A New Generation of Postbiotics for Skin and Scalp: In Situ Production of Lipid Metabolites by Malassezia.

Effects of pre- and probiotics on intestinal health are well researched and microbiome-targeting solutions are commercially available. Even though a trend to appreciate the presence of certain microbes on the skin is seeing an increase in momentum, our understanding is limited as to whether the utilization of skin-resident microbes for beneficial effects holds the same potential as the targeted manipulation of the gut microflora. Here, we present a selection of molecular mechanisms of cross-communication between human skin and the skin microbial community and the impact of these interactions on the host's cutaneous health with implications for the development of skin cosmetic and therapeutic solutions. Malassezia yeasts, as the main fungal representatives of the skin microfloral community, interact with the human host skin via lipid mediators, of which several are characterized by exhibiting potent anti-inflammatory activities. This review therefore puts a spotlight on Malassezia and provides a comprehensive overview of the current state of knowledge about these fungal-derived lipid mediators and their capability to reduce aesthetical and sensory burdens, such as redness and itching, commonly associated with inflammatory skin conditions. Finally, several examples of current skin microbiome-based interventions for cosmetic solutions are discussed, and models are presented for the use of skin-resident microbes as endogenous bio-manufacturing platforms for the in situ supplementation of the skin with beneficial metabolites.

Age-dependent changes in skin features and perceived facial appearance in women of five ethnic groups.

OBJECTIVE: Research documents effects of skin features on assessments of age, health and attractiveness of female faces. Ethnic variation also has been reported for the impact of age-related changes in skin features on face assessments. Here, we investigate women's self-ratings across age cohorts and ethnic groups and discrepancies with (non-expert) assessor ratings of facial appearance together with age-dependent changes in skin features. METHODS: Faces of women 20-65 years from five ethnic groups (each n = 36) were imaged. Participants provided self-ratings of age, health and attractiveness, and were judged on these attributes by members of the same ethnic group (each n = 120). Digital image analysis was used to quantify skin gloss, tone evenness, wrinkling and sagging. Age-dependent changes in ratings and skin features within and between ethnic groups were assessed by comparing information from 10-year cohorts. We also tested whether menopausal status could be predicted by self-ratings, assessor ratings and image-based skin features. RESULTS: Women of all ethnic groups judged themselves younger and higher in attractiveness and health compared to third-party assessors, with the largest discrepancies for age in French women and for attractiveness and health in South African women. In Indian and South African women, specular gloss and skin tone evenness were lower compared to other participants, and sagging was higher in Indian, Japanese and South African women compared to Chinese and French women. Women's menopausal status could be predicted from assessor ratings and image-based skin features but not from self-ratings. CONCLUSION: There are differences between women's self-ratings and assessor ratings of facial appearance. These discrepancies vary with female age and ethnicity. Age and ethnicity effects also are evident in age-dependent changes in skin features within and across ethnic groups, which together with assessor (but not self-) ratings of facial appearance predict menopausal status.

OBJECTIF: l'étude documente les effets des caractéristiques de la peau sur les évaluations de l'âge, de la santé et de l'attractivité des visages féminins. Des variations ethniques ont également été rapportées en ce qui concerne l'impact des changements liés à l'âge dans les caractéristiques de la peau sur les évaluations du visage. Ici, nous étudions les auto­évaluations des femmes à travers les cohortes d'âge et les groupes ethniques et les divergences avec les évaluations (non expertes) de l'apparence du visage ainsi que les changements des caractéristiques de la peau dépendant de l'âge. MÉTHODES: les visages des femmes âgées de 20 à 65 ans issues de cinq groupes ethniques (chacun n = 36) ont été examinés par imagerie. Les participantes ont fourni des auto­évaluations de leur âge, de leur santé et de leur attractivité, et ont été jugées sur ces attributs par les membres du même groupe ethnique (chacun n = 120). L'analyse d'images numériques a été utilisée pour quantifier la luminosité de la peau, l'uniformité du teint, les rides et le relâchement cutané. Les changements dépendants de l'âge dans les évaluations et les caractéristiques de la peau au sein et entre les groupes ethniques ont été évalués en comparant les informations provenant de cohortes sur 10 ans. Nous avons également évalué si le statut ménopausique pouvait être prédit par les auto­évaluations, les évaluations de l'évaluateur et les caractéristiques de la peau basées sur l'imagerie. RÉSULTATS: les femmes de tous les groupes ethniques se sont jugées plus jeunes et plus performantes en termes d'attractivité et de santé par rapport aux évaluateurs tiers, les plus grandes discordances concernant l'âge chez les femmes françaises et l'attractivité et la santé chez les femmes sud­africaines. Chez les femmes indiennes et sud­africaines, la luminosité spéculaire et l'uniformité du teint de la peau étaient inférieures à celles des autres participantes, et le relâchement cutané était plus élevé chez les femmes indiennes, japonaises et sud­africaines que chez les femmes chinoises et françaises. Le statut ménopausique des femmes pouvait être prédit à partir des évaluations de l'évaluateur et des caractéristiques cutanées basées sur l'imagerie, mais pas à partir des auto­évaluations. CONCLUSION: il existe des différences entre les auto­évaluations des femmes et les évaluations de l'apparence faciale par l'évaluateur. Ces divergences varient en fonction de l'âge et de l'origine ethnique des femmes. Les effets sur l'âge et l'origine ethnique sont également évidents dans les changements dépendants de l'âge des caractéristiques de la peau au sein et entre les groupes ethniques, qui, avec les évaluations de l'évaluateur (mais pas de l'auto­évaluation) de l'apparence du visage, prédisent le statut ménopausique.

