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EMBO J. 2019 Oct 21:e101982. doi: 10.15252/embj.2019101982. [Epub ahead of print]

Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction.

Author information

1
Ageing Research Laboratories, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK.
2
Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK.
3
Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
4
Unilever Discover, Colworth Science Park, Sharnbrook, Bedfordshire, UK.
5
Department of Dermatology, Mayo Clinic, Rochester, MN, USA.
6
Vanderbilt University Medical Center, Nashville, TN, USA.
7
Institute of Cancer Sciences, CR-UK Beatson Institute, University of Glasgow, Glasgow, UK.
8
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
9
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
10
Netherlands Consortium for Healthy Aging, Leiden University Medical Center, Leiden, The Netherlands.
11
Department of Biomedical Data Sciences, Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
12
Max Planck Institute for Biology of Ageing, Cologne, Germany.

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.

KEYWORDS:

SASP ; melanocytes; senescence; skin ageing; telomeres

PMID:
31633821
DOI:
10.15252/embj.2019101982

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