A miRNA-based epigenetic molecular clock for biological skin-age prediction.

Skin aging is one of the visible characteristics of the aging process in humans. In recent years, different biological clocks have been generated based on protein or epigenetic markers, but few have focused on biological age in the skin. Arrest the aging process or even being able to restore an organism from an older to a younger stage is one of the main challenges in the last 20 years in biomedical research. We have implemented several machine learning models, including regression and classification algorithms, in order to create an epigenetic molecular clock based on miRNA expression profiles of healthy subjects to predict biological age-related to skin. Our best models are capable of classifying skin samples according to age groups (18-28; 29-39; 40-50; 51-60 or 61-83 years old) with an accuracy of 80% or predict age with a mean absolute error of 10.89 years using the expression levels of 1856 unique miRNAs. Our results suggest that this kind of epigenetic clocks arises as a promising tool with several applications in the pharmaco-cosmetic industry.

Improving dermal fibroblast-to-epidermis communications and aging wound repair through extracellular vesicle-mediated delivery of Gstm2 mRNA.

Skin aging is characterized by the disruption of skin homeostasis and impaired skin injury repair. Treatment of aging skin has long been limited by the unclear intervention targets and delivery techniques. Engineering extracellular vesicles (EVs) as an upgraded version of natural EVs holds great potential in regenerative medicine. In this study, we found that the expression of the critical antioxidant and detoxification gene Gstm2 was significantly reduced in aging skin. Thus, we constructed the skin primary fibroblasts-derived EVs encapsulating Gstm2 mRNA (EVsGstm2), and found that EVsGstm2 could significantly improve skin homeostasis and accelerate wound healing in aged mice. Mechanistically, we found that EVsGstm2 alleviated oxidative stress damage of aging dermal fibroblasts by modulating mitochondrial oxidative phosphorylation, and promoted dermal fibroblasts to regulate skin epidermal cell function by paracrine secretion of Nascent Polypeptide-Associated Complex Alpha subunit (NACA). Furthermore, we confirmed that NACA is a novel skin epidermal cell protective molecule that regulates skin epidermal cell turnover through the ROS-ERK-ETS-Cyclin D pathway. Our findings demonstrate the feasibility and efficacy of EVs-mediated delivery of Gstm2 for aged skin treatment and unveil novel roles of GSTM2 and NACA for improving aging skin.

Is diet related to skin condition? A Mendelian randomization study.

Observational studies have revealed associations between various dietary factors and skin conditions. However, the causal relationship between diet and skin condition is still unknown. Data on 17 dietary factors were obtained from the UK Biobank. Data on four skin conditions were derived from the UK Biobank and another large-scale GWAS study. Genetic predictions suggested that the intake of oily fish was associated with a lower risk of skin aging (OR: 0.962, P = 0.036) and skin pigmentation (OR: 0.973, P = 0.033); Tea intake was associated with a lower risk of skin pigmentation (OR: 0.972, P = 0.024); Salad/raw vegetables intake was associated with a lower risk of keratinocyte skin cancer (OR: 0.952, P = 0.007). Coffee intake was associated with increased risk of skin aging (OR: 1.040, P = 0.028); Pork intake was associated with increased risk of skin aging (OR: 1.134, P = 0.020); Beef intake was associated with increased risk of cutaneous melanoma (OR: 1.013, P = 0.016); Champagne plus white wine intake was associated with increased risk of cutaneous melanoma (OR: 1.033, P = 0.004); Bread intake was associated with increased risk of keratinocyte skin cancer (OR: 1.026, P = 0.013). Our study results indicate causal relationships between genetically predicted intake of oily fish, tea, salad/raw vegetables, coffee, pork, beef, champagne plus white wine, and bread and skin conditions.

Effectiveness of topical hyaluronic acid of different molecular weights in xerosis cutis treatment in elderly: a double-blind, randomized controlled trial.