Menopause and facial skin microbiomes: a pilot study revealing novel insights into their relationship.

Introduction: The human skin microbial composition is affected by age. Previous studies reported skin microbiome diversity shifts between elderly and significantly younger subjects. Some studies implied that menopausal status, which is inherently linked to age, could be associated with changes in skin microbial compositions. Nevertheless, the influence of menopausal status on skin microbiome profiles while minimizing the impact of aging-associated changes in skin parameters still needs further clarification. Methods: We performed an observational study on healthy Caucasian female volunteers, which were grouped according to their pre- or postmenopausal status. Bacterial community structures on facial skin were analyzed using 16S rRNA gene sequencing. Cutometer® measurements were performed to evaluate aging-associated changes in facial skin biophysical properties. Results: The relative abundance of the lipophilic Cutibacterium genus was decreased, and bacterial diversity was increased in skin samples of postmenopausal volunteers. The mean age difference between examined groups in this study was 12.4 years only. Accordingly, Cutometer® measurements revealed no differences in aging-associated skin biophysical parameters between pre- and postmenopausal groups. Consequently, no correlation was detected between Shannon diversity and measured age-dependent biomechanical properties of facial skin. Discussion: These findings are in line with previous studies, which investigated the wide-ranging impact of chronological aging on skin microbial communities. However, this work reports for the first time a direct association between menopausal status and facial microbiomes on skin of similarly aged study participants, and hence uncouples aging-associated skin biophysical parameters, such as viscoelastic properties, from the equation. These findings open avenues for the development of microbiome-targeting strategies for treatment of menopause-associated skin disorders.

Predictors of female age, health and attractiveness perception from skin feature analysis of digital portraits in five ethnic groups.

OBJECTIVE: Research indicates the impact of skin colour, tone evenness and surface topography on ratings of age, health and attractiveness in women. In addition to subjective assessments, these effects have been quantified with objective measures derived from skin image analysis. Signs of skin ageing may manifest differently across ethnic groups. However, comparisons have been limited to research with two ethnic groups, preventing conclusions about an ethnicity-specific ranking of skin ageing signs. METHODS: We report results from a multi-ethnic and multi-centre study in which faces of women (n = 180; aged 20-69 years) from five ethnic groups were imaged. Facial images were rated for age, health and attractiveness by members of the same ethnic group (each n = 120). Digital image analysis was used to quantify skin colour, gloss, tone evenness and wrinkling/sagging. We assessed associations between face ratings and skin image measurements in the total sample (i.e. all ethnic groups) and separately by ethnicity. RESULTS: Skin image analysis revealed differences between ethnic groups, including skin colour, gloss, tone evenness, wrinkling and sagging. Differences in the relative predictive utility of individual skin features in accounting for ratings of age, health and attractiveness also were observed between ethnic groups. Facial wrinkling and sagging were the best predictors of face ratings in each ethnic group, with some differences in the type (or predictive magnitude) of skin features. CONCLUSION: The current findings corroborate previous reports of differences between ethnic groups in female facial skin and indicate differential effects of skin features on ratings of age, health and attractiveness, within and between ethnic groups. Facial wrinkling and sagging were the best predictors of age and attractiveness ratings, and skin tone evenness and gloss had an additional role in ratings of health.

