Cellular senescence is characterized by a permanent cell cycle arrest associated with an active metabolism (Hayflick and Moorhead, 1961). Referred to as replicative senescence, it was later associated with critical attrition of the telomeres (Harley et al., 1990). Oncogene expression, mitochondrial dysfunction, or exposures to various oxidative and/or genotoxic stress can also induce senescence (Hernandez-Segura et al., 2018; Wiley et al., 2016). Senescent cells display a common phenotype mainly characterized by irreversible cell cycle arrest, enlarged and flattened cell morphology, senescence-associated β-galactosidase (SA-βgal) activity, persistent DNA damage, and resistance to apoptosis (González-Gualda et al., 2021). They also secrete a set of cytokines, chemokines, growth factors, proteases, extracellular vesicles, and bioactive lipids, referred to as the senescence-associated secretory phenotype (SASP) (Coppé et al., 2008; Narzt et al., 2021), whose composition can vary depending on the cell type, the senescence trigger, and the time (Basisty et al., 2020). Finally, senescent cells exhibit several alterations in their metabolic state, including altered lipid metabolism, dysregulated autophagy, and disruption of the homeostasis of transition metals (for a review, see the study by Wiley and Campisi [2021]). Senescent cells were shown to accumulate with age in tissues such as the skin (Dimri et al., 1995; Ressler et al., 2006). However, it is still unknown how they appear in vivo. It is unlikely that their presence is related to the exhaustion of their proliferative potential, but because they are notably detected at sites of chronic inflammation, they could therefore result from chronic stress and/or inflammation (Del Pinto and Ferri, 2018; Pilkington et al., 2021).

Some tissues, especially the skin, are largely exposed to such chronic stress. Skin aging is first impacted by age, that is, intrinsic or chronological aging, but in exposed areas, extrinsic aging superimposes, resulting from the impact of a series of environmental stresses referred to as the skin exposome (Krutmann et al., 2017; Wlaschek et al., 2001). Among them, UV rays are identified as the most damaging stressors, leading to tissue dysfunction, photoaging, and susceptibility to cancer (Mullenders, 2018). Senescent cells accumulate with age in the dermis but also in the basal layer of the epidermis (Ressler et al., 2006; Waaijer et al., 2012). Dermal fibroblasts exhibit the common biomarkers of senescence. Of note, epidermal keratinocytes (KCs) in culture reach a senescence plateau only after a few passages. This senescence is independent of telomeres shortening but is associated with oxidative stress and defects in DNA single-strand break repair mechanism (Nassour et al., 2016). Melanocytes show a gradual cell cycle arrest that is p16^INK-4A and telomere-shortening dependent and accumulate with age (Bandyopadhyay et al., 2001; Victorelli et al., 2019). In addition, senescence can also be induced in these cell types after UVB exposures (Debacq-Chainiaux et al., 2005; Lewis et al., 2008; Victorelli et al., 2019). UVB (280‒320 nm) penetrates the epidermis, leading to oxidative stress and direct DNA damage through the formation of pyrimidine dimers (Ichihashi et al., 2003). KCs are the first cells to be impacted by UVB and potentially able to react with their neighboring cells after irradiation. UVB-induced senescence in KCs is characterized by growth arrest, increased SA-βgal activity, and lamin B1 (LMNB1) loss; is p53 dependent; and requires a functional IGF-1R (Bertrand-Vallery et al., 2010; Lewis et al., 2008; Wang et al., 2017).

In this study, we showed that the UVB-induced senescence of normal human epidermal KCs is associated with persistent DNA damage and a long-term DNA damage response (DDR) activation. We also reported that UVB-induced senescent KCs secreted SASP factors, which were able to influence the migration of cutaneous squamous cell carcinoma cells. RNA-sequencing analysis highlighted a downregulation of the expression of several amino acid transporters (AATs) in senescent KCs. This was corroborated by lower intracellular levels of glycine, leucine, and alanine. We showed that the inhibition of the glycine transporter SLC6A9/GlyT1 was able to prematurely induce senescence traits and that its overexpression protects from the induction of several biomarkers of senescence. These results revealed that SLC6A9/GlyT1 can be involved in the tuning of senescence in KCs.