Dry skin is a common dermatological condition that frequently affects the elderly. A contributing cause to dry skin is a reduced concentration of hyaluronic acid (HA) in both the epidermis and dermis. The effectiveness of moisturizer containing HA as a therapy for dry skin is impacted by its specific molecular weight. Low molecular weight HA (LMWHA) is believed to be more effective in replenishing skin hydration in aging skin compared to High Molecular Weight HA (HMWHA) due to its ability to penetrate the stratum corneum. However, there is a lack of clinical research supporting this claim. A double-blind, randomized controlled trial was conducted on 36 residents of a nursing home in Jakarta. The participants, aged between 60 and 80 years, had been diagnosed with dry skin. Each test subject was administered three distinct, randomized moisturizing lotions (LMWHA, HMWHA, or vehicle), to be topically applied to three separate sites on the leg. Skin capacitance (SCap), transepidermal water loss (TEWL), and specified symptom sum score (SRRC) were measured at weeks 0, 2, and 4. After four weeks of therapy, area that was treated with LMWHA showed greater SCap values compared to the area treated with HMWHA (56.37 AU vs. 52.37 AU, p = 0.004) and vehicle (56.37 AU vs. 49.01 AU, p < 0.001). All groups did not show any significant differences in TEWL and SRRC scores. No side effects were found in all groups. The application of a moisturizer containing LMWHA to the dry skin of elderly resulted in significant improvements in skin hydration compared to moisturizers containing HMWHA and vehicle. Furthermore, these moisturizers demonstrated similar safety in treating dry skin in the elderly. ClinicalTrials.gov Identifier NCT06178367, https://clinicaltrials.gov/study/NCT06178367 .

The combination of tetramethylpyrazine and vitamin A acid in the treatment of skin photoaging by activating the HIF-1α pathway.

Skin photoaging is a skin degenerative disease that causes patients to develop malignant tumors. The existing clinical treatment of photoaging has limitations. This greatly reduces the recovery rate of photoaging patients. Studies have confirmed that Ligusticum wallichii Franch (LWF) monomer tetramethylpyrazine (TMP) alleviates various skin diseases. The combination of traditional Chinese medicine and Western medicine helps with this process. Our research aimed to explore the specific treatment mode and molecular mechanism of TMP in treating skin photoaging. CCK-8 assays were used to evaluate the activity and toxicity of HaCaT cells. ß-galactosidase aging, Carbonyl compound and nitrosylated tyrosine assays were used to analyze the aging of HaCaT cells. ROS assays and ELISA were used to analyze the enrichment of ROS. The molecular docking experiment analyzed the binding of TMP and HIF-1α. qRT-PCR and Western blot were used to detect the activation of skin aging-related pathways. HE staining was used to analyze the thickness of the stratum corneum skin on the back skin of mice. 200µg/L LWF alleviates cellular photoaging and mouse skin photoaging by reducing ROS enrichment. Its monomer TMP plays an important role in this process. The combination of TMP and HIF-1α accelerates the degradation of ROS by activating the Nrf2/ARE signaling pathway. This process reduces the apoptosis of cells damaged by light. In addition, we also found that the combination of TMP and retinoic acid (RA) is more beneficial for the treatment of skin damage caused by light in mice. The combination therapy of TMP and RA alleviates skin oxidative stress response through overexpression of HIF-1α. This plan is beneficial for the treatment of skin photoaging.

A review: Structure, bioactivity and potential application of algal polysaccharides in skin aging care and therapy.

Skin is the first barrier of body which stands guard for defending aggressive pathogens and environmental pressures all the time. Cutaneous metabolism changes in harmful exposure, following with skin dysfunctions and diseases. Lots of researches have reported that polysaccharides extracted from seaweeds exhibited multidimensional bioactivities in dealing with skin disorder. However, few literature systematically reviews them. The aim of the present paper is to summarize structure, bioactivities and structure-function relationship of algal polysaccharides acting on skin. Algal polysaccharides show antioxidant, immunomodulating, hydration regulating, anti-melanogenesis and extracellular matrix (ECM) regulating abilities via multipath ways in skin. These bioactivities are determined by various parameters, including seaweed species, molecular weight, monosaccharides composition and substitute groups. In addition, potential usages of algae-derived polysaccharides in skin care and therapy are also elaborated. Algal polysaccharides are potential ingredients in formulation that providing anti-aging efficacy for skin.

Upper eyelid morphology and age-related changes in Japanese and Chinese females.

