Acitretin-Induced Repigmentation of Gray Hair: A Case Report.

Acitretin is an oral retinoid with alopecia as a possible adverse effect. However, repigmentation of the hair color after acitretin is not a well-documented phenomenon. Herein, we introduce a case where a patient's hair color darkened after a course of acitretin.

Premature gray hair development in the interbrow region owing to the loss of maxillary first molars in young mice.

The exact sites of premature hair graying and whether tooth loss causes this condition remain unknown. In this study, we aimed to explore the effect of reduced mastication on premature hair graying. Maxillary first molars were extracted from young mice, and the mice were observed for 3 months, along with non-extraction control group mice. After 3 months, gray hair emerged in the interbrow region of mice in the tooth extraction group but not in the control group. The expression of tyrosinase-related protein-2 (TRP-2) mRNA was lower in the interbrow tissues of young mice without maxillary molars than in those with maxillary molars. Tooth loss leads to interbrow gray hair growth, possibly because of weakened trigeminal nerve input, suggesting that reduced mastication causes premature graying. Thus, prompt prosthetic treatment after molar loss is highly recommended.

Irradiation-induced hair graying in mice: an experimental model to evaluate the effectiveness of interventions targeting oxidative stress, DNA damage prevention, and cellular senescence.

Hair graying, also known as canities or achromotrichia, is a natural phenomenon associated with aging and is influenced by external factors such as stress, environmental toxicants, and radiation exposure. Understanding the mechanisms underlying hair graying is an ideal approach for developing interventions to prevent or reverse age-related changes in regenerative tissues. Hair graying induced by ionizing radiation (γ-rays or X-rays) has emerged as a valuable experimental model to investigate the molecular pathways involved in this process. In this review, we examine the existing evidence on radiation-induced hair graying, with a particular focus on the potential role of radiation-induced cellular senescence. We explore the current understanding of hair graying in aging, delve into the underlying mechanisms, and highlight the unique advantages of using ionizing-irradiation-induced hair graying as a research model. By elucidating the molecular pathways involved, we aim to deepen our understanding of hair graying and potentially identify novel therapeutic targets to address this age-related phenotypic change.

Signaling pathways in hair aging.

Hair follicle (HF) homeostasis is regulated by various signaling pathways. Disruption of such homeostasis leads to HF disorders, such as alopecia, pigment loss, and hair aging, which is causing severe health problems and aesthetic concerns. Among these disorders, hair aging is characterized by hair graying, hair loss, hair follicle miniaturization (HFM), and structural changes to the hair shaft. Hair aging occurs under physiological conditions, while premature hair aging is often associated with certain pathological conditions. Numerous investigations have been made to determine the mechanisms and explore treatments to prevent hair aging. The most well-known hypotheses about hair aging include oxidative stress, hormonal disorders, inflammation, as well as DNA damage and repair defects. Ultimately, these factors pose threats to HF cells, especially stem cells such as hair follicle stem cells, melanocyte stem cells, and mesenchymal stem cells, which hamper hair regeneration and pigmentation. Here, we summarize previous studies investigating the above mechanisms and the existing therapeutic methods for hair aging. We also provide insights into hair aging research and discuss the limitations and outlook.

Dietary Restriction Delays But Cannot Heal Irradiation-Induced Hair Graying by Preserving Hair Follicle Stem Cells in Quiescence.

DNA damage represents one of the cell intrinsic causes of stem cell aging, which leads to differentiation-induced removal of damaged stem cells in skin and blood. Dietary restriction (DR) retards aging across various species, including several strains of laboratory mice. Whether, DR has the potential to ameliorate DNA damage-driven stem cell exhaustion remains incompletely understood. In this study, we show that DR strongly extends the time to hair graying in response to γ-irradiation (ionizing radiation [IR])-induced DNA damage of C57BL/6 J mice. The study shows that DR prolongs resting phase of hair follicles. DR-mediated prolongation of hair follicle stem cell (HFSC) quiescence blocks hair growth and prevents the depletion of HFSCs and ckit+ melanoblasts in response to IR. However, prolongation of HFSC quiescence also correlates with a suppression of DNA repair and cannot prevent melanoblast loss and hair graying in the long run, when hair cycling is reinitiated even after extended periods of time. Altogether, these results support a model indicating that nutrient deprivation can delay but not heal DNA damage-driven extinction of melanoblasts by stalling HFSCs in a prolonged state of quiescence coupled with inhibition of DNA repair. Disconnecting these two types of responses to DR could have the potential to delay stem cell aging.

