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Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction

Lookup NU author(s): Stella Victorelli, Dr Anthony Lagnado, Jessica Halim, Dr James Chapman, Dr Jodie Birch, Dr Mikolaj Ogrodnik, Dr Diana Jurk, Dr Joao Passos

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Abstract

© 2019 The AuthorsCellular 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.


Publication metadata

Author(s): Victorelli S, Lagnado A, Halim J, Moore W, Talbot D, Barrett K, Chapman J, Birch J, Ogrodnik M, Meves A, Pawlikowski JS, Jurk D, Adams PD, van Heemst D, Beekman M, Slagboom PE, Gunn DA, Passos JF

Publication type: Article

Publication status: Published

Journal: EMBO Journal

Year: 2019

Volume: 38

Issue: 23

Print publication date: 02/12/2019

Online publication date: 21/10/2019

Acceptance date: 18/09/2019

ISSN (print): 0261-4189

ISSN (electronic): 1460-2075

Publisher: Wiley-Blackwell Publishing Ltd.

URL: https://doi.org/10.15252/embj.2019101982

DOI: 10.15252/embj.2019101982

PubMed id: 31633821


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