The m6A writer KIAA1429 regulates photoaging progression via MFAP4-dependent collagen synthesis.

BACKGROUND: N6-Methyladenosine (m6A) methylation, a common form of RNA modification, play an important role in the pathogenesis of various diseases and in the ontogeny of organisms. Nevertheless, the precise function of m6A methylation in photoaging remains unknown. OBJECTIVES: This study aims to investigate the biological role and underlying mechanism of m6A methylation in photoaging. METHODS: m6A dot blot, Real-time quantitative PCR (RT-qPCR), western blot and immunohistochemical (IHC) assays were employed to detect the m6A level and specific m6A methylase in ultraviolet ray (UVR)-induced photoaging tissue. The profile of m6A-tagged mRNA was identified by methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq analysis. Finally, we investigated the regulatory mechanism of KIAA1429 by MeRIP-qPCR, RNA knockdown and immunofluorescence assay. RESULTS: m6A levels were increased in photoaging and were closely associated with the upregulation of KIAA1429 expression. 1331 differentially m6A methylated genes were identified in the UVR group compared with the control group, of which 1192 (90%) were hypermethylated. Gene ontology analysis showed that genes with m6A hypermethylation and mRNA downregulation were mainly involved in extracellular matrix metabolism and collagen metabolism-related processes. Furthermore, KIAA1429 knockdown abolished the downregulation of TGF-bRII and upregulation of MMP1 in UVR-irradiated human dermal fibroblasts (HDFs). Mechanically, we identified MFAP4 as a target of KIAA1429-mediated m6A modification and KIAA1429 might suppress collagen synthesis through an m6A-MFAP4-mediated process. CONCLUSIONS: The increased expression of KIAA1429 hinders collagen synthesis during UVR-induced photoaging, suggesting that KIAA1429 represents a potential candidate for targeted therapy to mitigate UVR-driven photoaging.

Macrophage migration inhibitory factor mediates skin aging via CD74: Insights from single-cell and bulk RNA sequencing data.

Cell-cell communication is crucial for regulating signaling and cellular function. However, the precise cellular and molecular changes remain poorly understood in skin aging. Based on single-cell and bulk RNA data, we explored the role of cell-cell ligand-receptor interaction in skin aging. We found that the macrophage migration inhibitory factor (MIF)/CD74 ligand-receptor complex was significantly upregulatedin aged skin, showing the predominant paracrine effect of keratinocytes on fibroblasts. Enrichment analysis and in vitro experiment revealed a close association of the activation of the MIF/CD74 with inflammatory pathways and immune response. Mechanistically, MIF/CD74 could significantly inhibit PPARγ protein, which thus significantly increased the degree of fibroblast senescence, and significantly up-regulated the expression of senescence-associated secretory phenotype (SASP) factors and FOS gene. Therefore, our study reveals that MIF/CD74 inhibits the activation of the PPAR signaling pathway, subsequently inducing the production of SASP factors and the upregulation of FOS expression, ultimately accelerating fibroblast senescence.

Integrated bioinformatics analysis and experimental validation identifies CPE as a potential biomarker and therapeutic target for skin aging.

Ageing is an inevitable biological process characterized by progressive decline in physiological functions. It is a complex natural phenomenon that will cause structural and functional decline. Despite substantial progress in understanding the mechanism of ageing, both predictive biomarkers and preventive therapies remain limited. Using Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning techniques, we identified Carboxypeptidase E (CPE) as a pivotal marker of skin ageing, based on ageing-related bulk transcriptome and single-cell transcriptome data. Next, our investigation reveals downregulation of CPE in replicative, UVA-induced, and H2O2-induced senescent human dermal fibroblast cells (HDFs). Furthermore, shRNA-mediated CPE knockdown induced HDFs senescence, and overexpression of CPE delayed HDFs senescence. Moreover, downregulated CPE inhibits collagen synthesis and induces inflammation, highlighting its potential as a therapeutic target for skin ageing. In conclusion, our study demonstrated that CPE functions as a predictor and optional target for therapeutic intervention of skin ageing.