Natural product rhynchophylline prevents stress-induced hair graying by preserving melanocyte stem cells via the ß2 adrenergic pathway suppression.

Norepinephrine (NA), a stress hormone, can accelerate hair graying by binding to ß2 adrenergic receptors (ß2AR) on melanocyte stem cells (McSCs). From this, NA-ß2AR axis could be a potential target for preventing the stress effect. However, identifying selective blockers for ß2AR has been a key challenge. Therefore, in this study, advanced computer-aided drug design (CADD) techniques were harnessed to screen natural molecules, leading to the discovery of rhynchophylline as a promising compound. Rhynchophylline exhibited strong and stable binding within the active site of ß2AR, as verified by molecular docking and dynamic simulation assays. When administered to cells, rhynchophylline effectively inhibited NA-ß2AR signaling. This intervention resulted in a significant reduction of hair graying in a stress-induced mouse model, from 28.5% to 8.2%. To gain a deeper understanding of the underlying mechanisms, transcriptome sequencing was employed, which revealed that NA might disrupt melanogenesis by affecting intracellular calcium balance and promoting cell apoptosis. Importantly, rhynchophylline acted as a potent inhibitor of these downstream pathways. In conclusion, the study demonstrated that rhynchophylline has the potential to mitigate the negative impact of NA on melanogenesis by targeting ß2AR, thus offering a promising solution for preventing stress-induced hair graying.

Recent omics advances in hair aging biology and hair biomarkers analysis.

Aging is a complex natural process that leads to a decline in physiological functions, which is visible in signs such as hair graying, thinning, and loss. Although hair graying is characterized by a loss of pigment in the hair shaft, the underlying mechanism of age-associated hair graying is not fully understood. Hair graying and loss can have a significant impact on an individual's self-esteem and self-confidence, potentially leading to mental health problems such as depression and anxiety. Omics technologies, which have applications beyond clinical medicine, have led to the discovery of candidate hair biomarkers and may provide insight into the complex biology of hair aging and identify targets for effective therapies. This review provides an up-to-date overview of recent omics discoveries, including age-associated alterations of proteins and metabolites in the hair shaft and follicle, and highlights the significance of hair aging and graying biomarker discoveries. The decline in hair follicle stem cell activity with aging decreased the regeneration capacity of hair follicles. Cellular senescence, oxidative damage and altered extracellular matrix of hair follicle constituents characterized hair follicle and hair shaft aging and graying. The review attempts to correlate the impact of endogenous and exogenous factors on hair aging. We close by discussing the main challenges and limitations of the field, defining major open questions and offering an outlook for future research.

Genetics of hair graying with age.

Hair graying is an early and obvious phenotypic and physiological trait with age in humans. Several recent advances in molecular biology and genetics have increased our understanding of the mechanisms of hair graying, which elucidate genes related to the synthesis, transport, and distribution of melanin in hair follicles, as well as genes regulating these processes above. Therefore, we review these advances and examine the trends in the genetic aspects of hair graying from enrichment theory, Genome-Wide association studies, whole exome sequencing, gene expression studies, and animal models for hair graying with age, aiming to overview the changes in hair graying at the genetic level and establish the foundation for future research. Meanwhile, by summarizing the genetics, it's of great value to explore the possible mechanism, treatment, or even prevention of hair graying with age.

Regulatory Effects of Thai Rice By-Product Extracts from Oryza sativa L. cv. Bue Bang 3 CMU and Bue Bang 4 CMU on Melanin Production, Nitric Oxide Secretion, and Steroid 5α-Reductase Inhibition.

Alopecia and gray hair are common hair abnormalities affecting physical appearance and causing psychological problems. Chemical treatments partially restore hair disorders but have distressing side effects. Bioactive plant compounds constitute promising sources of potential medicinal substances instead of chemical agents, producing high side effects. In this study, we focused on the waste of local rice cultivars: Bue Bang 3 CMU (BB3CMU) and Bue Bang 4 CMU (BB4CMU) from the north of Thailand. The rice bran oil (RBO), defatted rice bran extract (DFRB), and rice husk (H) were determined for in vitro hair revitalization in melanin production, nitric oxide (NO) secretion, and steroid 5α-reductase inhibition. The results indicated that BB4CMU-RBO with high contents of iron, zinc, and free fatty acids showed a comparable induction of melanin production on melanocytes (130.18 ± 9.13% of control) to the standard drug theophylline with no significant difference (p > 0.05). This promising melanin induction could be related to activating the NO secretion pathway, with the NO secretion level at 1.43 ± 0.05 µM. In addition, BB4CMU-RBO illustrated a significant inhibitory effect on both steroid 5α-reductase genes (SRD5A) type 1 and type 2, which relates to its primary source of tocopherols. Hence, rice bran oil from the Thai rice variety BB4CMU could be applied as a promising hair revitalizing candidate, from natural resources, to help promote hair growth and re-pigmentation effects.

