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.

Comparisons between wrinkles and photo-ageing detected and self-reported by the participant or identified by trained assessors reveal insights from Chinese individuals in the Singapore/Malaysia Cross-sectional Genetics Epidemiology Study (SMCGES) cohort.

BACKGROUND: Changes develop on the facial skin as a person ages. Other than chronological time, it has been discovered that gender, ethnicity, air pollution, smoking, nutrition, and sun exposure are notable risk factors that influence the development of skin ageing phenotypes such as wrinkles and photo-ageing. These risk factors can be quantified through epidemiological collection methods. We previously studied wrinkles and photo-ageing in detail using photo-numeric scales. The analysis was performed on the ethnic Chinese skin by three trained assessors. Recent studies have shown that it is possible to use self-reported data to identify skin-related changes including skin colour and skin cancer. In order to investigate the association between risk factors and skin ageing phenotypic outcomes in large-scale epidemiological studies, it would be useful to evaluate whether it is also possible for participants to self-report signs of ageing on their skin. AIM: We have previously identified several validated photo-numeric scales for wrinkling and photo-ageing to use on ethnic Chinese skin. Using these scales, our trained assessors grade wrinkling and photo-ageing with moderately high inter-assessor concordance and agreement. The main objective of this study involves letting participants grade self-reported wrinkling and photo-ageing using these same scales. We aim to compare the concordance and agreement between signs of skin ageing by the participant and signs of ageing identified by our assessors. METHOD: Three trained assessors studied facial photo-ageing on 1081 ethnic Chinese young adults from the Singapore/Malaysia Cross-sectional Genetics Epidemiology Study (SMCGES) cohort. Self-reported facial photo-ageing data by the same 1081 participants were also collated and the two sets of data are compared. RESULTS: Here, we found that self-reported signs of photo-ageing are concordant with photo-ageing detected by our assessors. This finding is consistent whether photo-ageing is evaluated through studying wrinkle variations (Spearman's rank correlation (ρ) value: 0.246-0.329) or through studying dyspigmentation patterns (Spearman's rank correlation (ρ) value 0.203-0.278). When studying individual wrinkles, both participants and assessors often detect the presence of the same wrinkle (Spearman's rank correlation (ρ) value 0.249-0.366). A weak-to-fair level of agreement between both participants and assessors (Cohen's kappa (κ) values: 0.041-0.233) persists and is statistically significant after accounting for agreements due to chance. Both the participant and the assessor are largely consistent in evaluating the extent of photo-ageing (area under curve (AUC) values 0.689-0.769) and in discerning between the presence or absence of a given facial wrinkle (area under curve (AUC) values 0.601-0.856). CONCLUSION: When we analyse the overall appearance of the face, our results show that signs of photo-ageing identified by the participant are concordant with signs of photo-ageing identified by our assessors. When we focused our analysis on specific areas of the face, we found that participants were more likely to identify and self-report the same wrinkles that our assessors have also detected. Here, we found that self-reported signs of skin ageing provide a satisfactory approximation to the signs of skin ageing identified by our assessors. The ability to use self-reported signs of skin ageing should also be evaluated on scales beyond the ones discussed in this study. Currently, there are not as many photo-numeric scales for quantifying dyspigmentation patterns as there are for quantifying wrinkle variations. As Chinese skin is known to become dyspigmented more easily with age, more photo-numeric scales need to be developed and properly validated.

Role of epigenetics in the regulation of skin aging and geroprotective intervention: A new sight.

Multiple epigenetic factors play a regulatory role in maintaining the homeostasis of cutaneous components and are implicated in the aging process of the skin. They have been associated with the activation of the senescence program, which is the primary contributor to age-related decline in the skin. Senescent species drive a series of interconnected processes that impact the immediate surroundings, leading to structural changes, diminished functionality, and heightened vulnerability to infections. Geroprotective medicines that may restore the epigenetic balance represent valid therapeutic alliances against skin aging. Most of them are well-known Western medications such as metformin, nicotinamide adenine dinucleotide (NAD+), rapamycin, and histone deacetylase inhibitors, while others belong to Traditional Chinese Medicine (TCM) remedies for which the scientific literature provides limited information. With the help of the Geroprotectors.org database and a comprehensive analysis of the referenced literature, we have compiled data on compounds and formulae that have shown potential in preventing skin aging and have been identified as epigenetic modulators.