Relationships between circulating metabolites and facial skin aging: a Mendelian randomization study.

BACKGROUND: Blood metabolites are important to various aspects of our health. However, currently, there is little evidence about the role of circulating metabolites in the process of skin aging. OBJECTIVES: To examine the potential effects of circulating metabolites on the process of skin aging. METHOD: In the primary analyses, we applied several MR methods to study the associations between 249 metabolites and facial skin aging risk. In the secondary analyses, we replicated the analyses with another array of datasets including 123 metabolites. MR Bayesian model averaging (MR-BMA) method was further used to prioritize the metabolites for the identification of predominant metabolites that are associated with skin aging. RESULTS: In the primary analyses, only the unsaturation degree of fatty acids was found significantly associated with skin aging with the IVW method after multiple testing (odds ratio = 1.084, 95% confidence interval = 1.049-1.120, p = 1.737 × 10-06). Additionally, 11 out of 17 unsaturation-related biomarkers showed a significant or suggestively significant causal effect [p < 0.05 and > 2 × 10-4 (0.05/249 metabolites)]. In the secondary analyses, seven metabolic biomarkers were found significantly associated with skin aging [p < 4 × 10-4 (0.05/123)], while six of them were related to the unsaturation degree. MR-BMA method validated that the unsaturation degree of fatty acids plays a dominant role in facial skin aging. CONCLUSIONS: Our study used systemic MR analyses and provided a comprehensive atlas for the associations between circulating metabolites and the risk of facial skin aging. Genetically proxied unsaturation degree of fatty acids was highlighted as a dominant factor correlated with the risk of facial skin aging.

The extracellular matrix fibulin 7 maintains epidermal stem cell heterogeneity during skin aging.

Tissue stem cells (SCs) divide infrequently as a protective mechanism against internal and external stresses associated with aging. Here, we demonstrate that slow- and fast-cycling SCs in the mouse skin epidermis undergo distinct aging processes. Two years of lineage tracing reveals that Dlx1+ slow-cycling clones expand into the fast-cycling SC territory, while the number of Slc1a3+ fast-cycling clones gradually declines. Transcriptome analysis further indicate that the molecular properties of each SC population are altered with age. Mice lacking fibulin 7, an extracellular matrix (ECM) protein, show early impairments resembling epidermal SC aging, such as the loss of fast-cycling clones, delayed wound healing, and increased expression of inflammation- and differentiation-related genes. Fibulin 7 interacts with structural ECM and matricellular proteins, and the overexpression of fibulin 7 in primary keratinocytes results in slower proliferation and suppresses differentiation. These results suggest that fibulin 7 plays a crucial role in maintaining tissue resilience and epidermal SC heterogeneity during skin aging.

Genetic insights into the gut microbiota and risk of facial skin aging: A Mendelian randomization study.

BACKGROUND: A growing number of experimental studies have shown an association between the gut microbiota (GM) and facial skin aging. However, the causal relationship between GM and facial skin aging remains unclear to date. METHODS: We conducted a two-sample Mendelian randomization (MR) analysis to investigate the potential causal relationship between GM and facial skin aging. MR analysis was mainly performed using the inverse-variance weighting (IVW) method, complemented by the weighted median (MW) method, MR-Egger regression, and weighted mode, and sensitivity analysis was used to test the reliability of MR analysis results. RESULTS: Eleven GM taxa associated with facial skin aging were identified by IVW method analysis, Family Victivallaceae (p = 0.010), Genus Eubacterium coprostanoligenes group (p = 0.038), and Genus Parasutterella (p = 0.011) were negatively associated with facial skin aging, while Phylum Verrucomicrobia (p = 0.034), Family Lactobacillaceae (p = 0.017) and its subgroups Genus Lactobacillus (p = 0.038), Genus Parabacteroides (p = 0.040), Genus Eggerthella (p = 0.049), Genus Family XIII UCG001 (p = 0.036), Genus Phascolarctobacterium (p = 0.027), and Genus Ruminococcaceae UCG005 (p = 0.012) were positively associated with facial skin aging. At Class and Order levels, we did not find a causal relationship between GM and facial skin aging. Results of sensitivity analyses did not show evidence of pleiotropy and heterogeneity. CONCLUSION: Our findings confirm the causal relationship between GM and facial skin aging, providing a new perspective on delaying facial aging.