Melanocyte stem cells and hair graying.

OBJECTIVES: To explore the relationship between melanocyte stem cells in the hair follicle bulge and hair graying so as to fully understand their key role in the pathogenesis of hair graying. METHODS: The published articles about "hair graying, hair color, pigmentation disorders" and "melanocyte stem cells, melanocyte" were searched and analyzed in PubMed to explore their relationship. RESULTS: Melanocytes in hair bulb are involved in the pathogenesis of hair graying as well as the melanocyte stem cells in hair follicle bulge also play important roles in the formation of hair graying through some ways. CONCLUSION: Loss of melanocyte stem cells in hair follicle bulge is one of the main reasons of hair graying, and more researches are needed to explain the underlying mechanisms of ectopic differentiation of melanocyte stem cells in different individual.

Cerebrolysin induces hair repigmentation associated to MART-1/Melan-A reactivation.

Hair graying, a prototypical sign of human aging, is a progressive loss of pigmentation from growing hair shafts caused by disease and as a side effect of medications. Cerebrolysin is a neuropeptide preparation that mimics the effect of endogenous neurotrophic factors. Cerebrolysin has been widely used in neurologic conditions, such as cerebral stroke, Alzheimer's disease, and dementia, among others. Cerebrolysin treatment has achieved to regain or maintain the cognitive ability of affected patients; however, up to date, there are no reports about the reactivation of hair pigmentation. We describe a previously not described effect occurring on patients receiving Cerebrolysin treatment for neurologic diseases and whether this effect is associated in reactivation of melanocytes and melanin expression. Here, we report five patients (mean age, 70.6 years), who also had age-related hair graying and scalp hair repigmentation during Cerebrolysin treatment. Macroscopic analysis revealed hair repigmentation consisted in diffuse darkening of the scalp hair. Impregnation and immunostaining analysis were performed on scalp biopsies taken before and after Cerebrolysin treatment; the results showed greater melanin and melanocyte marker MART-1/Melan-A staining following Cerebrolysin treatment. We present, to our knowledge, the first report on hair repigmentation is a previously not described effect occurring following Cerebrolysin treatment.

Hair Graying Regulators Beyond Hair Follicle.

Hair graying is an interesting physiological alteration associated with aging and certain diseases. The occurrence is due to depigmentation of the hair caused by depletion and dysfunction of melanocyte stem cells (MeSCs). However, what causes the depletion and dysfunction of MeSCs remains unclear. MeSCs reside in the hair follicle bulge which provides the appropriate niche for the homeostasis of various stem cells within hair follicle including MeSCs. In addition to local signaling from the cells composed of hair follicle, emerging evidences have shown that nerves, adipocytes and immune cells outside of hair follicle per se also play important roles in the regulation of MeSCs. Here, we review the recent studies on different cells in the MeSCs microenvironment beyond the hair follicle per se, discuss their function in regulating hair graying and potentially novel treatments of hair graying.

Fuzhuan Brick Tea Boosts Melanogenesis and Prevents Hair Graying through Reduction of Oxidative Stress via NRF2-HO-1 Signaling.

The anti-graying effect of the hexane fraction of Fuzhuan brick tea is investigated in Melan-A cells and C57BL/6 mice. As a result, it is found that reactive oxygen species-induced damage is associated with the reduction of melanogenesis in hair bulb melanocytes when reactive oxygen species generation in Melan-A cells occurred. The results revealed that the hexane fraction of Fuzhuan brick tea could remarkably reduce reactive oxygen species generation in Melan-A cells; meanwhile, it could increase the cellular tyrosinase and melanin content, as well as up-regulate the expression of tyrosinase, tyrosinase related protein-1, tyrosinase related protein-2, and microphthalmia-associated transcription factor, and activate the MAP-kinase pathway through activating the phosphorylation of p38 c-Jun N terminal kinase/extracellular signal-regulated kinase. Furthermore, high-pressure liquid chromatography analysis reveals that the tea's major ingredients in hexane fraction include gallic acid, theaflavin, theobromine, caffeine, epicatechin, and quercetin. Together, the current results suggest that Fuzhuan brick tea proves to protect from the damage of hydroquinone, which induces hair pigment loss.

