Senile Lentigo Research Articles

A collagen biostimulator improves photoaging pigmentation

AbstractPhotoaging pigmentation conditions such as senile lentigo and melasma show epidermal melanogenic activity and dermal abnormalities, including collagen degradation. A dermal rejuvenation strategy with skin‐lightening therapy directly acting on melanocytes is suggested for photoaging pigmentation. This study investigates whether collagen biostimulation can result in skin lightening of photoaging skin. A split‐face clinical trial was conducted, involving 40 subjects with facial melasma and senile lentigo. Subjects received a poly‐DL‐lactic acid (PDLLA) treatment on one side of their face, whereas the contralateral side received a treatment of normal saline as a control. Assessments were scheduled every month after completing treatments for up to 3 months. Pigmentation was evaluated using the L* value as measured with a chromameter and by investigator global assessment scores (IGA). Subjects reported different outcomes in terms of overall skin quality, including pigmentation, wrinkles and elasticity. Skin biopsies were obtained before the treatment and 4 weeks after completing the treatment. Fontana‐Masson, Masson‐Trichrome and Verhoeff‐van Gieson staining, and fibroblast‐specific protein 1 (FSP1) immunostaining were conducted. The PDLLA treatment demonstrated significant improvements in the L* values and IGA scores from 8 weeks after the subject completed their treatments. These improvements were sustained over a 12‐week assessment period. The subjects reported substantial reductions in both pigmentation and wrinkle severity and elasticity throughout the assessment period. Fontana‐Masson staining showed a marked decrease in pigmentation upon a PDLLA injection compared to the baseline values. Increased immunogenicity of FSP1 and increases in collagen and elastic fibre staining were observed. This study demonstrated remarkable improvements in photoaging pigmentation along with collagen production with a collagen biostimulator. Thus, collagen biostimulators represent a promising therapeutic approach for addressing photoaging signs associated with melasma and senile lentigo. (ClinicalTrials.gov Identifier: NCT05913102).

Epidermal turnover and iron metabolism in senile lentigo.

Senile lentigo (SL) is a pigmentary disorder associated with disrupted epidermal turnover. Trace minerals in the skin are known to regulate keratinocyte proliferation and differentiation. To clarify the role of iron in SL, we compared the expression of molecules related to iron metabolism between SL lesion (lesion) and the surrounding normal skin (nonlesion). Our results revealed that proteins involved in iron uptake and utilization such as transferrin receptor 1, iron regulatory protein 1, mitoferrin 1, and divalent metal transporter 1 were expressed in the lower epidermis in the nonlesion, while expression of them was also observed in the upper epidermis in the lesion. Ferroportin (FPN), involved in iron export, was expressed in the upper epidermis in the nonlesion, but was only scarcely expressed in the upper epidermis in the lesion. Hepcidin, which promotes FPN degradation, was expressed in the lower epidermis in the nonlesion; however, its expression was also observed in the upper epidermis in the lesion. These changes in the expression of molecules involved in iron uptake/export/utilization might reflect the altered iron utilization state in SL, resulting in disruption of keratinocyte differentiation and disturbing epidermal turnover. Our results suggest that the metabolism of iron in keratinocytes in SL differs from that in the normal epidermis, and these changes could be associated with the abnormal epidermal turnover and decreased melanin excretion in SL.

Melasolv™: a potential preventive and depigmenting agent for the senescence of melanocytes.

