and a shorter health span and lifespan in mice [59][60][61][62] Astrocytes Neuropathology related to Parkinson's disease [57] Astrocytes and microglia Cognitive decline [18] Beige progenitor cells Age-related decline in beiging and thermogenesis [63] Beta cells Type 1 diabetes and type 2 diabetes [64,65] Cardiac progenitor cells Impaired heart regeneration [66] Cardiac fibroblasts Age-related cardiac fibrosis and dysfunction [61] Cardiomyocytes Cardiac ageing (fibrosis and hypertrophy) and heart failure [67][68][69] Cholangiocytes Liver fibrosis [70] Chondrocytes Osteoarthritis [71] Endothelial cells Atherosclerosis, artery stiffness, thrombosis and heart failure with a preserved ejection fraction [72][73][74] Endothelial progenitor cells Impaired neovascularization and preeclampsia [75] Fat progenitor cells Lipodystrophy and fat loss in old mice [76] Fibroblasts Atherosclerosis, lung fibrosis and decreased health and life span [77][78][79] Fibroblasts (in synovial tissue) Rheumatoid arthritis [80] Glial cells Neuropsychiatric disorders, including anxiety and depression [81] Hematopoietic stem cells Immune function decline [82] Hepatic stellate cells Liver fibrosis [20,83] Hepatocytes Age-related hepatic steatosis [84] Macrophages Atherosclerosis [47] Melanocytes Human skin ageing [85] Muscle stem cells Sarcopenia [82] Myofibroblasts Myocardial fibrosis reduction [86] Neural progenitor cells (SOX2 + ) Progressive multiple sclerosis [87] Oligodendrocyte prog...…”

Functional heterogeneity in senescence

“…Ageing of the skin introduces heterogeneity in naevi with different phenotypic changes in primary versus secondary skin senescence. p16 positive, senescent melanocytes accumulate dysfunctional telomeres during ageing [43]. However, neighbouring epidermal cells do not up-regulate p16, but instead display telomere dysfunction and DNA damage, indicating secondary senescence mediation in human naevi from melanocytes to epidermal cells [43].…”

Tissue engineering to better understand senescence: Organotypics come of age

“…For example, fibroblasts induced into a senescent state via mitomycin-C have been shown to cause an ageing epidermal phenotype in LSEs, demonstrating that senescent cell types can influence the surrounding tissues ( Diekmann et al, 2016 ). Indeed, melanocytes with shortened telomeres can trigger telomere damage and reduced proliferation in neighbouring keratinocytes ( Victorelli et al, 2019 ).…”

“…Plant extract 1201, which has senolytic properties, blocked the detrimental effects of the SASP from stress-induced premature senescence (SIPS) HDFs in a human LSE causing rescue of the senescent cell dependent reduction in epidermal thickness and impaired differentiation of keratinocytes ( Lammermann et al, 2018 ). In a 3D epidermal equivalent consisting of keratinocytes and melanocytes, incorporation of UV irradiated SIPS melanocytes induced paracrine senescence in surrounding keratinocytes and contributed to epidermal atrophy ( Victorelli et al, 2019 ). Elimination of senescent melanocytes with a senolytic treatment, ABT-737, prevented paracrine effects on neighbouring keratinocytes and subsequent epidermal atrophy.…”

“…Elimination of senescent melanocytes with a senolytic treatment, ABT-737, prevented paracrine effects on neighbouring keratinocytes and subsequent epidermal atrophy. Furthermore, treatment with a senostatic, mitochondria-targeted antioxidant, MitoQ, prevented paracrine telomere damage induction by senescent melanocytes and rescued epidermal thickness ( Victorelli et al, 2019 ). Studies have also extended beyond in vitro models of skin.…”