OBJECTIF: La présente étude montre l'impact de la couleur de la peau, de l'uniformité du teint, et de la texture cutanée sur l'évaluation de l'âge, de la santé et de l'attractivité chez les femmes. En plus d'évaluations subjectives, ces aspects ont été quantifiés à l'aide de mesures objectives provenant d'analyse d'image de la peau. Les signes de vieillissement de la peau peuvent se manifester différemment selon les groupes ethniques. Cependant, les précédentes recherches se limitent à des comparaisons entre deux groupes ethniques, empêchant ainsi de conclure sur un classement des signes de vieillissement cutané par ethnie. MÉTHODE: Nous présentons les résultats d'une étude multiethnique et multicentrique dans laquelle des visages de femmes (n = 180 ; âgées de 20 à 69 ans) de cinq groupes ethniques ont été imagés. Les images des visages ont été évaluées en termes d'âge, de santé et d'attractivité par des membres du même groupe ethnique (n = 120 par groupe). Des algorithmes d'analyse d'image ont été utilisés pour quantifier la couleur de la peau, la brillance, l'uniformité du teint et les rides/affaissement de la peau. Nous avons analysé les corrélations entre l'évaluation des visages et les mesures quantitatives issues de l'analyse d'image sur la totalité de l'échantillon (c'est-à-dire tous les groupes ethniques) et séparément par ethnie. RÉSULTATS: L'analyse d'image a révélé des différences entre les groupes ethniques, notamment en ce qui concerne la couleur de la peau, la brillance, l'uniformité du teint, les rides et le relâchement cutané. Des différences dans la valeur prédictive relative des différentes caractéristiques cutanées dans l'évaluation de l'âge, de la santé et de l'attractivité ont également été observées entre les groupes ethniques. Les rides et l'affaissement du visage ressortent comme les meilleurs prédicteurs de l'évaluation pour tous les groupes ethniques, avec quelques différences dans le type (ou l'ampleur de la prédiction) des différentes caractéristiques cutanées. CONCLUSION: Les résultats actuels corroborent les rapports précédents sur les différences entre les groupes ethniques concernant la peau du visage des femmes. Ils montrent également des effets différentiels des caractéristiques cutanées sur l'évaluation de l'âge, de la santé et de l'attractivité, au sein des groupes ethniques et entre eux. Les rides et l'affaissement du visage ressortent comme les meilleurs prédicteurs de l'âge et de l'attractivité, tandis que l'uniformité et la brillance du teint jouent un rôle supplémentaire dans l'évaluation de la santé.

Saccharide isomerate ameliorates cosmetic scalp conditions in a Chinese study population.

BACKGROUND: Scalp conditions such as flaky or oily scalp affect people across ethnicities and age groups. In addition to flaking, increased sebum secretion, itching, and compromised scalp barrier function were described. Scalp conditions are aesthetically disturbing and may cause psychological distress in affected individuals who are looking for mild and effective treatment at the same time. Saccharide isomerate has a long history as a skin moisturizer, and it was found to improve skin barrier function, also suggesting possible beneficial effects on scalp. AIMS: To provide relevant claim substantiation to introduce saccharide isomerate as a new scalp care active against scalp flaking condition. MATERIAL AND METHODS: We conducted a placebo-controlled clinical study in an adult Chinese population affected by dandruff scalp as assessed by an adherent scalp flaking score. We monitored transepidermal water loss (TEWL), sebum secretion, and scalp flaking during 28 days. RESULTS: Formulations containing Saccharide isomerate significantly improved all parameters both over time as well as compared to the placebo formulation. CONCLUSION: We propose Saccharide isomerate for cosmetic formulations directed toward improving scalp conditions such as dandruff or oily scalp.

An extract of Leontopodium alpinum inhibits catagen development ex vivo and increases hair density in vivo.