Introduction: Senescent melanocytes are major contributors to age-related changes in the skin, highlighting the contribution to skin aging. Moreover, prolonged photodamage, such as that caused by UV exposure, can result in melanin accumulation and accelerated melanocyte senescence, thereby exacerbating aging. Melasolv™ is a substance that induces potent depigmentation effects and exhibits low toxicity. The present study aimed to investigate the potential effect of Melasolv™ on senescent melanocytes. Methods: We profiled the transcriptomics of Melasolv™-treated melanocytes and identified the possible mechanism of action (MOA) and targets using connectivity mapping analysis. We identified differentially expressed genes in response to treatment with Melasolv™ and validated the data using quantitative real-time PCR. Moreover, we performed an in vitro β-gal assay in senescent melanocytes for further validation. Results: Melasolv™ reduced β-gal and melanin levels in senescent melanocytes. Moreover, the identified MOAs are associated with anti-aging and anti-senescence effects. Discussion: Our findings clearly indicate that Melasolv™ not only exhibits anti-senescent properties but can also potentially alleviate melanin accumulation in senescent cells. These findings could have far-reaching implications in the treatment of age-related photodamaged skin conditions, such as senile lentigo and melasma.

1203 Increased horizontal cell division and suppressed cell differentiation of pigmented basal keratinocytes in senile lentigo

1203 Increased horizontal cell division and suppressed cell differentiation of pigmented basal keratinocytes in senile lentigo

523 Targeting SDF-1 as an efficient strategy to resolve skin hyperpigmentation issues with Himanthalia elongata extract

Human skin is submitted to hyperpigmentation disorders during our life: senile lentigo, linked to intrinsic ageing, leads to a loss of melanogenesis’ control while solar lentigo, linked to UV exposure, promotes an increase of oxidized proteins, melanogenesis and lipofuscin accumulation. SDF1 (Stromal cell-derived factor 1) was recently identified as key regulator of pigmentation via the inhibition of cAMP pathway in melanocytes. SDF1 expression is reduced in senescent fibroblasts during senile lentigo, pushing this protein as a strategic target for skin hyperpigmentation.

Shining Light on Autophagy in Skin Pigmentation and Pigmentary Disorders.

Autophagy is a vital process for cell survival and it preserves homeostasis by recycling or disassembling unnecessary or dysfunctional cellular constituents. Autophagy ameliorates skin integrity, regulating epidermal differentiation and constitutive pigmentation. It induces melanogenesis and contributes to skin color through melanosome turnover. Autophagy activity is involved in skin phenotypic plasticity and cell function maintenance and, if altered, it concurs to the onset and/or progression of hypopigmentary and hyperpigmentary disorders. Overexpression of autophagy exerts a protective role against the intrinsic metabolic stress occurring in vitiligo skin, while its dysfunction has been linked to the tuberous sclerosis complex hypopigmentation. Again, autophagy impairment reduces melanosome degradation by concurring to pigment accumulation characterizing senile lentigo and melasma. Here we provide an updated review that describes recent findings on the crucial role of autophagy in skin pigmentation, thus revealing the complex interplay among melanocyte biology, skin environment and autophagy. Hence, targeting this process may also represent a promising strategy for treating pigmentary disorders.

Targeting SDF-1 as an efficient strategy to resolve skin hyperpigmentation issues with Himanthalia elongata extract.

During aging, human skin is facing hyperpigmentation disorders: senile lentigo (chronobiologic aging) leads to loss of melanogenesis' control while solar lentigo (UV exposure) promotes an increase of oxidized proteins, melanogenesis, and lipofuscin. Stromal-cell-derived-factor-1 (SDF-1) was identified as key regulator of hyperpigmentation and its expression is reduced in senescent fibroblasts, highlighting this protein as new target for skin hyperpigmentation. We developed two skin explant models mimicking of senile and solar lentigo, based on H2 O2 systemic treatment and UV irradiation, respectively. We evaluated Himanthalia elongata extract (HEX) on these models after 5 days of treatment and analyzed SDF-1 expression and skin pigmentation. For solar lentigo, we also analyzed oxidized proteins and lipofuscin accumulation. Finally, we evaluated HEX in vivo on nearly 100 multi ethnicities' volunteers. SDF-1 expression decreased in senile lentigo model, associated with hyperpigmentation. HEX application restored SDF-1 expression, leading to skin pigmentation decrease. For solar lentigo, we showed an impact of UVs on SDF-1 expression linked to hyperpigmentation, while the application of HEX restored SDF-1 expression and reduced skin pigmentation. On same model, HEX reduced oxidized proteins quantity and lipofuscin which increased after UV exposure. Clinically, HEX reduced dark spot pigmentation on Caucasian volunteers' hands and on Asian and African volunteers' face after 28 days. We have developed ex vivo models mimetic of senile and solar lentigo and showed for a very first time that SDF-1 can be also a key regulator for UV-induced hyperpigmentation. Our ex vivo and clinical studies highlighted the power of HEX with strong reduction of dark spots regardless of volunteers' ethnicities.

