Sun Exposure and its Impact on Keratinocyte Senescence and Function

Clinical Implications•UVB triggers DNA damage and premature senescence in skin keratinocytes (KCs).•Senescent KCs secrete factors that promote cancer cell migration.•Senescent KCs downregulate amino acid transporters.View Large Image Figure ViewerDownload Hi-res image Download (PPT) •UVB triggers DNA damage and premature senescence in skin keratinocytes (KCs).•Senescent KCs secrete factors that promote cancer cell migration.•Senescent KCs downregulate amino acid transporters. Aging is characterized by a time-dependent decline of cellular and organismal function. The skin is the largest organ of the body and protects it against environmental insults such as UVR and pollution, various stresses including microbes and mechanical forces, and also plays a role in thermoregulation. In the skin, the aging process commonly manifests as observable phenotypes, such as wrinkling, thinning, loss of elasticity, and aberrant pigmentation (Fitsiou et al., 2021Fitsiou E. Pulido T. Campisi J. Alimirah F. Demaria M. Cellular senescence and the senescence-associated secretory phenotype as drivers of skin photoaging.J Invest Dermatol. 2021; 141: 1119-1126Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar; Wang and Dreesen, 2018Wang A.S. Dreesen O. Biomarkers of cellular senescence and skin aging.Front Genet. 2018; 9: 247Crossref PubMed Scopus (197) Google Scholar). Over the years, many studies have characterized the various features of aged skin. However, the exact molecular mechanisms and cellular processes that drive skin aging and how the different skin cell types contribute to the various aging phenotypes remains elusive. A new study by Bauwens et al. (2022) provides novel insight into the mechanism of skin aging and how this may lead to tissue dysfunction. In particular, the authors provide insight on how UVB exposure triggers premature senescence in skin keratinocytes (KCs) and how this in turn modulates their function and environment. A feature of aging skin is the accumulation of senescent cell types in both the epidermis and dermis (Fitsiou et al., 2021Fitsiou E. Pulido T. Campisi J. Alimirah F. Demaria M. Cellular senescence and the senescence-associated secretory phenotype as drivers of skin photoaging.J Invest Dermatol. 2021; 141: 1119-1126Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar; Victorelli et al., 2019Victorelli S. Lagnado A. Halim J. Moore W. Talbot D. Barrett K. et al.Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction.EMBO J. 2019; 38e101982Crossref Scopus (95) Google Scholar; Waaijer et al., 2012Waaijer M.E.C. Parish W.E. Strongitharm B.H. van Heemst D. Slagboom P.E. de Craen A.J.M. et al.The number of p16INK4a positive cells in human skin reflects biological age.Aging Cell. 2012; 11: 722-725Crossref PubMed Scopus (174) Google Scholar; Wang and Dreesen, 2018Wang A.S. Dreesen O. Biomarkers of cellular senescence and skin aging.Front Genet. 2018; 9: 247Crossref PubMed Scopus (197) Google Scholar). Cellular senescence is defined as a stable, irreversible cell cycle arrest accompanied by senescence-associated-β-galactosidase (SA-β-gal) activity, secretion of inflammatory cytokines and metalloproteases, collectively known as the senescence-associated secretory phenotype (SASP), and remodeling of the nuclear lamina. Biomarkers to detect senescent cells include SA-β-gal activity, upregulation of p16 and p21, and the loss of lamin B1 and HMGB1. Senescence can be caused by a myriad of intrinsic factors, including telomere shortening and dysfunction, oncogene activation, persistent DNA damage, and extrinsic factors, such as the exposure to environmental conditions, namely UV and pollution. As a result of the accumulation of senescent cells in aging tissues, their repair and regeneration becomes impaired, thereby accelerating the onset of age-related chronic diseases. Conversely, clearance of senescent cells has been shown to improve tissue function and organismal health (Chaib et al., 2022Chaib S. Tchkonia T. Kirkland J.L. Cellular senescence and senolytics: the path to the clinic.Nat Med. 2022; 28: 1556-1568Crossref PubMed Scopus (56) Google Scholar). In the skin, it has been proposed that the accumulation of senescent cells may contribute to aberrant pigmentation, skin thinning, and extracellular matrix degradation and remodeling (Fitsiou et al., 2021Fitsiou E. Pulido T. Campisi J. Alimirah F. Demaria M. Cellular senescence and the senescence-associated secretory phenotype as drivers of skin photoaging.J Invest Dermatol. 2021; 141: 1119-1126Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar; Wang and Dreesen, 2018Wang A.S. Dreesen O. Biomarkers of cellular senescence and skin aging.Front Genet. 2018; 9: 247Crossref PubMed Scopus (197) Google Scholar). In addition, senescent KCs accumulate within the epidermis upon UVB irradiation, as well as in nevi and preneoplastic lesions such as actinic keratosis, a precursor of squamous cell carcinoma (SCC) (Ivanov et al., 2013Ivanov A. Pawlikowski J. Manoharan I. van Tuyn J. Nelson D.M. Rai T.S. et al.Lysosome-mediated processing of chromatin in senescence.J Cell Biol. 2013; 202: 129-143Crossref PubMed Scopus (333) Google Scholar; Michaloglou et al., 2005Michaloglou C. Vredeveld L.C. Soengas M.S. Denoyelle C. Kuilman T. van der Horst C.M. et al.BRAFE600-associated senescence-like cell cycle arrest of human naevi.Nature. 2005; 436: 720-724Crossref PubMed Scopus (1710) Google Scholar; Wang and Dreesen, 2018Wang A.S. Dreesen O. Biomarkers of cellular senescence and skin aging.Front Genet. 