Topical application of retinyl propionate, 4 hexyl resorcinol, and niacinamide reverses molecular and clinical features of ageing.

OBJECTIVE: Topical tretinoin is the mainstay of treatment for photoageing, despite the risk of skin irritation. Cosmetic combination anti-ageing formulations may offer similar efficacy to tretinoin, while improving on tolerability. We aim to demonstrate facial appearance benefits of a novel triple-active cosmetic formulation containing 4-hexylresorcinol, retinyl propionate, and niacinamide and to identify transcriptomic biomarkers underpinning these benefits. METHODS: A cosmetic prototype formulation containing 4-hexylresorcinol, retinyl propionate, and niacinamide was evaluated ex vivo and in a clinical study. For ex vivo experiments, the cosmetic formulation was applied for 3 days to healthy surgical discard skin from female donors aged 31-51 years, with tissues harvested for gene expression and histologic analyses. In the clinical study, females aged 47-66 years with moderate-to-severe overall visual photodamage on the face applied either topical 0.02% tretinoin or the cosmetic formulation to the face for 16 weeks and to forearms for 1 week, with forearm biopsies taken for gene expression analyses. Visual grading for facial photodamage and VISIA-CR images was taken throughout the clinical study. Safety was visually assessed during site visits, and adverse event monitoring was conducted throughout. RESULTS: Gene expression analyses in both studies revealed modulation of pathways associated with skin rejuvenation, with several genes of interest identified due to being implicated in ageing and differentially expressed following the application of the cosmetic formulation. Reversal of a consensus skin ageing gene signature was observed with the cosmetic formulation and tretinoin in the ex vivo and clinical studies. Both the cosmetic formulation and tretinoin clinically improved the overall appearance of photoageing, crow's feet, lines, wrinkles, and pores. Adverse event reporting showed that the cosmetic formulation caused less skin irritation than tretinoin. CONCLUSION: In a double-blind clinical study, the novel triple-active cosmetic combination formulation improved the visual appearance of photoageing similarly to prescription tretinoin. The cosmetic formulation and tretinoin reversed a consensus gene signature associated with ageing. Together with adverse event reporting, these results suggest that the cosmetic formulation may be a well-tolerated and efficacious alternative to tretinoin for improving the visual features of photoageing.

OBJECTIF: Le trétinoine topique est le pilier du traitement du photovieillissement, malgré le risque d'irritation cutanée. Les formulations cosmétiques combinés anti­âge peuvent offrir une efficacité similaire à la trétinoine, tout en améliorant la tolérance. Notre objectif est de démontrer les avantages esthétiques pour l'apparence du visage d'une nouvelle formulation cosmétique triple active contenant du 4­hexylrésorcinol, du rétinyl propionate et de la niacinamide, et d'identifier les biomarqueurs transcriptomiques sous­jacents à ces avantages. MÉTHODES: Une formulation cosmétique prototype contenant du 4­hexylrésorcinol, du rétinyl propionate et de la niacinamide a été évaluée ex vivo et lors d'une étude clinique. Pour les expériences ex vivo, la formulation cosmétique a été appliquée pendant 3 jours sur des peaux saines issues de donatrices âgées de 31 à 51 ans, avec prélèvement de tissus pour l'analyse de l'expression génique et l'histologie. Dans l'étude clinique, des femmes âgées de 47 à 66 ans présentant un photovieillissement visuel global modéré a sévère sur le visage ont appliqué soit du trétinoine topique à 0.02%, soit la formulation cosmétique sur le visage pendant 16 semaines et sur les avant­bras pendant 1 semaine, avec des biopsies d'avant­bras prélevées pour l'analyse de l'expression génique. L'évaluation visuelle du photovieillissement facial et les images VISIA­CR ont été réalisées tout au long de l'étude clinique. La sécurité a été évaluée visuellement lors des visites sur site, et une surveillance des événements indésirables a été effectuée. RÉSULTATS: Les analyses de l'expression génique dans les deux études ont révélé une modulation des voies associées au rajeunissement cutané, avec plusieurs gènes d'intérêts identifiés en raison de leur implication dans le vieillissement et de leur expression différentielle suite à l'application de la formulation cosmétique. Une inversion de la signature génique du vieillissement cutané consensuelle a été observée avec la formulation cosmétique et la trétinoine dans les études ex vivo et cliniques. La formulation cosmétique et la trétinoine ont toutes deux amélioré cliniquement l'apparence globale du photovieillissement, des pattes d'oie, des ridules, des rides et des pores. Les rapports sur les événements indésirables ont montré que la formulation cosmétique provoquait moins d'irritation cutanée que la trétinoine. CONCLUSION: Dans une étude clinique en double aveugle, la nouvelle formulation cosmétique triple active a amélioré l'apparence visuelle du photovieillissement de manière similaire à la trétinoine sur ordonnance. La formulation cosmétique et la trétinoine ont inversé une signature génique consensuelle associée au vieillissement. En tenant compte des rapports sur les événements indésirables, ces résultats suggèrent que la formulation cosmétique pourrait constituer une alternative bien tolérée et efficace à la trétinoine pour améliorer les caractéristiques visuelles du photovieillissement.