Skin-Aging Pigmentation: Who Is the Real Enemy?

Skin aging is induced and sustained by chronological aging and photoaging. Aging skin pigmentation such as mottled pigmentation (senile lentigo) and melasma are typical signs of photoaging. The skin, like other human organs, undergoes cellular senescence, and senescent cells in the skin increase with age. The crosstalk between melanocytes as pigmentary cells and other adjacent types of aged skin cells such as senescent fibroblasts play a role in skin-aging pigmentation. In this review, we provide an overview of cellular senescence during the skin-aging process. The discussion also includes cellular senescence related to skin-aging pigmentation and the therapeutic potential of regulating the senescence process.

Efficacy and safety of topical hydrogen peroxide 35% solution versus cryotherapy in the treatment of senile lentigo.

Senile lentigines (SLs) are hyperpigmented macules that predominantly affect the elderly. We aimed to compare the efficacy and safety of hydrogen peroxide35% solution with cryotherapy in the treatment of SLs. This clinical trial included 33 patients with SLs referred to our center. Lesions of each side of the body were randomly allocated to receive 3 sessions of treatment with hydrogen peroxide or cryotherapy at a three-week interval. All patients were followed up 1 week after each round of treatment for the evaluation of side effects, the general effect of the treatment, and the general assessment of response to treatment. Thirty-three patients were included in this study with the mean age of 61.79 ± 4.59 years. Average and excellent effects were significantly higher with cryotherapy after the 2nd and 3rd sessions of treatment, respectively. Positive response to treatment was significantly higher with cryotherapy at all time points. Severe erythema was only observed with cryotherapy. Pigmentation was significantly more frequent with cryotherapy than with hydrogen peroxide at any time point (p < 0.001). Also, blisters were only seen with cryotherapy. Moreover, the pain score was significantly higher with cryotherapy at all time points (p < 0.001). Up to one week after the 3rd session of treatment, no recurrence of lesions occurred in any of the groups. Cryotherapy appears to be more efficacious for the treatment of SLs compared to hydrogen peroxide 35% solution; however, hydrogen peroxide seems to have fewer side effects.

Stabilized Cysteamine 5% Cream for the Treatment of Senile Lentigo

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Three-dimensional structure analysis of melanocytes and keratinocytes in senile lentigo.

Senile lentigo or age spots are hyperpigmented macules of skin that commonly develop following long-term exposure to ultraviolet radiation. This condition is caused by accumulation of large numbers of melanosomes (melanin granules) produced by melanocytes within neighboring keratinocytes. However, there is still no consensus regarding the melanosome transfer mechanism in senile lentigo. To date, most pathohistological studies of skin have been two-dimensional and do not provide detailed data on the complex interactions of the melanocyte-keratinocyte network involved in melanosome transfer. We performed a three-dimensional reconstruction of the epidermal microstructure in senile lentigo using three different microscopic modalities to visualize the topological melanocyte-keratinocyte relationship and melanosome distribution. Confocal laser microscopy images showed that melanocyte dendritic processes are more frequently branched and elongated in senile lentigo skin than in normal skin. Serial transmission electron micrographs showed that dendritic processes extend into intercellular spaces between keratinocytes. Focused ion beam-scanning electron micrographs showed that dendritic processes in senile lentigo encircle adjacent keratinocytes and accumulate large numbers of melanosomes. Moreover, melanosomes transferred to keratinocytes are present not only in the supranuclear area but throughout the perinuclear area except on the basal side. The use of these different microscopic methods helped to elucidate the three-dimensional morphology and topology of melanocytes and keratinocytes in senile lentigo. We show that the localization of melanosomes in dendritic processes to the region encircling recipient keratinocytes contributes to efficient melanosome transfer in senile lentigo.