Bioinformatics-based analysis of the relationship between plasminogen regulatory genes and photoaging.

BACKGROUND: Ultraviolet radiation causes skin photoaging by producing a variety of enzymes, which impact both skin health and hinder beauty. Currently, the early diagnosis and treatment of photoaging remain a challenge. Bioinformatics analysis has strong advantages in exploring core genes and the biological pathways of photoaging. AIMS: To screen and validate key risk genes associated with plasminogen in photoaging and to identify potential target genes for photoaging. METHODS: Two human transcriptome datasets were obtained by searching the Gene Expression Omnibus (GEO) database, and the mRNAs in the GSE131789 dataset were differentially analyzed, and then the weighted gene co-expression network analysis (WGCNA) was performed to find out the strongest correlations. Template genes, interaction analysis of differentially expressed genes (DEGs), modular genes with the most WGCNA correlations, and genecard database genes related to plasminogen were performed, and further Kyoto genes and Genome Encyclopedia (KEGG) pathway analysis. Two different algorithms, least absolute shrinkage and selection operator (LASSO) and support vector machines-recursive feature elimination (SVM-RFE), were used to find key genes. Then the data set (GSE206495) was validated and analyzed. Real-time PCR was performed to validate the expression of key genes through in vitro cellular experiments. RESULTS: IFI6, IFI44L, HRSP12, and BMP4 were screened from datasets as key genes for photoaging and further analysis showed that these genes have significant diagnostic value for photoaging. CONCLUSION: IFI6, IFI44L, HRSP12, and BMP4 play a key role in the pathogenesis of photoaging, and serve as promising potential predictive biomarkers for 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.

Fine Wrinkle Improvement through Bioactive Materials That Modulate EDAR and BNC2 Gene Expression.

Skin aging is a multifaceted biological phenomenon influenced by a combination of intrinsic or extrinsic factors. There is an increasing interest in anti-aging materials including components that improve skin wrinkles. Despite the availability of several such wrinkle-improving materials, the demand for ingredients with outstanding efficacy is increasing. Therefore, this study aimed to explore the mechanisms of wrinkle-related genes reported in previous genome-wide association studies (GWASs), identify materials that regulate these genes, and develop an effective anti-wrinkle formula containing the active ingredients that regulate the expression of these genes. We selected two candidate genes, EDAR and BNC2, that are reportedly related to periorbital wrinkles. We investigated their functions in the skin through in vitro experiments using human skin cell lines (keratinocytes and fibroblasts). Moreover, we identified ingredients that regulate the expression of these two genes and confirmed their efficacy through in vitro experiments using the skin cell lines. Finally, we developed a formula containing these ingredients and confirmed that it enhanced dermal collagen in the 3D skin and improved fine wrinkles under the eyes more effectively than retinol in humans, when applied for 8 weeks. Our results are significant and relevant, as we have discovered a special formula for wrinkle improvement with reliable efficacy that surpasses the efficacy of retinol and does not cause side-effects such as skin irritation.

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.

Beverage consumption and facial skin aging: Evidence from Mendelian randomization analysis.

BACKGROUND: Observational studies have linked coffee, alcohol, tea, and sugar-sweetened beverage (SSB) consumption to facial skin aging. However, confounding factors may influence these studies. The present two-sample Mendelian randomization (MR) investigated the potential causal association between beverage consumption and facial skin aging. METHODS: The single-nucleotide polymorphisms (SNPs) associated with coffee, alcohol, and tea intake were derived from the IEU project. The SSB-associated SNPs were selected from a genome-wide association study (GWAS). Data on facial skin aging were derived from the largest GWAS involving 16 677 European individuals. The inverse variance-weighted (IVW) was the main MR analysis method, supplemented by other methods (MR-Egger, weighted median, simple mode, and weighted mode). The MR-Egger intercept analysis was used for sensitivity analysis. Moreover, we conducted a replication analysis using data from another GWAS dataset on coffee consumption to validate our findings. RESULTS: Four instrumental variables (IVs) sets were used to examine the causal association between beverage consumption (coffee, alcohol, tea, SSB) and facial skin aging. Our results revealed that genetically predicted higher coffee consumption reduced the risk of facial skin aging (OR: 0.852; 95% CI: 0.753-0.964; p = 0.011, IVW method). The sensitivity analysis confirmed the robustness of the findings, with no evidence of pleiotropy or heterogeneity. The results of replicated MR analysis on coffee consumption were consistent with the initial analysis (OR = 0.997; 95% CI = 0.996-0.999; p = 0.003, IVW method). CONCLUSIONS: This study manifests that higher coffee consumption is significantly associated with a reduced risk of facial skin aging. These findings can offer novel strategies for identifying the underlying etiology of facial skin aging.