BACKGROUND: Many consumers use cosmetic eye products to counteract age-related changes in appearance. Measurements of eyelid shape in Asian women have been reported in the frontal view or 45-degree profile only. The aim of this study was to describe morphological characteristics of the upper eyelid in Japanese and Chinese females from the frontal and profile aspects and examine morphological changes with age. MATERIALS AND METHODS: Standardized digital photographs of 772 Japanese and 346 Chinese women (15-79 years of age) were acquired in frontal and 90-degree profile aspects. Eleven upper eyelid parameters (e.g., width, length, depth, aperture, and curvature) were measured using image analysis to determine age-related changes and compare by ethnicity. RESULTS: Eyelid width, area between eyebrow and eyelid, and eyelid curvature were comparable for both ethnicities under age 40, but the aging effect was more pronounced in Chinese subjects. Eyelid height, depth, and upper eyelid aperture angle were also comparable for both ethnicities under age 40, but the aging effect was more evident in Japanese subjects. Upper eyelid incline angle, eye orientation, and upper eyelid protrusion angle changed comparably with age for both ethnicities. No prominent age-related changes were evident for eyelid length or area between eyebrow and eye with the eye closed. CONCLUSION: Upper eyelid morphology changes with age in Japanese and Chinese females, starting around 40 years of age. Ethnic differences are limited in younger age groups but become more prominent with age. The findings suggest that aging affects some upper eyelid features earlier than others.

An update on the safety of hydroquinone.

Hydroquinone has been used for years for multiple conditions, including melasma, post-inflammatory hyperpigmentation, dyschromia from photoaging, and solar lentigines. It is known to be a very effective lightening agent, but several concerns have been raised about this widely used agent. The recent U.S. ban on over-the-counter skin lightening products containing hydroquinone has prompted further questioning of the safety of this widely used agent. While there have been prior informative, large-scale reviews on the safety of hydroquinone, new findings have since been reported. Here, we provide an updated review of studies published in the past 15 years on hydroquinone safety.

Vascular feature identification in actinic keratosis grades I-III using dynamic optical coherence tomography with automated, quantitative analysis.

Clinical grading of actinic keratosis (AK) is based on skin surface features, while subclinical alterations are not taken into consideration. Dynamic optical coherence tomography (D-OCT) enables quantification of the skin´s vasculature, potentially helpful to improve the link between clinical and subclinical features. We aimed to compare microvascular characteristics across AK grades using D-OCT with automated vascular analysis. This explorative study examined AK and photodamaged skin (PD) on the face or scalp. AKs were clinically graded according to the Olsen Classification scheme before D-OCT assessment. Using an open-source software tool, the OCT angiographic analyzer (OCTAVA), we quantified vascular network features, including total and mean vessel length, mean vessel diameter, vessel area density (VAD), branchpoint density (BD), and mean tortuosity from enface maximum intensity projection images. Additionally, we performed subregional analyses on selected scans to overcome challenges associated with imaging through hyperkeratosis (each lesion group; n = 18). Our study included 45 patients with a total of 205 AKs; 93 grade I lesions, 65 grade II, 47 grade III and 89 areas with PD skin. We found that all AK grades were more extensively vascularized relative to PD, as shown by greater total vessel length and VAD (p ≤ 0.009). Moreover, AKs displayed a disorganized vascular network, with higher BD in AK I-II (p < 0.001), and mean tortuosity in AK II-III (p ≤ 0.001) than in PD. Vascularization also increased with AK grade, showing significantly greater total vessel length in AK III than AK I (p = 0.029). Microvascular quantification of AK unveiled subclinical, quantitative differences among AK grades I-III and PD skin. D-OCT-based microvascular assessment may serve as a supplement to clinical AK grading, potentially raising perspectives to improve management strategies.

A multicenter, double-blind, randomized, parallel-group, active-controlled, phase 3 clinical trial to compare the effectiveness and safety of two botulinum toxin type A formulations for improving moderate to severe glabellar wrinkles in Asians.