Comparisons between Caucasian-validated photo-numeric scales and Korean-validated photo-numeric scales for photo-ageing. Insights from the Singapore/Malaysia cross-sectional genetics epidemiology study (SMCGES) cohort.

BACKGROUND: Photo-ageing is a form of skin ageing which affects the entire face. A photo-aged skin has a diverse variety of wrinkles and dyspigmentation all over the face. Here, we discuss photo-ageing on the Chinese skin evaluated using a photo-numeric scale developed and validated on Caucasian skin (i.e., Caucasian scale) and evaluated using a photo-numeric scale developed and validated on Korean skin (i.e., Korean scale). The Korean scale can be subdivided into two scales that separately address the wrinkling and dyspigmentation constituents of photo-ageing. AIM: As there are currently no photo-ageing scales for Chinese skin, the main objective of this study is to adapt existing photo-ageing photo-numeric scales for use on ethnic Chinese skin. METHOD: Three trained assessors studied facial photo-ageing on 1,081 ethnic Chinese young adults from the Singapore/Malaysia Cross-sectional Genetics Epidemiology Study (SMCGES) cohort. RESULTS: All assessors are highly internally consistent (Weighted Kappa (κw) values≥0.952). We found that the Caucasian scale and Korean scale give nearly synonymous results for the wrinkling constituent of photo-ageing (R2 = 0.9386). The two scales are strongly concordant (Spearman's Rank Correlation (ρ) value: 0.62 ± 0.06, p = 1.31×10-84). A weak-to-moderate inter-scalar level of agreement (Cohen's Kappa (κ) values: 0.38 ± 0.05, p = 8.87×10-53) persists and is statistically significant after accounting for agreements due to chance. When tested on ethnic Chinese skin, both scales detect photo-ageing consistently (Area under curve [AUC] values: 0.76-0.84). Additionally, the Korean scale for the dyspigmentation constituent of photo-ageing is concordant with both the Caucasian scale (R2 = 0.7888) and the Korean scale for the wrinkling constituent of photo-ageing (R2 = 0.7734). CONCLUSION: Our results show that the Caucasian scale is suitable for capturing photo-ageing on Chinese skin, especially wrinkle variations. The Korean dyspigmentation scale supplements the Caucasian scale to capture dyspigmentation patterns on Chinese skin that may be absent on Caucasian skin. Currently, photo-ageing scales for Chinese skin are absent. When developed, these photo-ageing scales must be properly validated for their ability to capture photo-ageing of the entire face.

Causal relationship between dyslipidemia and risk of facial aging: Insights from Mendelian randomization in East Asian populations.

BACKGROUND: Emerging observational studies showed an association between dyslipidemia and aging. However, it remains unclear whether this association is causal, particularly in the case of Asians, which are aging more rapidly than other continents. Given the visible manifestations of aging often include changes in facial appearance, the objective of this study is to assess the causal relationship between dyslipidemia and facial aging in East Asian populations. METHODS: SNPs related to dyslipidemia in East Asian people such as Total cholesterol (TC), High-density-lipoprotein cholesterol (HDL), Low-density-lipoprotein cholesterol (LDL), and Triglyceride (TG) along with outcomes data on facial aging, were extracted from public genome-wide association studies (GWAS). A two-sample Mendelian randomization (MR) analysis was then performed using publicly available GWAS data to investigate the potential causal relationship. The effect estimates were primarily calculated using the fixed-effects inverse variance weighted (IVW) method. RESULTS: Totally, 88 SNPs related to HDL among 70657 East Asian participants in GWAS. Based on the primary causal effects model using MR analyses with the IVW method, high HDL level was demonstrated as significantly related to the risk of facial aging (OR, 1.060; 95% CI, 1.005-1.119, p = 0.034), while high TC level (OR, 0.995; 95% CI, 0.920-1.076, p = 0.903), high LDL level (OR, 0.980, 95% CI, 0.924-1.041, p = 0.515), as well as high TG level (OR, 0.999, 95% CI, 0.932-1.071, p = 0.974), showed no significant correlation with facial aging. CONCLUSIONS: The two-sample MR analysis conducted in this study revealed a positive causal relationship between high HDL levels and facial aging. In contrast, facial aging demonstrated no significant correlation with high levels of TC, LDL, or TG. Further large-sample prospective studies are needed to validate these findings and to provide appropriate recommendations regarding nutrition management to delay the aging process among old patients in East Asia.