Association between SPRY1 and TET3 in skin photoaging and natural aging mechanisms.

BACKGROUND: SPRY1 is associated with the invasiveness and prognosis of various tumors, and TET3 affects aging by regulating gene expression. AIMS: We investigated the roles of SPRY1 and TET3 in natural skin aging, replicative aging, and photoaging, along with the effect of UVA on genome-wide DNA methylation in HaCaT cells. METHODS: TET3 and SPRY1 expression were measured in the skin of patients of different age groups, as well as in vitro human skin, HaCaT cell replicative senescence, and HaCaT and HaCaT-siTET3 cell photoaging models. Senescence was verified using ß-galactosidase staining, and DNA damage was detected using immunofluorescence staining for γ-H2A.X. 5-Methyl cytosine (5-mC) content in the genome was determined using ELISA. RESULTS: SPRY1 expression increased with age, whereas TET3 expression decreased. Similarly, SPRY1 was upregulated and TET3 was downregulated with increasing cell passages. TET3-siRNA upregulated SPRY1 expression in HaCaT cells. UVA irradiation promoted HaCaT cell senescence and induced cellular DNA damage. SPRY1 was upregulated and TET3 was downregulated upon UVA irradiation. Genome-wide 5-mC content increased upon TET3 silencing and UVA irradiation, indicating a surge in overall methylation. CONCLUSIONS: SPRY1 and TET3 are natural skin aging-related genes that counteract to regulate replicative aging and UVA-induced photoaging in HaCaT cells. The cell photoaging model may limit experimental bias caused by different exposure times of skin model samples.

Potential to Enhance Large Scale Molecular Assessments of Skin Photoaging through Virtual Inference of Spatial Transcriptomics from Routine Staining.

The advent of spatial transcriptomics technologies has heralded a renaissance in research to advance our understanding of the spatial cellular and transcriptional heterogeneity within tissues. Spatial transcriptomics allows investigation of the interplay between cells, molecular pathways, and the surrounding tissue architecture and can help elucidate developmental trajectories, disease pathogenesis, and various niches in the tumor microenvironment. Photoaging is the histological and molecular skin damage resulting from chronic/acute sun exposure and is a major risk factor for skin cancer. Spatial transcriptomics technologies hold promise for improving the reliability of evaluating photoaging and developing new therapeutics. Challenges to current methods include limited focus on dermal elastosis variations and reliance on self-reported measures, which can introduce subjectivity and inconsistency. Spatial transcriptomics offers an opportunity to assess photoaging objectively and reproducibly in studies of carcinogenesis and discern the effectiveness of therapies that intervene in photoaging and preventing cancer. Evaluation of distinct histological architectures using highly-multiplexed spatial technologies can identify specific cell lineages that have been understudied due to their location beyond the depth of UV penetration. However, the cost and interpatient variability using state-of-the-art assays such as the 10x Genomics Spatial Transcriptomics assays limits the scope and scale of large-scale molecular epidemiologic studies. Here, we investigate the inference of spatial transcriptomics information from routine hematoxylin and eosin-stained (H&E) tissue slides. We employed the Visium CytAssist spatial transcriptomics assay to analyze over 18,000 genes at a 50-micron resolution for four patients from a cohort of 261 skin specimens collected adjacent to surgical resection sites for basal cell and squamous cell keratinocyte tumors. The spatial transcriptomics data was co-registered with 40x resolution whole slide imaging (WSI) information. We developed machine learning models that achieved a macro-averaged median AUC and F1 score of 0.80 and 0.61 and Spearman coefficient of 0.60 in inferring transcriptomic profiles across the slides, and accurately captured biological pathways across various tissue architectures.