Botulinum toxin type A (BoNT-A) was first isolated in 1946, and since then, several formulations have been developed and widely used to treat wrinkles by inducing muscle paralysis. This multicenter, double-blind, randomized, parallel-group, active-controlled phase 3 clinical trial was designed to evaluate the efficacy and safety of a newly developed BoNT-A formulation, BMI2006, in improving moderate to severe glabellar wrinkles and to compare with existing onabotulinumtoxin A (OBoNT) injections. A total of 276 subjects were enrolled and received 20 units of the randomized material, which was intramuscularly injected into five different locations on the forehead. The primary endpoint, assessed at 4 weeks, showed no statistically significant difference in the improvement rate of glabellar wrinkles between the two groups, with BMI2006 demonstrating non-inferiority to comparator BoNT-A. Secondary endpoints, evaluated by both treating investigators and independent investigators, also exhibited similar improvement rates throughout the study period. Both groups reported high levels of satisfaction with no statistical difference between the two groups. Safety evaluations indicated mild and transient adverse events, with no serious reactions observed. In conclusion, BMI2006 is an effective and safe BoNT-A for treating glabellar wrinkles with an expected duration of action between 8 and 12 weeks.

Poly-l-lactic acid microspheres delay aging of epidermal stem cells in rat skin.

Objective: Injectable skin fillers offer a wider range of options for cutaneous anti-aging and facial rejuvenation. PLLA microspheres are increasingly favored as degradable and long-lasting fillers. The present study focused solely on the effect of PLLA on dermal collagen, without investigating its impact on the epidermis. In this study, we investigated the effects of PLLA microspheres on epidermal stem cells (EpiSCs). Methods: Different concentrations of PLLA microspheres on epidermal stem cells (EpiSCs) in vitro through culture, and identification of primary rat EpiSCs. CCK-8 detection, apoptosis staining, flow cytometry, Transwell assay, wound healing assay, q-PCR analysis, and immunofluorescence staining were used to detect the effects of PLLA on EpiSCs. Furthermore, we observed the effect on the epidermis by injecting PLLA into the dermis of the rat skin in vivo. Results: PLLA microspheres promote cell proliferation and migration while delaying cell senescence and maintaining its stemness. In vitro, Intradermal injection of PLLA microspheres in the rat back skin resulted in delayed aging, as evidenced by histological and immunohistochemical staining of the skin at 2, 4, and 12 weeks of follow-up. Conclusion: This study showed the positive effects of PLLA on rat epidermis and EpiSCs, while providing novel insights into the anti-aging mechanism of PLLA.

Anti-aging trends in Australia.

Anti-aging trends in Australia have changed considerably since the country emerged from the lockdowns associated with the SARS-Cov2 pandemic. People now rely on social media influencers for skin care advice and skin care products, including professional skin care treatments that can be purchased on Internet platforms. The quest for the perfect 'zoom face' led to a 300% rise in cosmetic procedures across Australia in the year to April 2021. People now want to use less products on their skin, while looking healthy and natural (termed 'skin minimalism'). The popularity of retinoid derivatives for preventing wrinkles has been superseded by non-irritating actives like hyaluronic acid (HA) and niacinamide that provide skin barrier protection, skin hydration, plumping and anti-inflammatory effects. Botulinum toxin injections remain the most popular non-surgical cosmetic procedure, followed by HA fillers, and biostimulators that promote the synthesis of collagen and give longer lasting but more gradual results than HA fillers. Laser resurfacing is widely used for epidermal resurfacing and skin tightening, as well as non-ablative lasers, intense pulsed light and radiofrequency or ultrasound skin tightening devices. Superficial chemical peels are still popular because they are relatively gentle, inexpensive, and require no downtime, whereas medium-to-deep chemical peels have largely been superseded by laser technology. However, the most efficient approach to prevent skin aging is adopting a healthy lifestyle and taking action against all factors of the skin aging exposome.

Top weapons in skin aging and actives to target the consequences of skin cell senescence.

Skin aging has long been considered a purely cosmetic problem. However, as life expectancy increases, skin aging is taking on a functional dimension that goes beyond cosmetics and appearance. Preventive or therapeutic strategies are needed to target cellular senescence, a key process underlying the alterations in skin function and appearance that occur with aging, as well as to address the age-related skin changes associated with 'dermatoporosis' and chronic skin insufficiency/fragility syndrome. Thus, given the need for effective anti-aging products that improve both the appearance and function of the skin, it is essential to distinguish active ingredients that have been proven to be effective, among the large number of available over-the-counter cosmeceuticals. This brief review focuses on a core group of topical actives, describing their clinical effects on senescence and aging, and their molecular mechanisms of action. These actives include hyaluronic acid, which has hydrating and viscoelastic properties and has been shown to reduce skin atrophy; retinaldehyde, which activates retinoid receptors and increases cutaneous elasticity; vitamins C and E, which provide stable oxidative protection; and niacinamide, which reduces inflammation and mitigates the effects of senescence.