Development of a biomarker-based platform for comprehensive skin characterization using minimally invasive skin sampling and quantitative real-time PCR.

BACKGROUND: Classifying diverse skin types is crucial for promoting skin health. However, efficiently identifying and analyzing relevant biomarkers from a vast array of available genetic data is challenging. Therefore, this study aimed to develop a precise and efficient platform for analyzing specific skin biomarkers using quantitative real-time PCR (qRT-PCR) with the minimal invasive skin sampling method (MISSM). MATERIALS AND METHODS: MISSM was used for RNA extraction from skin samples, followed by qRT-PCR analysis to quantify the expression of 20 biomarkers associated with skin characteristics (four biomarkers each for five skin characteristics). Noninvasive measurements from 299 Korean participants were utilized to correlate biomarker expression with skin parameters. Statistical analyses were conducted between biomarker expression levels and noninvasive skin measurements to select the relatively best-performing biomarker for each skin characteristic. RESULTS: Collagen type 1 alpha 1 (COL1A1) and moesin (MSN) were identified as skin aging biomarkers. Krüppel-like factor 4 (KLF4) and serine peptidase inhibitor Kazal type 5 (SPINK5) were identified as skin dryness biomarkers, whereas melan-A (MLANA) was selected as a biomarker for understanding pigmentation dynamics. Myelin protein zero like 3 (MPZL3) and high mobility group box 2 (HMGB2) were identified as markers of oily skin and skin sensitivity, respectively. Statistically significant correlations were found between the biomarker expression levels and noninvasive skin characteristic measurements. CONCLUSION: This study successfully developed a platform for the precise evaluation of individual skin characteristics using MISSM and qRT-PCR biomarker analysis. By selecting biomarkers that correlate with noninvasive measurements of skin characteristics, we demonstrated the platform's efficacy in assessing diverse skin conditions.

LincRNA-EPS Promotes Proliferation of Aged Dermal Fibroblast by Inducing CCND1.

The aging process is linked to numerous cellular changes, among which are modifications in the functionality of dermal fibroblasts. These fibroblasts play a crucial role in sustaining the healing of skin wounds. Reduced cell proliferation is a hallmark feature of aged dermal fibroblasts. Long intergenic non-coding RNA (lincRNAs), such as LincRNA-EPS (Erythroid ProSurvival), has been implicated in various cellular processes. However, its role in aged dermal fibroblasts and its impact on the cell cycle and its regulator, Cyclin D1 (CCND1), remains unclear. Primary dermal fibroblasts were isolated from the skin of 17-week-old (young) and 88-week-old (aged) mice. Overexpression of LincRNA-EPS was achieved through plasmid transfection. Cell proliferation was detected using the MTT assay. Real-time PCR was used to quantify relative gene expressions. Our findings indicate a noteworthy decline in the expression of LincRNA-EPS in aged dermal fibroblasts, accompanied by reduced levels of CCND1 and diminished cell proliferation in these aging cells. Significantly, the overexpression of LincRNA-EPS in aged dermal fibroblasts resulted in an upregulation of CCND1 expression and a substantial increase in cell proliferation. Mechanistically, LincRNA-EPS induces CCND1 expression by sequestering miR-34a, which was dysregulated in aged dermal fibroblasts, and directly targeting CCND1. These outcomes underscore the crucial role of LincRNA-EPS in regulating CCND1 and promoting cell proliferation in aged dermal fibroblasts. Our study provides novel insights into the molecular mechanisms underlying age-related changes in dermal fibroblasts and their implications for skin wound healing. The significant reduction in LincRNA-EPS expression in aged dermal fibroblasts and its ability to induce CCND1 expression and enhance cell proliferation highlight its potential as a therapeutic target for addressing age-related skin wound healing.