Functionally similar genes exhibit comparable/similar time-course expression kinetics in the UV-induced photoaged mouse model.

Skin photoaging induced by ultraviolet (UV) irradiation contributes to the formation of thick and coarse wrinkles. Humans are exposed to UV light throughout their lives. Therefore, it is crucial to determine the time-sequential effects of UV on the skin. In this study, we irradiated the mouse back skin with UV light for eight weeks and observed the changes in gene expressions via microarray analysis every week. There were more downregulated genes (514) than upregulated genes (123). The downregulated genes had more functional diversity than the upregulated genes. Additionally, the number of downregulated genes did not increase in a time-dependent manner. Instead, time-dependent kinetic patterns were observed. Interestingly, each kinetic cluster harbored functionally enriched gene sets. Since collagen changes in the dermis are considered to be a major cause of photoaging, we hypothesized that other gene sets contributing to photoaging would exhibit kinetics similar to those of the collagen-regulatory genes identified in this study. Accordingly, co-expression network analysis was conducted using 11 well-known collagen-regulatory seed genes to predict genes with similar kinetics. We ranked all downregulated genes from 1 to 504 based on their expression levels, and the top 50 genes were suggested to be involved in the photoaging process. Additionally, to validate and support our identified top 50 gene lists, we demonstrated that the genes (FN1, CCDC80, PRELP, and TGFBR3) we discovered are downregulated by UV irradiation in cultured human fibroblasts, leading to decreased collagen levels, which is indicative of photoaging processes. Overall, this study demonstrated the time-sequential genetic changes in chronically UV-irradiated skin and proposed 50 genes that are involved in the mechanisms of photoaging.

Epigenetics insights from perceived facial aging.

Facial aging is the most visible manifestation of aging. People desire to look younger than others of the same chronological age. Hence, perceived age is often used as a visible marker of aging, while biological age, often estimated by methylation markers, is used as an objective measure of age. Multiple epigenetics-based clocks have been developed for accurate estimation of general biological age and the age of specific organs, including the skin. However, it is not clear whether the epigenetic biomarkers (CpGs) used in these clocks are drivers of aging processes or consequences of aging. In this proof-of-concept study, we integrate data from GWAS on perceived facial aging and EWAS on CpGs measured in blood. By running EW Mendelian randomization, we identify hundreds of putative CpGs that are potentially causal to perceived facial aging with similar numbers of damaging markers that causally drive or accelerate facial aging and protective methylation markers that causally slow down or protect from aging. We further demonstrate that while candidate causal CpGs have little overlap with known epigenetics-based clocks, they affect genes or proteins with known functions in skin aging, such as skin pigmentation, elastin, and collagen levels. Overall, our results suggest that blood methylation markers reflect facial aging processes, and thus can be used to quantify skin aging and develop anti-aging solutions that target the root causes of aging.

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.

Assessment of efficacy of carboxytherapy in management of skin aging through evaluation of gene expression profile: a 2-split randomized clinical trial.

Skin aging is a continuous and irreversible process which results in impairment of the skin role as barrier against all aggressive exogenous factors. It mainly manifests by photoaging, laxity, sagging, wrinkling, and xerosis. Carboxytherapy is considered as a safe, minimally invasive modality used for rejuvenation, restoration, and recondition of the skin. In the current study, the efficacy of carboxytherapy in the treatment of skin aging was assessed through investigation of gene expression profile for Coll I, Coll III, Coll IV, elastin, FGF, TGF-ß1, and VEGF. Our study is a 2-split clinical trial in which carboxytherapy was performed on one side of the abdomen in 15 cases with intrinsically skin aging manifestations weekly for 10 sessions, while the other side of the abdomen was left without treatment. Two weeks after the last session, skin biopsies were taken from both the treated and control sides of the abdomen in order to assess gene expression profile by qRT-PCR. The analysis of gene expression levels for all of Coll I, Coll III, Coll IV, elastin, TGF-ß1, FGF and VEGF genes showed a statistically significant difference between the interventional and control groups. The findings for all of these seven genes showed increase in the interventional group, among which Coll IV, VEGF, FGF, and elastin showed the higher mean changes. Our study confirmed the effectiveness of carboxytherapy in treating and reversing the intrinsically aging skin.Clinical Trial Registration Code and Date of Registration: ChiCTR2200055185; 2022/1/2.