Autophagy Declines with Premature Skin Aging resulting in Dynamic Alterations in Skin Pigmentation and Epidermal Differentiation.

Autophagy is a membrane traffic system that provides sustainable degradation of cellular components for homeostasis, and is thus considered to promote health and longevity, though its activity declines with aging. The present findings show deterioration of autophagy in association with premature skin aging. Autophagy flux was successfully determined in skin tissues, which demonstrated significantly decreased autophagy in hyperpigmented skin such as that seen in senile lentigo. Furthermore, an exacerbated decline in autophagy was confirmed in xerotic hyperpigmentation areas, accompanied by severe dehydration and a barrier defect, which showed correlations with skin physiological conditions. The enhancement of autophagy in skin ex vivo ameliorated skin integrity, including pigmentation and epidermal differentiation. The present results indicate that the restoration of autophagy can contribute to improving premature skin aging by various intrinsic and extrinsic factors via the normalization of protein homeostasis.

The Development of a Skin Cancer Classification System for Pigmented Skin Lesions Using Deep Learning.

Recent studies have demonstrated the usefulness of convolutional neural networks (CNNs) to classify images of melanoma, with accuracies comparable to those achieved by dermatologists. However, the performance of a CNN trained with only clinical images of a pigmented skin lesion in a clinical image classification task, in competition with dermatologists, has not been reported to date. In this study, we extracted 5846 clinical images of pigmented skin lesions from 3551 patients. Pigmented skin lesions included malignant tumors (malignant melanoma and basal cell carcinoma) and benign tumors (nevus, seborrhoeic keratosis, senile lentigo, and hematoma/hemangioma). We created the test dataset by randomly selecting 666 patients out of them and picking one image per patient, and created the training dataset by giving bounding-box annotations to the rest of the images (4732 images, 2885 patients). Subsequently, we trained a faster, region-based CNN (FRCNN) with the training dataset and checked the performance of the model on the test dataset. In addition, ten board-certified dermatologists (BCDs) and ten dermatologic trainees (TRNs) took the same tests, and we compared their diagnostic accuracy with FRCNN. For six-class classification, the accuracy of FRCNN was 86.2%, and that of the BCDs and TRNs was 79.5% (p = 0.0081) and 75.1% (p < 0.00001), respectively. For two-class classification (benign or malignant), the accuracy, sensitivity, and specificity were 91.5%, 83.3%, and 94.5% by FRCNN; 86.6%, 86.3%, and 86.6% by BCD; and 85.3%, 83.5%, and 85.9% by TRN, respectively. False positive rates and positive predictive values were 5.5% and 84.7% by FRCNN, 13.4% and 70.5% by BCD, and 14.1% and 68.5% by TRN, respectively. We compared the classification performance of FRCNN with 20 dermatologists. As a result, the classification accuracy of FRCNN was better than that of the dermatologists. In the future, we plan to implement this system in society and have it used by the general public, in order to improve the prognosis of skin cancer.

Epidermal keratin 5 expression and distribution is under dermal influence.

Human skin melanin pigmentation is regulated by systemic and local factors. According to the type of melanin produced by melanocytes, the transfer and degradation of melanosomes differ, thus accounting for most variations between ethnicities. We made the surprising observation that in a drastically changed environment, white and black phenotypes are reversible since Caucasian skin grafted onto nude mice can become black with all black phenotypic characteristics. Black xenografts differed essentially from other grafts by the levels of epidermal FGF-2 and keratin 5. In vitro analysis confirmed that FGF-2 directly regulates keratin 5. Interestingly, this phenomenon may be involved in human pathology. Keratin 5 mutations in Dowling-Degos Disease (DDD) have already been associated with the pheomelanosome-eumelanosome transition. In a DDD patient, keratin 5 was expressed in the basal and spinous layers, as observed in black xenografts. Furthermore, in a common age-related hyperpigmentation disorder like senile lentigo (SL), keratin 5 distribution is also altered. In conclusion, modulation of keratin 5 expression and distribution either due to mutations or factors may account for the development of pigmentary disorders.