LncRNA PVT1 delays skin photoaging by sequestering miR-551b-3p to release AQP3 expression via ceRNA mechanism.

Understanding human skin photoaging requires in-depth knowledge of the molecular and functional mechanisms. Human dermal fibroblasts (HDFs) gradually lose their ability to produce collagen and renew intercellular matrix with aging. Therefore, our study aims to reveal the mechanistic actions of a novel ceRNA network in the skin photoaging by regulating HDF activities. Photoaging-related genes were obtained in silico, followed by GO and KEGG enrichment analyses. Differentially expressed lncRNAs and miRNAs were screened from the GEO database to construct the ceRNA co-expression network. In skin photoaging samples, PVT1 and AQP3 were poorly expressed, while miR-551b-3p was highly expressed. The relationships among the lncRNA, miRNA and mRNA were explored through the ENCORI database and dual luciferase reporter assay. Mechanistically, PVT1 could sequester miR-551b-3p to upregulate the expression of AQP3, which further inactivated the ERK/p38 MAPK signaling pathway. HDFs were selected to construct an in vitro cell skin photoaging model, where the senescence, cell cycle distribution and viability of young and senescent HDFs were detected by SA-ß-gal staining, flow cytometry and CCK-8 assay. In vitro cell experiments confirmed that overexpression of PVT1 or AQP3 enhanced viability of young and senescent HDFs and inhibited HDF senescence, while miR-551b-3p upregulation counteracted the effect of PVT1. In conclusion, PVT1-driven suppression of miR-551b-3p induces AQP3 expression to inactivate the ERK/p38 MAPK signaling pathway, thereby inhibiting HDF senescence and ultimately delaying the skin photoaging.

CircRNA-406918 enhances the degradation of advanced glycation end products in photoaged human dermal fibroblasts via targeting cathepsin D.

BACKGROUND: Lysosomal cathepsin D (CTSD) can degrade internalized advanced glycation end products (AGEs) in dermal fibroblasts. CTSD expression is decreased in photoaged fibroblasts, which contributes to intracellular AGEs deposition and further plays a role in AGEs accumulation of photoaged skin. The mechanism under downregulated CTSD expression is unclear. OBJECTIVE: To explore possible mechanism of regulating CTSD expression in photoaged fibroblasts. METHODS: Dermal fibroblasts were induced into photoaging with repetitive ultraviolet A (UVA) irradiation. The competing endogenous RNA (ceRNA) networks were constructed to predict candidate circRNAs or miRNAs related with CTSD expression. AGEs-BSA degradation by fibroblasts was studied with flow cytometry, ELISA, and confocal microscopy. Effects of overexpressing circRNA-406918 via lentiviral transduction on CTSD expression, autophagy, AGE-BSA degradation were analyzed in photoaged fibroblasts. The correlation between circRNA-406918 and CTSD expression or AGEs accumulation in sun-exposed and sun-protected skin was studied. RESULTS: CTSD expression, autophagy, and AGEs-BSA degradation were significantly decreased in photoaged fibroblasts. CircRNA-406918 was identified to regulate CTSD expression, autophagy, and senescence in photoaged fibroblasts. Overexpressing circRNA-406918 potently decreased senescence and increased CTSD expression, autophagic flux, and AGEs-BSA degradation in photoaged fibroblasts. Moreover, circRNA-406918 level was positively correlated with CTSD mRNA expression and negatively associated with AGEs accumulation in photodamaged skin. Further, circRNA-406918 was predicted to mediate CTSD expression through sponging eight miRNAs. CONCLUSION: These findings suggest that circRNA-406918 regulates CTSD expression and AGEs degradation in UVA-induced photoaged fibroblasts and might exert a role in AGEs accumulation in photoaged skin.