Combined multilevel anti-aging strategies and practical applications of dermocosmetics in aesthetic procedures.

Management of the signs of facial aging and other cosmetic skin problems have greatly evolved in the past years. People are also seeking to improve their well-being and global skin appearance, and when they consider using cosmetic procedures, they expect natural and long-lasting aesthetic results. Combined dermocosmetic approaches that address the signs of facial aging at all levels are increasingly being used by dermatologists to meet patient expectations while ensuring their safety. Minimally invasive and reversible procedures that can be performed in only one session are popular approaches for skin restructuring and volumizing as they are flexible, rapid and less burdensome for patients. These interventions can achieve even better outcomes when they are combined with cosmeceuticals as pre- or post-procedural adjuvants to prepare the skin, accelerate recovery and sustain results. The use of topical dermocosmetics is also recommended as part of the daily skin care routine to improve skin quality and help maintain skin barrier function. This review thus outlines the most commonly used combined multilevel anti-aging strategies, which start by addressing the deepest skin layers and then the more superficial signs of skin aging. Examples of multi-active cosmeceuticals and skin delivery enhancing systems are also presented, together with examples of the use of dermocosmetics as supportive care for aesthetic procedures, to provide insights into current applications of dermocosmetic products.

Looking for the philosopher's stone: Emerging approaches to target the hallmarks of aging in the skin.

Senescence and epigenetic alterations are two important hallmarks of cellular aging. During aging, cells subjected to stress undergo many cycles of damage and repair before finally entering either apoptosis or senescence, a permanent state of cell cycle arrest. The first biomarkers of senescence to be identified were increased ß-galactosidase activity and induction of p16INK4a. Another feature of senescent cells is the senescence-associated secretory phenotype (SASP), a complex secretome containing more than 80 pro-inflammatory factors including metalloproteinases, growth factors, chemokines and cytokines. The secretome is regulated through a dynamic process involving a self-amplifying autocrine feedback loop and activation of the immune system. Senescent cells play positive and negative roles depending on the composition of their SASP and may participate in various processes including wound healing and tumour suppression, as well as cell regeneration, embryogenesis, tumorigenesis, inflammation and finally aging. The SASP is also a biomarker of age, biological aging and age-related diseases. Recent advances in anti-age research have shown that senescence can be now prevented or delayed by clearing the senescent cells or mitigating the effects of SASP factors, which can be achieved by a healthy lifestyle (exercise and diet), and senolytics and senomorphics, respectively. An alternative is tissue rejuvenation, which can be achieved by stimulating aged stem cells and reprogramming deprogrammed aged cells. These non-clinical findings will open up new avenues of clinical research into the development of treatments capable of preventing or treating age-related pathologies in humans.

Photoaging and cosmeceutical solutions in sun-overexposed countries: The experience of Australia and Brazil.

Skin aging is the result of physiological changes determined by genetically driven processes and intrinsic factors, and exacerbated by a combination of multiple environmental factors, the main one being sun exposure. The effects of photoaging are particularly apparent on the face, where the appearance of aging signs can have a significant impact on the emotions conveyed and well-being. Photoprotection and facial skin care for managing photoaging signs are thus of particular importance for both physical and mental health. Countries, like Australia and Brazil, where the level of sun exposure is high and the populations have predominantly outdoor lifestyles, are particularly aware of the harms of photoaging and have implemented several measures to help reduce the risk of skin cancer in their populations. However, sun-seeking behaviours are difficult to change, and it takes time before interventions provide perceptible results. Australia still has some of the highest skin cancer incidence and mortality rates in the world. Solutions that target individuals can also be used for minimizing the clinical signs of facial aging and for improving skin quality, with the ultimate aim being not only to improve the appearance of the skin but also to mitigate the occurrence of pre-malignant and malignant lesions. This review summarizes the features of facial skin photoaging in photo-exposed populations, based on evidence gained from studies of Australian individuals, and discusses the various available solutions for skin photoaging, in particular those that are most popular in Brazil, which is a country with many years of experience in managing photoaged skin.

Downregulated SPESP1-driven fibroblast senescence decreases wound healing in aged mice.