781 The association between senile lentigo and intracutaneous nerve structure

781 The association between senile lentigo and intracutaneous nerve structure

Evaluation of the Novel Synthetic Tyrosinase Inhibitor (Z)-3-(3-bromo-4-hydroxybenzylidene)thiochroman-4-one (MHY1498) In Vitro and In Silico.

Tyrosinase is a key enzyme in melanin synthesis, catalyzing the initial rate-limiting steps of melanin synthesis. Abnormal and excessive melanin synthesis is the primary cause of serious skin disorders including melasma, senile lentigo, freckles, and age spots. In attempts to find potent and safe tyrosinase inhibitors, we designed and synthesized a novel compound, (Z)-3-(3-bromo-4-hydroxybenzylidene)thiochroman-4-one (MHY1498), and evaluated its tyrosinase inhibitory activity in vitro and in silico. The chemical structures of (Z)-3-benzylidenethiochroman-4-one analogues, including the novel compound MHY1498, were rationally designed and synthesized as hybrid structures of reported potent tyrosinase inhibitors, which were confirmed both in vitro and in vivo: (Z)-5-(substituted benzylidene)thiazolidine-2,4-diones (Compound A) and 2-(substituted phenyl)benzo[d]thiazoles (Compound B). During screening, MHY1498 showed a strong dose-dependent inhibitory effect on mushroom tyrosinase. The IC50 value of MHY1498 (4.1 ± 0.6 μM) was significantly lower than that of the positive control, kojic acid (22.0 ± 4.7 μM). In silico molecular multi-docking simulation and inhibition mechanism studies indicated that MHY1498 interacts competitively with the tyrosinase enzyme, with greater affinity for the active site of tyrosinase than the positive control. Furthermore, in B16F10 melanoma cells treated with α-melanocyte-stimulating hormone, MHY1498 suppressed both melanin production and tyrosinase activity. In conclusion, our data demonstrate that MHY1498, a synthesized novel compound, effectively inhibits tyrosinase activity and has potential for treating hyperpigmentation and related disorders.

Inhibitors of Melanogenesis: An Updated Review.

Melanins are pigment molecules that determine the skin, eye, and hair color of the human subject to its amount, quality, and distribution. Melanocytes synthesize melanin and provide epidermal protection from various stimuli, such as harmful ultraviolet radiation, through the complex process called melanogenesis. However, serious dermatological problems occur when there is excessive production of melanin in different parts of the human body. These include freckles, melasma, senile lentigo, pigmented acne scars, and cancer. Therefore, controlling the production of melanin is an important approach for the treatment of pigmentation related disorderes. In this Perspective, we focus on the inhibitors of melanogenesis that directly/indirectly target a key enzyme tyrosinase as well as its associated signaling pathways.

Senescent fibroblasts drive ageing pigmentation: ​A potential therapeutic target for senile lentigo.

Cutaneous ageing is an important extrinsic process that modifies the pigmentary system. Because cellular senescence is a fundamental ageing mechanism, we examined the role of senescent cells in ageing pigmentation.Methods: Biopsies obtained from senile lentigo and perilesional normal skin were assayed for a marker of cellular senescence, p16INK4A. To determine the secretory phenotypes of senescent fibroblasts, we performed microarray, RNA sequencing and methylation array analyses in senile lentigo and senescent fibroblasts. To further investigate the impact of senescent cells on ageing-related pigmentation, an intervention that targeted senescent cells using radiofrequency was performed.Results: In vivo, senescent fibroblasts accumulated at the sites of age-related pigmentation. Phenotype switching of the cells resulted in the repression of stromal-derived factor 1 (SDF1) by promoter methylation. SDF1 induced melanocyte differentiation via stromal-epithelial interactions, ultimately driving skin pigmentation. Furthermore, the elimination of senescent fibroblasts from pigmented skin using radiofrequency was accompanied by skin lightening, rendering it a potential target for treatment.Conclusion: Aged pigmented skin contains an increasing proportion of senescent fibroblasts. Cells with phenotype switching exhibited a loss of SDF1, which stimulates the melanogenic process and thereby contributes to aging pigmentation. These data may promote the development of new therapeutic paradigms, such as a stroma-targeting therapy for pigmentary disorders.