Bone marrow mesenchymal stem cell-derived exosome miR-29b-3p alleviates UV irradiation-induced photoaging in skin fibroblast.

BACKGROUND: Mesenchymal stem cells-derived exosome (MSCs-exo) was identified to reduce photoaging. The purpose of this study was to investigate the potential role of microRNA (miR)-29b-3p derived from bone marrow MSCs-exo (BMSCs-exo) in photoaging. METHODS: Exosomes were isolated from BMSCs and verified by Western blot. A photoaging cell model was constructed by UVB irradiation of human dermal fibroblasts (HDFs). Quantitative real-time PCR (RT-qPCR) was performed to detect the mRNA levels of miR-29b-3p, collagen type I and matrix metalloproteinases (MMPs). CCK-8, Transwell and flow cytometry were applicated to examine cell viability, migration and apoptosis. Commercial kits are used to measure levels of oxidative stress indicators. Finally, a dual-luciferase reporter assay was applied to validate the target of miR-29b-3p. RESULTS: Extracted exosomes were positive for HSP70 and CD9. Survival of HDFs increased in an exosome concentration-dependent manner. UVB irradiation inhibited miR-29b-3p levels compared with controls, but BMSCs-exo treatment restored miR-29b-3p levels (p < .05). Additionally, BMSCs-exo-miR-29b-3p reversed the inhibition of HDFs migration and oxidative stress by UVB irradiation, as well as the promotion of apoptosis. However, this reversal was attenuated by the suppression of miR-29b-3p (p < .05). Furthermore, BMSCs-exo-miR-29b-3p also inhibited the degradation of collagen type I and the production of MMPs in photoaging, and they were also eliminated by the reduced miR-29b-3p. Finally, MMP-2 was the target gene of miR-29b-3p. CONCLUSION: Our study presented a novel role for BMSCs-exo-miR-29b-3p in improving skin photoaging function, and these findings may provide new insights into the targeted treatment of skin photoaging.

Recent advances in exosomal non-coding RNA-based therapeutic approaches for photoaging.

BACKGROUND: Photoaging is a degenerative biological process that affects the quality of life. It is caused by environmental factors including ultraviolet radiation (UVR), deep skin burns, smoking, active oxygen, chemical substances, and trauma. Among them, UVR plays a vital role in the aging process. AIM: With the continuous development of modern medicine, clinical researchers have investigated novel approaches to treat aging. In particular, mesenchymal stem cells (MSCs), non-coding RNAs are involved in various physiological processes have broad clinical application as they have the advantages of convenient samples, abundant sources, and avoidable ethical issues. METHODS: This article reviews research progress on five types of stem cell, exosomes, non-coding RNA in the context of photoaging treatment: adipose-derived stem cell, human umbilical cord MSCs, epidermal progenitor cells, keratinocyte stem cells, and hair follicle stem cells (HFSCs). It also includes stem cell related exosomes and their non-coding RNA research. RESULTS: The results have clinical guiding significance for prevention and control of the onset and development of photoaging. It is found that stem cells secrete cytokines, cell growth factors, non-coding RNA, exosomes and proteins to repair aging skin tissues and achieve skin rejuvenation. In particular, stem cell exosomes and non-coding RNA are found to have significant research potential, as they possess the benefits of their source cells without the disadvantages which include immune rejection and granuloma formation.

Prediction and association analyses of skin phenotypes in Japanese females using genetic, environmental, and physical features.