Nicotinamide effects on the metabolism of human fibroblasts and keratinocytes assessed by quantitative, label-free fluorescence imaging.

Alterations in metabolism are central to the aging process. Therefore, understanding the subcellular functional and structural changes associated with metabolic aging is critical. Current established methods for exploring cell metabolism either require the use of exogenous agents or are destructive to the tissue or cells. Two-photon excited fluorescence (TPEF) imaging has emerged as a method for monitoring subtle metabolic changes non-invasively. In this study, we use TPEF imaging to acquire high-resolution fluorescence images from two coenzymes, NAD(P)H (reduced form of nicotinamide adenine dinucleotide) and FAD (flavin adenine dinucleotide), within human fibroblasts and keratinocytes in response to B3 (a nicotinamide precursor) supplementation and/or UV irradiation, without addition of exogenous labels. In addition, multi-parametric analysis methods are used to extract functional information of cellular metabolism, including cellular redox state, NAD(P)H fluorescence lifetime, and mitochondrial organization. Our results demonstrate that such optical metabolic assessments can serve as sensitive, label-free, non-destructive reporters of known effects of B3 to maintain and in some cases even enhance the respiratory function of mitochondria, while lowering oxidative damage. Thus, TPEF imaging, supported by highly-quantitative analysis, can serve as a tool to understand aging-dependent metabolic changes as well as the effect of actives on human epidermal and dermal cells.

The t(8;21) fusion protein, AML1 ETO, specifically represses the transcription of the p14(ARF) tumor suppressor in acute myeloid leukemia.

The t(8;21) is one of the most frequent chromosomal translocations associated with acute leukemia. This translocation creates a fusion protein consisting of the acute myeloid leukemia-1 transcription factor and the eight-twenty-one corepressor (AML1 ETO), which represses transcription through AML1 (RUNX1) DNA binding sites and immortalizes hematopoietic progenitor cells. We have identified the p14(ARF) tumor suppressor, a mediator of the p53 oncogene checkpoint, as a direct transcriptional target of AML1 ETO. AML1 ETO repressed the p14(ARF) promoter and reduced endogenous levels of p14(ARF) expression in multiple cell types. In contrast, AML1 stimulated p14(ARF) expression and induced phenotypes consistent with cellular senescence. Chromatin immunoprecipitation assays demonstrated that AML1 ETO was specifically bound to the p14(ARF) promoter. In acute myeloid leukemia samples containing the t(8;21), levels of p14(ARF) mRNA were markedly lower when compared with other acute myeloid leukemias lacking this translocation. Repression of p14(ARF) may explain why p53 is not mutated in t(8;21)-containing leukemias and suggests that p14(ARF) is an important tumor suppressor in a large number of human leukemias.