Organismal aging is associated with typical aging phenotypes with structural changes and functional declines of organs. Hair loss is one of the most typical aging phenotypes in mammals, but the underlying mechanisms are still largely unclear. Here we report that the aging of hair follicles progresses in a step-wise manner with a distinct program in hair follicle stem cells (HFSCs) to cause irreversible hair loss. We found that DNA damage response (DDR) in murine HFSCs cause profound proteolysis of type XIIV collagen (COL17A1), a critical molecule for HFSC maintenance. Systematic fate analysis of those primed HFSCs with genetic stem cell tagging demonstrates that they locally initiate an epidermal differentiation program with the induction of c-MYC and NOTCH1, key regulators of epidermal differentiation within the stem cell niche, without renewing themselves or supplying follicular keratinocytes for hair growth. Those cells migrate from the bulge area through the junctional zone toward the epidermis and are eventually desquamated from the epidermal surface. Strikingly, similar aging processes were prematurely induced by Col17a1 deficiency in HFSCs or in progeric mouse models. In addition, we revealed that human scalps gradually cause hair follicle miniaturization by aging and COL17A1 expression is significantly impaired in miniaturized hair follicles through the provocation of COL17A1 protease by DDR. Furthermore, the entire aging program was significantly rescued by the forced maintenance of COL17A1 in HFSCs of aging mice, demonstrating that progression of such tissue aging programs can be controlled through changes in the expression of key molecule COL17A1 in mammalian somatic stem cells.

In response to a myriad of environmental stresses, including ultraviolet-B (UVB) irradiation, eukaryotic cells rapidly modulate protein synthesis. An important mechanism for translation regulation involves phosphorylation of the a subunit of eukaryotic initiation factor 2 (eIF2a), which results in a rapid decrease in global protein synthesis, concurrent with preferential translation of cytoprotective gene transcripts, via a set of pathways collectively called the Integrated Stress Response (ISR). Although the ISR has been implicated in carcinogenesis in a variety of tissues, little is known about whether the ISR can modulate the development of cancer in human skin. We previously defined the cytoprotective role of the ISR in response to UVB-irradiation of human keratinocytes in vitro, in part through the enhanced translation of genes involved in DNA repair. To address how the ISR is involved during photocarcinogenesis in vivo, we analyzed the expression of ISR proteins (phosphorylated eIF2aeIF2a, ATF4, CHOP, GADD34) in the progression of cutaneous squamous cell carcinoma (cSCC). The tissues examined included normal skin, chronically UVB-exposed skin, actinic keratosis (AK), and cSCC tumors. In normal skin, the expression of ISR proteins was found in the more differentiated layers of the epidermis. In contrast, in chronic UVB-irradiated skin and AK tissue, ATF4 expression was greatly increased in all but the basal cell layer of the epidermis. CHOP and GADD34 expression, as well as eIF2a phosphorylation, followed a similar induced pattern in these tissues. Progression to cSCC resulted in a striking decrease in ISR protein expression. ATF4 and CHOP expression were absent, no eIF2a phosphorylation was detected, and GADD34 expression was greatly diminished. Therefore, the normal ISR response in differentiating keratinocytes is enhanced in AK lesions but silenced as the tumor progresses to cSCC. These results suggest that sustaining the ISR response in UVB-damaged epidermis could be a valuable therapeutic target for the prevention of SCC development. 1141Melanocyte UVB skin damage is inversely affected by S. epidermis versus P. acne Specific skin commensal bacteria, such as Staphylococcus epidermidis (SE), have been implicated in skin cell immune response. Recently, Propionibacterium acnes (PA) has also emerged as an important player in the skin innate immune system, especially with respect to its role in the control of nucleic HDAC 8 and 9 in keratinocytes and monocytes. However, little is known about whether or how the skin microbiome, SE and PA, have effects on conditioning melanocyte behavior after UVB exposure. An in vitro system of UVB irradiated normal human melanocytes (NHM) with 50 mJ/cm 2 was used for this study. NHMs were preconditioned with LTA (lipoteichoic acid, TLR2 ligand), PA and SE supernatant. Irradiated NHM FACS analysis showed that LTA prevented early apoptosis and PA had a strong proapoptotic effect during the early and late apoptotic stage. LTA and SE prevented apoptosis, allowing the proliferatio...