BACKGROUND: Skin characteristics show great variation from person to person and are affected by multiple factors, including genetic, environmental, and physical factors, but details of the involvement and contributions of these factors remain unclear. OBJECTIVES: We aimed to characterize genetic, environmental, and physical factors affecting 16 skin features by developing models to predict personal skin characteristics. METHODS: We analyzed the associations of skin phenotypes with genetic, environmental, and physical features in 1472 Japanese females aged 20-80 years. We focused on 16 skin characteristics, including melanin, brightness/lightness, yellowness, pigmented spots, wrinkles, resilience, moisture, barrier function, texture, and sebum amount. As genetic factors, we selected 74 single-nucleotide polymorphisms of genes related to skin color, vitamin level, hormones, circulation, extracellular matrix (ECM) components and ECM-degrading enzymes, inflammation, and antioxidants. Histories of ultraviolet (UV) exposure and smoking as environmental factors and age, height, and weight as physical factors were acquired by means of a questionnaire. RESULTS: A linear association with age was prominent for increase in the area of crow's feet, increase in number of pigmented spots, decrease in forehead sebum, and increase in VISIA wrinkle parameters. Associations were analyzed by constructing linear regression models for skin feature changes and logistic regression models to predict whether subjects show lower or higher skin measurement values in the same age groups. Multiple genetic factors, history of UV exposure and smoking, and body mass index were statistically selected for each skin characteristic. The most important association found for skin spots, such as lentigines and wrinkles, was adolescent sun exposure. CONCLUSION: Genetic, environmental, and physical factors associated with interindividual differences of the selected skin features were identified. The developed models should be useful to predict the skin characteristics of individuals and their age-related changes.

The aging skin microenvironment dictates stem cell behavior.

Aging manifests with architectural alteration and functional decline of multiple organs throughout an organism. In mammals, aged skin is accompanied by a marked reduction in hair cycling and appearance of bald patches, leading researchers to propose that hair follicle stem cells (HFSCs) are either lost, differentiate, or change to an epidermal fate during aging. Here, we employed single-cell RNA-sequencing to interrogate aging-related changes in the HFSCs. Surprisingly, although numbers declined, aging HFSCs were present, maintained their identity, and showed no overt signs of shifting to an epidermal fate. However, they did exhibit prevalent transcriptional changes particularly in extracellular matrix genes, and this was accompanied by profound structural perturbations in the aging SC niche. Moreover, marked age-related changes occurred in many nonepithelial cell types, including resident immune cells, sensory neurons, and arrector pili muscles. Each of these SC niche components has been shown to influence HF regeneration. When we performed skin injuries that are known to mobilize young HFSCs to exit their niche and regenerate HFs, we discovered that aged skin is defective at doing so. Interestingly, however, in transplantation assays in vivo, aged HFSCs regenerated HFs when supported with young dermis, while young HFSCs failed to regenerate HFs when combined with aged dermis. Together, our findings highlight the importance of SC:niche interactions and favor a model where youthfulness of the niche microenvironment plays a dominant role in dictating the properties of its SCs and tissue health and fitness.

Genome-wide association studies in Japanese women identified genetic loci associated with wrinkles and sagging.

Wrinkles and sagging are caused by various factors, such as ultraviolet rays; however, recent findings demonstrated that some individuals are genetically predisposed to these phenotypes of skin aging. The contribution of single nucleotide polymorphisms (SNPs) to the development of wrinkles and sagging has been demonstrated in genome-wide association studies (GWAS). However, these findings were mainly obtained from European and Chinese populations. Limited information is currently available on the involvement of SNPs in the development of wrinkles and sagging in a Japanese population. Therefore, we herein performed GWAS on wrinkles at the outer corners of the eyes and nasolabial folds in 1041 Japanese women. The results obtained revealed that 5 SNPs (19p13.2: rs2303098 (p = 3.39 × 10-8 ), rs56391955 (p = 3.39 × 10-8 ), rs67560822 (p = 3.50 × 10-8 ), rs889126 (p = 3.78 × 10-8 ), rs57490083 (p = 3.99 × 10-8 )) located within the COL5A3 gene associated with wrinkles at the outer corners of the eyes. Regarding nasolabial folds, 8q24.11 (rs4876369; p = 1.05 × 10-7 , rs6980503; p = 1.25 × 10-7 , rs61027543; p = 1.25 × 10-7 , rs16889363; p = 1.38 × 10-7 ) was suggested to be associated with RAD21 gene expression. These SNPs have not been reported in other populations, and were first found in Japanese women population. These SNPs may be used as markers to examine the genetic predisposition of individuals to wrinkles and sagging.