OBJECTIVES: Hair loss and reduction in hair volume are hallmarks of hair disorders, such as telogen effluvium, or male or female pattern hair loss, and hair ageing, which can cause severe distress in both men and women. Common anti-hair loss drugs carry some side effects; therefore, novel, safer approaches targeting milder phenotypes are highly advocated. In this context, we investigated an extract of the alpine plant Edelweiss, Leontopodium alpinum var. Helvetia, for its ability to modulate hair follicle (HF) growth ex vivo and inhibit hair loss while increasing hair regeneration in vivo. METHODS: Human amputated HFs were microdissected from three donors, two women and one man, and cultured ex vivo for 6 days. After treatment with 0.001% Edelweiss extract (EWDE), we investigated hair shaft production and anagen/catagen conversion, and measured known parameters associated with hair growth, that is hair matrix keratinocyte proliferation and apoptosis, dermal papilla inductivity, and growth factors, by quantitative (immuno)histomorphometry. To assess the anti-hair loss potential of the alpine plant compound, we performed a randomized, placebo-controlled human study enrolling Caucasian women and men, aged 18 to 65 years, with normal hair loss. After 5 months' daily use of an extract containing leave-on serum, we analysed hair density and anagen-to-catagen/telogen ratio by the Trichogram analysis. RESULTS: Our results revealed a significant prolongation in the anagen phase in HFs treated with 0.001% Edelweiss, as indicated by an increase in HFs remaining in anagen and a significant decrease in hair cycle score. In line with this effect, EWDE significantly stimulated hair matrix (HM) keratinocyte proliferation, and dermal papilla inductivity, as shown by a significant up-regulation of versican expression and alkaline phosphatase activity, and a tendential increase in FGF7 immunoreactivity in the dermal papilla of all HFs or only anagen VI HFs. Corroborating the ex vivo results, we observed a significant increase in growing hair shaft numbers (hair density) after treatment with Edelweiss extract formulation, and a tendential up-regulation in the anagen-to-catagen/telogen ratio. CONCLUSIONS: We show here, through several lines of evidence, that the selected extract of the alpine plant Leontopodium alpinum var Helvetia (Edelweiss) inhibits premature catagen induction, possibly by stimulating dermal papilla inductivity. It is therefore worth exploiting this extract clinically as an anti-hair loss agent, both for preventing ageing-associated hair shedding and as an adjuvant therapy for hair loss disorders.

OBJECTIFS: La perte de cheveux et la réduction du volume des cheveux sont caractéristiques des troubles capillaires, tels que l'effluvium télogène, ou la calvitie chez l'homme ou la femme, et le vieillissement des cheveux, qui peuvent causer une certaine détresse chez les hommes et les femmes. Les médicaments courants contre la chute des cheveux ont des effets secondaires, par conséquent, de nouvelles approches plus sûres ciblant des phénotypes légers sont fortement recommandées. Dans ce contexte, nous avons étudié un extrait de la plante alpine Edelweiss, Leontopodium alpinum var. Helvetia, pour sa capacité à stimuler la croissance du follicule pileux (HF) ex vivo et à inhiber la chute des cheveux tout en augmentant la régénération des fibres capillaires in vivo. MÉTHODES: Les follicules pileux (HF) humains prélevés ont été microdisséqués chez trois donneurs, deux femmes et un homme, et cultivés ex vivo pendant 6 jours. Après le traitement avec l'extrait d'Edelweiss à 0,001 % (EWDE), nous avons étudié la production de fibre capillaire et la conversion anagène/catagène, ainsi que mesuré les paramètres connus associés à la croissance des cheveux, à savoir, la prolifération des kératinocytes dans la matrice capillaire et l'apoptose, l'induction des papilles dermiques, et des facteurs de croissance, par (immuno-)histomorphométrie quantitative. Pour évaluer le potentiel des propriétés anti-chute du cheveu de l'extrait de plante alpine, nous avons réalisé une étude clinique aléatoire avec placebo, sur des femmes et des hommes de type caucasien âgés de 18 à 65 ans présentant une perte de cheveux normale. Après cinq mois d'utilisation quotidienne d'un sérum sans rinçage contenant l'extrait de plante, nous avons analysé la densité capillaire et le rapport anagène à catagène/télogène par trichogramme. RÉSULTATS: Nos résultats ont révélé une prolongation significative de la phase anagène dans les HF traités avec 0,001% d'Edelweiss, comme l'indique une augmentation des HF restant en phase anagène et une diminution significative du « hair cycle score ¼. En ligne avec cet effet, EWDE a stimulé de façon significative la matrice du cheveux (HM), la prolifération des kératinocytes, et l'induction de la papille dermique, comme le montre une augmentation significative de l'expression du versican et de l'activité de la phosphatase alcaline, et une augmentation tendancielle de l'immunoréactivité FGF7 dans la papille dermique de tous les HF ou seulement des HF anagènes VI. Corroborant les résultats ex vivo, nous avons observé une augmentation significative du nombre de fibres capillaires (densité de cheveux) après le traitement avec la formulation d'extrait d'Edelweiss, et une augmentation tendancielle dans le rapport anagène à catagène/télogène. CONCLUSIONS: Nous montrons ici, à travers plusieurs éléments de preuve, que l'extrait sélectionné de la plante alpine Leontopodium alpinum var Helvetia (Edelweiss) inhibe l'induction prématurée de la phase catagène, en stimulant la papille dermique. Il est donc possible d'utiliser cet extrait comme un agent anti-chute, à la fois pour prévenir la chute des cheveux associée au vieillissement mais aussi comme une thérapie complémentaire pour les troubles liés à la perte des cheveux.

