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      Biomarkers of Cellular Senescence and Skin Aging

      review-article
      1 , 1 , 2 , *
      Frontiers in Genetics
      Frontiers Media S.A.
      senescence, skin, aging, biomarkers, photoaging, cancer

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          Abstract

          Cellular senescence is an irreversible growth arrest that occurs as a result of different damaging stimuli, including DNA damage, telomere shortening and dysfunction or oncogenic stress. Senescent cells exert a pleotropic effect on development, tissue aging and regeneration, inflammation, wound healing and tumor suppression. Strategies to remove senescent cells from aging tissues or preneoplastic lesions can delay tissue dysfunction and lead to increased healthspan. However, a significant hurdle in the aging field has been the identification of a universal biomarker that facilitates the unequivocal detection and quantification of senescent cell types in vitro and in vivo. Mammalian skin is the largest organ of the human body and consists of different cell types and compartments. Skin provides a physical barrier against harmful microbes, toxins, and protects us from ultraviolet radiation. Increasing evidence suggests that senescent cells accumulate in chronologically aged and photoaged skin; and may contribute to age-related skin changes and pathologies. Here, we highlight current biomarkers to detect senescent cells and review their utility in the context of skin aging. In particular, we discuss the efficacy of biomarkers to detect senescence within different skin compartments and cell types, and how they may contribute to myriad manifestations of skin aging and age-related skin pathologies.

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          Most cited references131

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          Persistent DNA damage signaling triggers senescence-associated inflammatory cytokine secretion

          Cellular senescence suppresses cancer by stably arresting the proliferation of damaged cells1. Paradoxically, senescent cells also secrete factors that alter tissue microenvironments2. The pathways regulating this secretion are unknown. We show that damaged human cells develop persistent chromatin lesions bearing hallmarks of DNA double-strand breaks (DSBs), which initiate increased secretion of inflammatory cytokines such as interleukin-6 (IL-6). Cytokine secretion occurred only after establishment of persistent DNA damage signaling, usually associated with senescence, not after transient DNA damage responses (DDR). Initiation and maintenance of this cytokine response required the DDR proteins ATM, NBS1 and CHK2, but not the cell cycle arrest enforcers p53 and pRb. ATM was also essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence. Further, DDR activity and IL-6 were elevated in human cancers, and ATM-depletion suppressed the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. Thus, in addition to orchestrating cell cycle checkpoints and DNA repair, a novel and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue.
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            Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a.

            Oncogenic ras can transform most immortal rodent cells to a tumorigenic state. However, transformation of primary cells by ras requires either a cooperating oncogene or the inactivation of tumor suppressors such as p53 or p16. Here we show that expression of oncogenic ras in primary human or rodent cells results in a permanent G1 arrest. The arrest induced by ras is accompanied by accumulation of p53 and p16, and is phenotypically indistinguishable from cellular senescence. Inactivation of either p53 or p16 prevents ras-induced arrest in rodent cells, and E1A achieves a similar effect in human cells. These observations suggest that the onset of cellular senescence does not simply reflect the accumulation of cell divisions, but can be prematurely activated in response to an oncogenic stimulus. Negation of ras-induced senescence may be relevant during multistep tumorigenesis.
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              Chemokine signaling via the CXCR2 receptor reinforces senescence.

              Cells enter senescence, a state of stable proliferative arrest, in response to a variety of cellular stresses, including telomere erosion, DNA damage, and oncogenic signaling, which acts as a barrier against malignant transformation in vivo. To identify genes controlling senescence, we conducted an unbiased screen for small hairpin RNAs that extend the life span of primary human fibroblasts. Here, we report that knocking down the chemokine receptor CXCR2 (IL8RB) alleviates both replicative and oncogene-induced senescence (OIS) and diminishes the DNA-damage response. Conversely, ectopic expression of CXCR2 results in premature senescence via a p53-dependent mechanism. Cells undergoing OIS secrete multiple CXCR2-binding chemokines in a program that is regulated by the NF-kappaB and C/EBPbeta transcription factors and coordinately induce CXCR2 expression. CXCR2 upregulation is also observed in preneoplastic lesions in vivo. These results suggest that senescent cells activate a self-amplifying secretory network in which CXCR2-binding chemokines reinforce growth arrest.
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                Author and article information

                Contributors
                Journal
                Front Genet
                Front Genet
                Front. Genet.
                Frontiers in Genetics
                Frontiers Media S.A.
                1664-8021
                23 August 2018
                2018
                : 9
                : 247
                Affiliations
                [1] 1Cell Ageing, Skin Research Institute of Singapore (SRIS), A∗STAR , Singapore, Singapore
                [2] 2Lee Kong Chian School of Medicine, Nanyang Technological University , Singapore, Singapore
                Author notes

                Edited by: Anis Larbi, Singapore Immunology Network (A STAR), Singapore

                Reviewed by: George A. Garinis, Foundation for Research and Technology – Hellas, Greece; Kaoru Tominaga, Jichi Medical University, Japan

                *Correspondence: Oliver Dreesen, oliver_dreesen@ 123456sris.a-star.edu.sg

                This article was submitted to Genetics of Aging, a section of the journal Frontiers in Genetics

                Article
                10.3389/fgene.2018.00247
                6115505
                30190724
                795992dc-0b89-4dad-952a-99ca684caf93
                Copyright © 2018 Wang and Dreesen.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 26 April 2018
                : 22 June 2018
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 205, Pages: 14, Words: 0
                Categories
                Genetics
                Review

                Genetics
                senescence,skin,aging,biomarkers,photoaging,cancer
                Genetics
                senescence, skin, aging, biomarkers, photoaging, cancer

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