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.

Network-based analysis identifies key regulatory transcription factors involved in skin aging.

Skin aging is a complex process involving intricate genetic and environmental factors. In this study, we performed a comprehensive analysis of the transcriptional regulatory landscape of skin aging in canines. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to identify aging-related gene modules. We subsequently validated the expression changes of these module genes in single-cell RNA sequencing (scRNA-seq) data of human aging skin. Notably, basal cell (BC), spinous cell (SC), mitotic cell (MC), and fibroblast (FB) were identified as the cell types with the most significant gene expression changes during aging. By integrating GENIE3 and RcisTarget, we constructed gene regulation networks (GRNs) for aging-related modules and identified core transcription factors (TFs) by intersecting significantly enriched TFs within the GRNs with hub TFs from WGCNA analysis, revealing key regulators of skin aging. Furthermore, we demonstrated the conserved role of CTCF and RAD21 in skin aging using an H2O2-stimulated cell aging model in HaCaT cells. Our findings provide new insights into the transcriptional regulatory landscape of skin aging and unveil potential targets for future intervention strategies against age-related skin disorders in both canines and humans.

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.

Matrix Metalloproteinase-1 Expression in Fibroblasts Accelerates Dermal Aging and Promotes Papilloma Development in Mouse Skin.

Fragmentation, disorganization, and depletion of the collagen-rich dermal extracellular matrix are hallmarks of aged human skin. These deleterious alterations are thought to critically mediate many of the prominent clinical attributes of aged skin, including thinning, fragility, impaired wound healing, and a propensity for carcinoma. Matrix metalloproteinase-1 (MMP1) initiates the cleavage of collagen fibrils and is significantly increased in dermal fibroblasts in aged human skin. To investigate the role of elevated MMP1 in skin aging, we generated a conditional bitransgenic mouse (type I collagen alpha chain 2; human MMP1 [Col1a2;hMMP1]) that expresses full-length, catalytically active hMMP1 in dermal fibroblasts. hMMP1 expression is activated by a tamoxifen-inducible Cre recombinase that is driven by the Col1a2 promoter and upstream enhancer. Tamoxifen induced hMMP1 expression and activity throughout the dermis Col1a2:hMMP1 mice. At 6 months of age, Col1a2;hMMP1 mice displayed loss and fragmentation of dermal collagen fibrils, which was accompanied by many of the features of aged human skin, such as contracted fibroblast morphology, reduced collagen production, increased expression of multiple endogenous MMPs, and proinflammatory mediators. Interestingly, Col1a2;hMMP1 mice displayed substantially increased susceptibility to skin papilloma development. These data demonstrate that fibroblast expression of hMMP1 is a critical mediator of dermal aging and creates a dermal microenvironment that promotes keratinocyte tumor development.

Exploring the role of mitochondria transfer/transplant and their long-non-coding RNAs in regenerative therapies for skin aging.

Advancing age and environmental stressors lead to mitochondrial dysfunction in the skin, inducing premature aging, impaired regeneration, and greater risk of cancer. Cells rely on the communication between the mitochondria and the nucleus by tight regulation of long non-coding RNAs (lncRNAs) to avoid premature aging and maintain healthy skin. LncRNAs act as key regulators of cell proliferation, differentiation, survival, and maintenance of skin structure. However, research on how the lncRNAs are dysregulated during aging and due to stressors is needed to develop therapies to regenerate skin's function and structure. In this article, we discuss how age and environmental stressors may alter lncRNA homeodynamics, compromising cell survival and skin health, and how these factors may become inducers of skin aging. We describe skin cell types and how they depend on mitochondrial function and lncRNAs. We also provide a list of mitochondria localized and nuclear lncRNAs that can serve to better understand skin aging. Using bioinformatic prediction tools, we predict possible functions of lncRNAs based on their subcellular localization. We also search for experimentally determined protein interactions and the biological processes involved. Finally, we provide therapeutic strategies based on gene editing and mitochondria transfer/transplant (AMT/T) to restore lncRNA regulation and skin health. This article offers a unique perspective in understanding and defining the therapeutic potential of mitochondria localized lncRNAs (mt-lncRNAs) and AMT/T to treat skin aging and related diseases.