BACKGROUND: Human dermal fibroblasts (HDFs) are essential in the processes of skin ageing and wound healing. However, the underlying mechanism of HDFs in skin healing of the elderly has not been well defined. This study aims to elucidate the mechanisms of HDFs senescence and how senescent HDFs affect wound healing in aged skin. METHODS: The expression and function of sperm equatorial segment protein 1 (SPESP1) in skin ageing were evaluated via in vivo and in vitro experiments. To delve into the potential molecular mechanisms by which SPESP1 influences skin ageing, a combination of techniques was employed, including proteomics, RNA sequencing, immunoprecipitation, chromatin immunoprecipitation and liquid chromatography-mass spectrometry analyses. Clearance of senescent cells by dasatinib plus quercetin (D+Q) was investigated to explore the role of SPESP1-induced senescent HDFs in wound healing. RESULTS: Here, we define the critical role of SPESP1 in ameliorating HDFs senescence and retarding the skin ageing process. Mechanistic studies demonstrate that SPESP1 directly binds to methyl-binding protein, leading to Decorin demethylation and subsequently upregulation of its expression. Moreover, SPESP1 knockdown delays wound healing in young mice and SPESP1 overexpression induces wound healing in old mice. Notably, pharmacogenetic clearance of senescent cells by D+Q improved wound healing in SPESP1 knockdown skin. CONCLUSIONS: Taken together, these findings reveal the critical role of SPESP1 in skin ageing and wound healing, expecting to facilitate the development of anti-ageing strategies and improve wound healing in the elderly.

Lapagyl mitigates UV-induced inflammation and immunosuppression via Foxp3+ Tregs and CCL pathway: A single-cell transcriptomics study.

BACKGROUND: As the largest organ of the body, the skin is constantly subjected to ultraviolet radiation (UVR), leading to inflammations and changes that mirror those seen in chronological aging. Although various small molecule drugs have been explored for treating skin photoaging, they typically suffer from low stability and a high incidence of adverse reactions. Consequently, the continued investigation of photoaging treatments, particularly those utilizing herbal products, remains a critical clinical endeavor. One such herbal product, Lapagyl, is derived from the bark of the lapacho tree and possesses antioxidant efficacies that could be beneficial in combating skin photoaging. PURPOSE: This research aimed to evaluate the efficacy of the herbal product Lapagyl in combating UVR-induced skin photoaging. Additionally, it sought to unravel the mechanisms by which Lapagyl promotes the regeneration of the skin extracellular matrix. METHODS: To investigate whether Lapagyl can alleviate skin aging and damage, a UVR radiation model was established using SKH-1 hairless mice. The dorsal skins of these mice were evaluated for wrinkle formation, texture, moisture, transepidermal water loss (TEWL), and elasticity. Pathological assessments were conducted to determine Lapagyl's efficacy. Additionally, single-cell sequencing and spectrum analysis were employed to elucidate the working mechanisms and primary components of Lapagyl in addressing UVR-induced skin aging and injury. RESULTS: Lapagyl markedly reduced UVR-induced wrinkles, moisture loss, and elasticity decrease in SKH-1 mice. Single-cell sequencing demonstrated that Lapagyl corrected the imbalance in cell proportions caused by UVR, decreased UVR-induced ROS expression, and protected basal and spinous cells from skin damage. Additionally, Lapagyl effectively prevented the entry of inflammatory cells into the skin by reducing CCL8 expression and curtailed the UVR-induced formation of Foxp3+ regulatory T cells (Tregs) in the skin. Both pathological assessments and ex vivo skin model results demonstrated that Lapagyl effectively reduced UVR-induced damage to collagen and elastin. Spectrum analysis identified Salidroside as the primary compound remaining in the skin following Lapagyl treatment. Taken together, our study elucidated the skin protection mechanism of the herbal product Lapagyl against UVR damage at the cellular level, revealing its immunomodulatory effects, with salidroside identified as the primary active compound for skin. CONCLUSION: Our study provided a thorough evaluation of Lapagyl's protective effects on skin against UVR damage, delving into the mechanisms at the cellular level. We discovered that Lapagyl mitigates skin inflammation and immunosuppression by regulating Foxp3+ Tregs and the CCL pathway. These insights indicate that Lapagyl has potential as a novel therapeutic option for addressing skin photoaging.