Discovery of a Highly Selective MC1R Agonists Pentapeptide to Be Used as a Skin Pigmentation Enhancer and with Potential Anti-Aging Properties.

One of the first lines of cutaneous defense against photoaging is a) the synthesis of melanin and b) the initiation of an oxidative stress response to protect skin against the harmful effects of solar radiation. Safe and selective means to stimulate epidermal pigmentation associated with oxidative stress defense are; however, scarce. Activation of the melanocortin-1 receptor (MC1R) on epidermal melanocytes represents a key step in cutaneous pigmentation initiation and, additionally, it regulates cellular defense mechanisms like oxidative stress and DNA-repair. Thus, making the activation of MC1R an attractive strategy for modulating skin pigmentation and oxidative stress. In this context, we designed and synthesized pentapeptides that act as MC1R agonists. These peptides bound, with high potency, to MC1R and activated cAMP synthesis in CHO cells expressing human MC1R. Using one lead pentapeptide, we could show that this activation of MC1R was specific as testing the activation of other G-protein coupled receptors, including the MC-receptor family, was negative. In vitro efficacy on mouse melanoma cells showed similar potency as for the synthetic MC1R agonist alpha-melanocyte stimulating hormone (NDP-alpha-MSH). Moreover, we could reproduce this activity in human skin tissue culture. The lead pentapeptide was able to induce ex-vivo protein expression of key melanogenesis markers melanocyte inducing transcription factor (MITF), tyrosinase (TYR), and tyrosinase-related protein 1 (TYRP-1). Concerning oxidative stress response, we found that the pentapeptide enhanced the activation of Nrf2 after UVA-irradiation. Our results make this pentapeptide an ideal candidate as a skin pigmentation enhancer that mimics alpha-MSH and may also have anti-photoaging effects on the skin.

Effects of the selective TrkA agonist gambogic amide on pigmentation and growth of human hair follicles in vitro.

The human hair follicle is a neuroendocrine mini-organ that can be used to study aging processes in vitro. Neurotrophins maintain homeostasis in hair biology via the Trk-family of receptors. TrkA, the high affinity receptor for nerve growth factor (NGF), is expressed in hair follicle melanocytes and keratinocytes, where it regulates proliferation, differentiation and apoptosis and may thereby play a role in hair pigmentation and growth. We investigated TrkA expression during the human hair cycle and the effects of a selective high affinity TrkA agonist, Gambogic Amide, on hair pigmentation and hair growth in human hair follicles in vitro. In human scalp skin, TrkA expression was strongest in proliferating melanocytes re-establishing the pigmentary unit in the hair bulb during the early hair growth phase, anagen. During high anagen and in the de-composing pigmentary-unit of the regression phase, catagen, bulb-melanocytes lost TrkA expression and only undifferentiated outer root sheath melanocytes maintained it. In cultured human anagen hair follicles, Gambogic Amide was able to prevent gradual pigment loss, while it stimulated hair shaft elongation. This was achieved by increased melanocyte activation, migration and dendricity, highlighted by distinct c-KIT-expression in melanocyte sub-populations. Our results suggest that Gambogic Amide can maintain hair follicle pigmentation by acting on undifferentiated melanocytes residing in the outer root sheath and making them migrate to establish the pigmentary-unit. This suggests that the selective TrkA agonist Gambogic Amide acts as an anti-hair greying and hair growth promoting molecule in vitro.

Appearance of aging signs in differently pigmented facial skin by a novel imaging system.