2018; 9: 247Crossref PubMed Scopus (197) Google Scholar; Wang et al., 2022Wang A.S. Nakamizo S. Ishida Y. Klassen G. Chong P. Wada A. et al.Identification and quantification of senescent cell types by lamin B1 and HMGB1 in actinic keratosis lesions.J Dermatol Sci. 2022; 105: 61-64Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar, Wang et al., 2017Wang A.S. Ong P.F. Chojnowski A. Clavel C. Dreesen O. Loss of lamin B1 is a biomarker to quantify cellular senescence in photoaged skin.Sci Rep. 2017; 7: 15678Crossref PubMed Scopus (62) Google Scholar). However, relatively little is known on how senescence changes the function of different skin cell types and how their accumulation affects skin function. The recent study by Bauwens et al. (2022) seeks to bridge the understanding between UVB-induced senescence in KCs and epidermal skin aging. As anticipated, UVB-exposed KCs accumulated cyclobutane pyrimidine dimers and p53-binding protein 1 (53BP1) foci, activated a DNA damage response, as shown by phosphorylation of ATM (Ser, 1981), CHK2(Thr68), and p53(Ser15), and underwent premature senescence, as judged by SA-β-gal staining and elevated levels of p16 and p21. These findings were, to some extent, recapitulated in vivo with increased DNA damage markers observed in aged samples and upon UV exposure. To investigate how the SASP of senescent KCs may affect their neighboring cells, the authors incubated A431 SCC cells with conditioned media (CM) from UVB-induced senescent KCs and found that senescent CM stimulated A431 migration in scratch assays. This is the first time a migration-stimulating property is shown in SASP factors secreted by senescent KCs and could provide insight on how the presence of these cells may promote skin cancer metastasis. In an attempt to provide a better understanding on how senescence may modulate the function of KCs, the authors conducted RNA sequencing analysis on cells undergoing UVB-induced or replicative senescence versus nonexposed and proliferating controls. Through this analysis, they found that senescent KCs downregulate the expression of several amino acid transporters. This downregulation was accompanied by reduced intracellular levels of glycine, alanine, and leucine. Of the downregulated amino acid transporters, the sodium- and chloride-dependent glycine transporter SLC6A9/GlyT1 was of particular interest as it was similarly downregulated during replicative senescence in both KCs and fibroblasts. The authors found that the inhibition of SLC6A9/GlyT1 by bitopertin, a selective inhibitor of SLC6A9, leads to premature senescence, as judged by increased SA-β-gal expression and decreased proliferation. Interestingly, overexpression of SLC6A9 seemed to ameliorate some UVB-induced hallmarks of senescence. Collectively, the findings presented by Bauwens et al. (2022) provide new insight on how UVB-induced senescence changes the physiology of epidermal KCs and how their secreted factors stimulate the migration of SCC cells. Because the inhibition of these factors may serve as an interesting therapeutic target to prevent skin cancer metastasis, it will be important to identify the responsible factor(s) and determine whether they can be detected in precancerous lesions in vivo. Another significant finding by Bauwens et al. (2022) is the downregulation of the amino acid transporter SLC6A9/GlyT1, which seems to play an active role in the induction of senescence in KCs. However, the potential causal relationship between downregulation of SLC6A9/GlyT1, decreased intracellular glycine levels, the onset of cellular senescence, and its relevance to other cell types in the skin and other tissues in vivo, remains to be further explored. Taken together, the skin plays an intricate role in protecting the body from environmental assault, and it has been suggested that the damage sustained over time accumulates in the form of senescent cells within different layers of the skin. In addition, there is increasing evidence that the accumulation of senescent cells contributes to, or drives skin aging (Fitsiou et al., 2021Fitsiou E. Pulido T. Campisi J. Alimirah F. Demaria M. Cellular senescence and the senescence-associated secretory phenotype as drivers of skin photoaging.J Invest Dermatol. 2021; 141: 1119-1126Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar; Victorelli et al., 2019Victorelli S. Lagnado A. Halim J. Moore W. Talbot D. Barrett K. et al.Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction.EMBO J. 2019; 38e101982Crossref Scopus (95) Google Scholar; Waaijer et al., 2012Waaijer M.E.C. Parish W.E. Strongitharm B.H. van Heemst D. Slagboom P.E. de Craen A.J.M. et al.The number of p16INK4a positive cells in human skin reflects biological age.Aging Cell. 2012; 11: 722-725Crossref PubMed Scopus (174) Google Scholar; Wang et al., 2017Wang A.S. Ong P.F. Chojnowski A. Clavel C. Dreesen O. Loss of lamin B1 is a biomarker to quantify cellular senescence in photoaged skin.Sci Rep. 2017; 7: 15678Crossref PubMed Scopus (62) Google Scholar). However, it remains unclear how different senescent skin cell types may cause the various age-associated changes in the skin. To address these questions, a better understanding is required of how different senescence and aging biomarkers cross-correlate with each other and with the various characteristics of biologically aged skin. Defining these biomarkers will provide insight into the mechanism(s) that drive skin aging and cancer and pave the way for the development of better therapeutic interventions. Xin Er Lee: http://orcid.org/0000-0002-7413-7603 Oliver Dreesen: http://orcid.org/0000-0003-1148-3557 The authors state no conflict of interest. Senescence Induced by UVB in Keratinocytes Impairs Amino Acids BalanceJournal of Investigative DermatologyVol. 143Issue 4PreviewSkin is one of the most exposed organs to external stress. Namely, UV rays are the most harmful stress that could induce important damage leading to skin aging and cancers. At the cellular level, senescence is observed in several skin cell types and contributes to skin aging. However, the origin of skin senescent cells is still unclear but is probably related to exposure to stresses. In this work, we developed an in vitro model of UVB-induced premature senescence in normal human epidermal keratinocytes. Full-Text PDF