The accelerated aging skin in rhino-like SHJHhr mice.

SHJHhr mice line is rhino-like mice with a nonsense Hairless (Hr) mutant, which shows the characteristic of shedding hair and wrinkled skin with increasing age. Through histological analysis and aging indexes detection, SHJHhr mice show an increased thickness skin with degraded hair follicle and dermal cysts and disorganized collagen fibres, as well as decreased level of Hyp. Meanwhile, the aging markers p16 and p21 are significantly higher in SHJHhr mouse skin than ICR mouse skin at same age. Moreover, the data of MDA and SOD show a higher oxidative stress in SHJHhr mouse skin, and the levels of Nrf2 and its targets are significantly downregulated, which suggests SHJHhr mice have a faster aging skin and its reason maybe poor antioxidative protection. Overall, this study shows SHJHhr mice with an accelerated aging skin, which suggests the role of Hr gene in skin aging.

Non-coding RNAs in photoaging-related mechanisms: a new paradigm in skin health.

The aging of skin is a biological process affected by environmental or genetic factors. Exposure to ultraviolet (UV) radiation is the main environmental factor causing skin aging. Cumulative UV-induced photodamage of the skin tissue is associated with premature cellular senescence, extracellular degradation, and inflammatory responses in photoaging processes. Non-coding RNAs (ncRNAs) are untranslated transcripts and master regulators of protein-coding genes. ncRNAs have a critical regulatory role in maintaining skin structure, skin barrier function, morphogenesis, and development. Altered ncRNA expression has been reported in various skin disorders such as photoaging and skin cancers. ncRNAs contribute to the suppression and promotion of photoaging by modulating signaling pathways such as mitogen-activated protein kinase (MAPK) pathway and regulating inflammatory cytokines, matrix metalloproteinases (MMPs), and senescence-associated genes. Elucidation of the functions of ncRNAs will improve the identification of molecular mechanisms underlying photoaging, and can be used in the development of therapeutic approaches in skin health and prevention of sun-induced aging. This review summarized the currently described ncRNAs and their functions in photoaging.

Transcriptomic and histological analysis of exposed facial skin areas wrinkled or not and unexposed skin.

BACKGROUND: Skin aging involves genetic, environmental and hormonal factors. Facial wrinkles also depend on muscular activity. Gene expression investigation may be useful for new anti-aging products. METHODS AND RESULTS: To evaluate structure and gene expression differences among exposed and unexposed skin in menopausal women. Cross-sectional study, including 15 menopausal women, 55-65 years, phototype III; photo-exposed, periorbital wrinkles (A1), preauricular, not wrinkled (A2), and unexposed gluteal (A3) areas were described and compared by non-invasive measures, histology, immunohistochemistry and gene expression (RNASeq); participants mean age was 61yo, presenting moderate periorbital wrinkles and light facial photodamage. Higher roughness, wrinkles number and echogenicity were observed in A1 and A2 versus A3. Decreased epidermal thickness and dermal collagen IV were demonstrated in A1 versus A2 and A3. Exposed areas impacted different pathways compared to unexposed. Exposed wrinkled skin (A1) showed impact on cell movement with decreased inflammatory activation state. Pathways related to lipid and aminoacids metabolism were modulated in non-wrinkled exposed (A2) compared to unexposed (A3) skin. CONCLUSIONS: Expected histological findings and gene expression differences among areas were observed. Photoaging in menopausal women may modulate lipid and aminoacids metabolism and decrease inflammatory and keratinization pathways, cellular homeostasis, immune response, fibrogenesis and filament formation. These findings may help development of new therapies for skin health and aging control.