653 New lipophilic pro-vitamin C, tetra-isopalmitoyl ascorbic acid (VC-IP), suppresses senile lentigo through controlling of melanocytes-keratinocytes interaction

Senile lentigo are hyperpigmented macules of skin that occur in irregular shapes, appearing most commonly in the sun-exposed areas of the skin such as on the face and back of the hands, and are a common component of photoaged skin. Vitamin C is well known to play an important role in maintaining skin physiology, especially as a skin whitening and blighting agent. We previously demonstrated that a new stable lipophilic pro-vitamin C derivative, tetra-isopalmitoyl ascorbic acid (VC-IP), showed significant suppressive effect for UVB-induced skin pigmentation by conversion into vitamin C in skin tissue. In addition, we reported that VC-IP showed multiple physiological activities represented by scavenging of ROS and reduction of inflammatory cytokines, IL-1α and PGE2, in keratinocytes. In this study, we evaluated that effectiveness of VC-IP on senile lentigo by conducting clinical test approved by the institutional ethical committee. VC-IP significantly improved brightness of aging spot and skin tone to evenness by mechanical measurements. Moreover, self-assessment study demonstrated that subjects were satisfied with the following parameters; appearance of aged spot, skin brightness, fading of dullness or yellowing and zero adverse reaction. Furthermore, we newly identified that VC-IP strongly suppressed the melanin delivery by inhibition of dendrite elongation stimulated by endothelin-1 in melanocytes-keratinocytes co-culture system. There are still many discussions on how senile lentigo represents in skin, however, these results suggested possibility that VC-IP is effective for improving hyperpigmented spot based on controlling of melanocytes-keratinocytes interaction.

794 Effect of a new lipophilic pro-vitamin C, tetra-isopalmitoyl ascorbic acid (VC-IP), on senile lentigo (aging spot) via controlling of melanocytes-keratinocytes interaction

Senile lentigo or aging spots are hyperpigmented macules of skin that occur in irregular shapes, appearing most commonly in the sun-exposed areas of the skin such as on the face and back of the hands, and are a common component of photoaged skin. Vitamin C is well known to play an important role in maintaining skin physiology, especially as a skin whitening and blighting agent. We previously demonstrated that a new stable lipophilic pro-vitamin C derivative, tetra-isopalmitoyl ascorbic acid (VC-IP), showed significant suppressive effect for UVB-induced skin pigmentation by conversion into vitamin C in skin tissue. In addition, we reported that VC-IP showed multiple physiological activities represented by scavenging of ROS and reduction of inflammatory cytokines, IL-1α and PGE2, in keratinocytes. In this study, we evaluated that effectiveness of VC-IP on senile lentigo (aging spot) by conducting clinical test approved by the institutional ethical committee. VC-IP significantly improved brightness of aging spot and skin tone to evenness by mechanical measurements. Moreover, self-assessment study demonstrated that subjects were satisfied with the following parameters; appearance of aged spot, skin brightness, fading of dullness or yellowing and zero adverse reaction. Furthermore, we newly identified that VC-IP strongly suppressed the melanin delivery by inhibition of dendrite elongation stimulated by endothelin-1 in melanocytes-keratinocytes co-culture system. There are still many discussions on how senile lentigo represents in skin, however, these results suggested possibility that VC-IP is effective for improving hyperpigmented spot based on controlling of melanocytes-keratinocytes interaction without any adverse reaction.