Reversal of Premature Hair Graying Treated with a Topical Formulation Containing α-Melanocyte-Stimulating Hormone Agonist (Greyverse Solution 2%).

With aging, hair graying is a common sign resulting from complex regulation of melanogenesis. Multiple factors control the stimulation of melanogenesis at the level of the hair follicle, including melanin-stimulating hormone (MSH), adrenocorticotropic hormone, endothelin-1, prostaglandins, leukotrienes, neutrophils, fibroblast growth factor, nitric oxide, catecholamines, Vitamins, and minerals. Premature hair graying (PHG) has a major impact on the cosmesis, self-credibility, and social life of the affected individual. Currently, there is no medical treatment available for PHG. We present a case of a 25-year-old female with a history of graying of hair on the scalp. Clinical diagnosis revealed it as a case of premature graying/canities. She was prescribed a topical formulation (Greyverse solution) containing palmitoyl tetrapeptide 20, a biomimetic biopeptide of α-MSH for treating her PHG. The formulation was applied 1 mL twice daily directly on the affected part of the scalp. Hair supplements containing a combination of biotin and calcium pantothenate once daily orally were also prescribed. After 3 months, the patient showed some improvement, and the dose of the topical solution was reduced to 1 mL once daily. After 5 months, the patient achieved >90% conversion of gray hair to black hair.

Melanogenesis Markers Expression in Premature Graying of Hair: A Cross-Sectional Study.

BACKGROUND: Studies on mice and aging human hair follicles provide compelling evidence that graying of hair results from premature differentiation of melanocyte stem cells in the niche/bulge. OBJECTIVE: The aim of this study was to analyze whether differentiation of melanocyte stem cells is responsible for premature graying of hair (PGH). METHODS: Twenty-five patients with PGH (n = 25) attending the dermatology department were recruited. Five unpigmented and 5 pigmented hairs were obtained per patient by separating individual follicles after 1 mm punch biopsies. The hairs were dissected at a distance of 2 mm from the bulb to separate the stem cells (upper segment - US) from the melanocytes (lower segment - LS). RNA was extracted from hair follicle US and LS, and expression of GP100, tyrosinase (TYR), and tyrosinase-related protein-1 (TYRP1) genes was quantified using Qiagen one-step RT-PCR kit. RESULTS: We found melanogenesis gene expression in both temporary (US) and permanent (LS) segments of unpigmented and pigmented hair follicles. When compared between the US and LS of white hair, the expression of TYR and GP100 was much higher in US than LS, suggestive of melanogenesis in the bulge. Similarly, when compared between white and black US, the expression of all 3 genes was higher in white US than black US, although not statistically significant. LIMITATIONS: Low samples size and lack of data pertaining to the expression of genes at protein level are the limitations of current study. CONCLUSION: Even though this pilot study data yielded key information about the expression of GP100, TYR, and TYRP-1 at the mRNA level, further studies quantifying the expression of these genes at protein level are needed to provide additional clues to further address the results in detail.

The Effects of Smoking on Hair Health: A Systematic Review.

Smoking is not only a preventable cause of significant systemic disease but also affects the follicular growth cycle and fiber pigmentation. Ambient tobacco smoke exposure results in nicotine accumulation in hair follicles and the hair shaft. This review summarizes the evidence on the association between smoking and hair health, as denoted by alopecia and premature hair graying (PHG). In July 2020, a review of the literature using PubMed/MEDLINE and CINAHL databases identified 32 studies investigating the relationship between smoking, PHG, and alopecia (androgenetic alopecia and frontal fibrosing alopecia). The prevalence of hair loss and PHG is more prevalent in smokers than nonsmokers. Smoking is associated with negative effects on hair health as evidenced in PHG and alopecia. Smoking status should be assessed in patients who are presenting to their dermatologist for evaluation of alopecia and PHG.

Epidemiological and biochemical factors (serum ferritin and vitamin D) associated with premature hair graying in Egyptian population.