BACKGROUND: Facial wrinkles, pores, and uneven skin tone are major beauty concerns. There is differential manifestation of aging signs in different ethnic groups. In this regard, studies on Black Africans from the African continent are scarce. OBJECTIVE: To investigate facial wrinkles, pores, and skin tone in Black African women from Mauritius Island and elucidate the differences to Caucasian women from France. METHODS: Facial images were taken using the imaging system ColorFace® . Wrinkles and pores were measured by their length, depth, surface, volume, and number; for skin tone, we measured L*a*b* and calculated ITA, IWANewtone , and color homogeneity. RESULTS: We found good correlations of wrinkle and pore scores with expert ranking done on ColorFace® images for Caucasians (Spearman's rho = 0.78 and 0.72) and Black Africans (Spearman's rho = 0.86 and 0.65). Caucasians showed more advanced facial signs of aging than Black Africans. Exceptions were vertical lines on upper lip and the depth of pores which were greatest for the Black African subjects. Black Africans had higher heterogeneity scores indicative for uneven skin tone. Luminance (L*) was significantly higher in Caucasians but a* and b* values were significantly higher in the Black African subjects. ITA and IWANewtone were significantly higher for Caucasians. CONCLUSIONS: The high correlation between expert ranking and wrinkle and pore measurements prove ColorFace® a valid imaging system to study skin aging. Our results show that Africans from the African continent show delayed signs of aging compared to Caucasians. Some exceptions suggest that ethnic differences in facial aging are a complex phenomenon.

Design, synthesis, and biological evaluation of novel selective peptide inhibitors of 11ß-hydroxysteroid dehydrogenase 1.

The enzyme 11ß-HSD1 plays a crucial role in the tissue-specific regulation of cortisol levels and it has been associated with various diseases. Inhibition of 11ß-HSD1 is an attractive intervention strategy and the discovery of novel selective 11ß-HSD1 inhibitors is of high relevance. In this study, we identified and evaluated a new series of selective peptide 11ß-HSD1 inhibitors with potential for skin care applications. This novel scaffold was designed with the aid of molecular modeling and two previously reported inhibitors. SAR optimization yielded highly active peptides (IC50 below 400 nM) that were inactive at 1 µM concentration against structurally related enzymes (11ß-HSD2, 17ß-HSD1 and 17ß-HSD2). The best performing peptides inhibited the conversion of cortisone into cortisol in primary human keratinocytes and the most active compound, 5d, was further shown to reverse cortisone-induced collagen damage in human ex-vivo tissue.

Novel 11ß-hydroxysteroid dehydrogenase 1 inhibitors reduce cortisol levels in keratinocytes and improve dermal collagen content in human ex vivo skin after exposure to cortisone and UV.

Activity and selectivity assessment of new bi-aryl amide 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) inhibitors, prepared in a modular manner via Suzuki cross-coupling, are described. Several compounds inhibiting 11ß-HSD1 at nanomolar concentrations were identified. Compounds 2b, 3e, 7b and 12e were shown to selectively inhibit 11ß-HSD1 over 11ß-HSD2, 17ß-HSD1 and 17ß-HSD2. These inhibitors also potently inhibited 11ß-HSD1 activity in intact HEK-293 cells expressing the recombinant enzyme and in intact primary human keratinocytes expressing endogenous 11ß-HSD1. Moreover, compounds 2b, 3e and 12e were tested for their activity in human skin biopsies. They were able to prevent, at least in part, both the cortisone- and the UV-mediated decreases in collagen content. Thus, inhibition of 11ß-HSD1 by these compounds can be further investigated to delay or prevent UV-mediated skin damage and skin aging.

Profiling mRNA of the graying human hair follicle constitutes a promising state-of-the-art tool to assess its aging: an exemplary report.

Determining hitherto uninvestigated and safe targets to halt the aging process is important in our aging society. Graying is a hallmark of the aging process and may be used to identify aging tissue for comparative analysis. Here we analyzed differential gene expressions between pigmented, gray, and white human scalp skin hair follicles (HFs) from identical donors. Forming intersections between five donors identified 194/192 downregulated and 186/177 upregulated genes in gray/white HFs. These included melanogenesis (tyrosinase; tyrosinase-related protein 1)- and melanosome structure (Melan-A; Pmel17)-associated genes and regulation of melanocyte relevant tyrosine kinases. Alongside these expected changes, regulated genes included nonmelanocyte-related genes associated with aging as well as nonaging-related genes associated with melanocytes. Intriguingly, among them, genes associated with energy metabolism (i.e., glutaminase) and axon guidance (plexin C1) were altered. These results were reflected by pathway analysis and exemplarily confirmed by PCR and immunohistochemical studies. Supplementing cultured HFs with glutamine or plexin C1 revealed biological relevance and pharmacointerventional potential of these microarray results in altering the HF aging process. Together, we present intriguing data obtained from intra-individual sample comparison that suggest the graying HF to be a valid aging model and a promising target for testing therapeutic interventions.