BACKGROUND: The etiology of premature hair graying (PHG) remains incompletely understood with limited treatment options, although has profound impacts on patient's quality of life. AIMS: To assess demographic and clinical profiles of Egyptian PHG patients and explore association of various epidemiological risk factors and serum vitamin D and ferritin levels with PHG. PATIENTS AND METHODS: Three hundred PHG patients and equal number of controls, aged <30 years, were included. Assessment of epidemiological and clinical characteristics, biometric data and stress perception using perceived stress scale (PSS-10) was done, with measurement of serum vitamin D and ferritin levels for all subjects. PHG was graded into mild, moderate, and severe if <10, 10-100, and >100 gray hairs, respectively. Statistical significance for various compared parameters was done employing suitable tests, with P-value ≤ .05 considered significant. RESULTS: Results reported significant positive relation of PHG with family history, sedentary life style, and stress (P = .001, .029, and .001, respectively), while no significant relation with smoking, body mass index, or frequent hair dyes use (>3 per year) (P = .425, .5, and .65, respectively). No significant difference was found in mean vitamin D between patients and controls (23.79 ± 13.01 ng/mL vs 24.85 ± 13.19 ng/mL, P = .701), while low serum ferritin (<20 ng/mL) was significantly associated with PHG (14.7 % patients vs 2.7% controls, P = .017). CONCLUSION: PHG in Egyptian population is significantly associated with positive family history, stress, sedentary life style, and low serum ferritin level, while role of vitamin D deficiency should be further evaluated.

Topical RT1640 treatment effectively reverses gray hair and stem cell loss in a mouse model of radiation-induced canities.

Gray hair is a visible sign of tissue degeneration during aging. Graying is attributed to dysfunction of melanocyte stem cells (McSCs) that results in depletion of their melanin-producing progeny. This non-lethal phenotype makes the hair follicle and its pigment system an attractive model for investigating mechanisms that contribute to tissue aging and therapeutic strategies to combat this process. One potential combination therapeutic is RT1640, which is comprised of two drugs that are known to stimulate hair growth (cyclosporine A [CsA] and minoxidil), along with RT175, a non-immunosuppressive immunophilin ligand that is implicated in tissue regeneration. Using the ionizing radiation-induced acute mouse model of hair graying, we demonstrate that RT1640, over CsA alone, promotes regeneration of the hair pigment system during and following treatment. In non-irradiated mice, RT1640 is also physiologically active and successfully speeds hair growth and expands the McSC pool. It appears that this effect relies on the combined activities of the three drugs within RT1640 to simultaneously activate hair growth and McSCs as RT175 alone was insufficient to induce hair cycling in vivo, yet sufficient to drive the upregulation of the melanogenic program in vitro. This study sets the stage for further investigation into RT1640 and its components in McSC biology and, ultimately, melanocyte hypopigmentary disorders associated with disease and aging.

Hair graying with aging in mice carrying oncogenic RET.

Hair graying is a representative sign of aging in animals and humans. However, the mechanism for hair graying with aging remains largely unknown. In this study, we found that the microscopic appearance of hair follicles without melanocyte stem cells (MSCs) and descendant melanocytes as well as macroscopic appearances of hair graying in RET-transgenic mice carrying RET oncogene (RET-mice) are in accordance with previously reported results for hair graying in humans. Therefore, RET-mice could be a novel model mouse line for age-related hair graying. We further showed hair graying with aging in RET-mice associated with RET-mediated acceleration of hair cycles, increase of senescent follicular keratinocyte stem cells (KSCs), and decreased expression levels of endothelin-1 (ET-1) in bulges, decreased endothelin receptor B (Ednrb) expression in MSCs, resulting in a decreased number of follicular MSCs. We then showed that hair graying in RET-mice was accelerated by congenitally decreased Ednrb expression in MSCs in heterozygously Ednrb-deleted RET-mice [Ednrb(+/-);RET-mice]. We finally partially confirmed common mechanisms of hair graying with aging in mice and humans. Taken together, our results suggest that age-related dysfunction between ET-1 in follicular KSCs and endothelin receptor B (Ednrb) in follicular MSCs via cumulative hair cycles is correlated with hair graying with aging.

Dietary Eriodictyon angustifolium Tea Supports Prevention of Hair Graying by Reducing DNA Damage in CD34+ Hair Follicular Keratinocyte Stem Cells.

Hair follicular keratinocyte stem cells (HFKSC) which provide a functional niche for melanocyte stem cells (MSC) are the primary target of hair graying. However, little research has been done on anti-hair graying medicines targeting HFKSC. We focused on Eriodictyon angustifolium (Ea), which reduces human hair graying when applied topically. To investigate the protective effect of dietary Ea tea (EaT) on hair pigmentation, we used an acute mouse model of hair graying that mimics X-ray-induced DNA damage associated with age-related hair graying. Our results suggest that dietary EaT maintained the niche HFKSC function against X-ray-induced DNA damage and hair graying. These results indicate that dietary EaT may prevent age-related hair graying and serve as an anti-hair graying herbal medicine.