|Year : 2017 | Volume
| Issue : 1 | Page : 7-12
Biology of hair pigmentation and its role in premature canities
Manu Sehrawat, Surabhi Sinha M.D D.N.B M.N. A.M.S Specialist , Neha Meena, Prafulla K Sharma
Department of Dermatology, PGIMER, Dr. Ram Manohar Lohia Hospital, New Delhi, India
|Date of Web Publication||19-Jun-2017|
C 403, Sabka Ghar C.G.H.S Plot 23, Sector 6, Dwarka, New Delhi, Delhi - 110 075
Source of Support: None, Conflict of Interest: None
In today’s world, physical appearance and the desire to look young are very important. Skin and hair play a powerful role in this as they impart much information, not only about our race, ethnicity, and health but also about gender and age. We experience a significant change in pigmentation during our journey of life from birth to puberty and then to young adulthood, middle age, and beyond. Graying of hair is a conspicuous sign of aging. It is said that 50% of the people have 50% gray hair by the age of 50. Premature graying or premature canities is defined as graying that occurs before the age of 20 in Caucasians, before 25 in Asians, and before 30 in Africans. The pathogenesis of premature canities is not yet clear but various hypotheses have been suggested including alteration in pH and cysteine levels in melanosomes, the role of trace metal ions, vitamin B12 and folic acid, vitamin D3, and oxidative stress. Along with increased awareness, there is an increased demand for treatment modalities but the options are limited and unsatisfactory. Various topical preparations containing phytic acid, amino acids, peptides, acetyl hexapeptide-1, melitane, capixyl, pea proteins, etc. are already available in the market. Currently, research is focusing on topical liposome targeting melanins, genes, and proteins selective to hair follicles for therapeutic and cosmetic modification of hair.
Keywords: Melanosomes, melitane, oxidative stress, canities, premature graying
|How to cite this article:|
Sehrawat M, Sinha S, Meena N, Sharma PK. Biology of hair pigmentation and its role in premature canities. Pigment Int 2017;4:7-12
| Introduction|| |
The color, density, and styling of hair have a colossal bearing on one’s self-esteem, especially in today’s times where a person’s first impression may turn out to his or her last impression. However, increased longevity of human life means that we spend an increasing proportion of our lives sporting signs of aging on our scalp. The most dramatic age-related change in hair is the onset of hair graying or canities, which is the gradual age-dependent dilution of hair color to gray or white, also known as senile canities (canities (L.), canus, hoary, gray). The graying of hair occurs due to an admixture of normally pigmented, hypomelanotic, and amelanotic melanosomes. White hair is the endpoint of graying. The age of onset of senile canities appears to be genetically controlled and inheritable. The average age for Caucasians is mid-30s; for Asians, late-30s; and for Africans, mid-40s. A good rule of thumb is that by 50 years of age, 50% of people have 50% gray hair.
| Biology of Hair Pigmentation|| |
Hair is said to gray prematurely, that is, premature canities or premature hair graying (PHG) if it occurs before the age of 20 in Caucasians, before 25 in Asians, and before 30 in Africans. Canities is a generalized loss of hair pigmentation, as compared to Poliosis, which refers to a circumscribed loss of pigmentation of hair. Diseases associated with premature canities are listed in [Table 1].
Hair color is due to two types of melanin: eumelanin and pheomelanin. If more eumelanin is present, the color of the hair is darker; if less eumelanin is present, the hair is lighter. The darker the hair color, the more noticeable early graying will be. Particular hair colors are associated with some ethnic groups. The Fischer–Saller scale, named after Eugen Fischer and Karl Saller, is used to determine the shades of hair color [Table 2]. Majority of the human population (80–90%) fall into the U to Y category (dark brown/black hair) of this scale.
Hair color is linked to the degree of polymorphism in expression of the Melanocortin-1 gene (MC1R). The Pro opiomelanocortin (POMC) peptides [α-melanocyte-stimulating hormone (α-MSH) and Adrenocortico tropic hormone (ACTH)] bind to MC1R to stimulate melanogenesis. Hair melanoblasts originate in the neural crest and migrate into the skin during embryogenesis, similar to other melanoblasts. Microphthalmia-associated transcription factor, sex-determining region of the Y chromosome (SRY)-related high mobility group protein (HMG)-BOX10 (SOX10), paired box 3 (Pax 3), KIT proto-oncogene receptor tyrosine kinase (KIT), fibroblast growth factor-2, and endothelin-3 are thought to be responsible for commitment of neural crest cells to melanocyte lineage. Transit/transient-amplifying melanocytes, which are progeny melanoblasts/melanocytes, leave the epidermal compartment and move into the developing hair follicle. They undergo proliferation as stem cells and/or differentiation into melanogenic melanocytes. All these processes are under autocrine and paracrine control of various growth factors, most importantly KIT–stem cell factor (SCF) interaction.
As shown in [Figure 1], melanoblasts may or may not express KIT (receptor for SCF) on their surface. Thus, KIT −ve melanoblasts migrate to the hair bulge area and give rise to the melanocyte stem cells. They are also amelanotic. KIT +ve melanoblasts concentrate in the hair bulb above the dermal papilla and give rise to melanogenic melanocytes. Further, as shown in [Figure 2], follicular melanocytes may be dihydroxyphenylalanine (DOPA) oxidase +ve or DOPA oxidase −ve. The DOPA oxidase +ve melanocytes concentrate in the upper hair bulb matrix just below the precortical line, express tyrosinase, and are the primary site for pigment production.
|Figure 1: Fate of melanoblasts with and without expression of KIT (receptor for SCF) on their surface|
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|Figure 2: Fate of DOPA oxidase +ve or DOPA oxidase −ve follicular melanocytes|
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This compartmentalization of follicular melanocyte subpopulations during development of skin is thought to be very important for renewal of melanocytes during the hair growth cycle, for the stem melanocyte reservoir, during age-related pigmentation changes and age-related depletion of functioning melanocytes during graying. The melanocyte stem cells express the cell markers Trp2, Bcl2, and Pax3 but are negative for Trp1, KIT, and Ki67, whereas the melanogenically active melanocytes express the full set of melanin biosynthesis enzymes and proteins (tyrosinase, Trp1, and pMel17).
Follicular melanogenesis occurs only during anagen. It starts in Anagen II, and a fully functional follicular pigmentary unit is present by Anagen IV. The melanocyte proliferation ceases by Anagen VI. Tyrosinase levels and its activity start decreasing in late Anagen VI and become undetectable by catagen. Melanogenesis stops before keratinocyte proliferation. Hence, the proximal telogen hair is unpigmented.
| What Happens During Physiological Aging (Canities)?|| |
The type of hair fiber keeps on changing with age. Neonates and fetuses have unpigmented lanugo hair while adults have short (mostly pigmented) vellus hair or fine pigmented intermediate hair and long terminal hair shafts. Similarly, surface morphology also shows variation with age, particularly with the reduction in the cuticular scale size. The synthetic capacity of hair bulb melanocytes is maximum during youth. An average scalp hair follicle usually receives 7 ± 15 melanocyte replacements from an outer root sheath reservoir to the hair bulb, which occurs in the first 45 years preceding the onset of gray hair.
Different theories have been suggested for the age-related gradual loss of pigmentation. This includes exhaustion of enzymes involved in melanogenesis, impaired deoxyribonucleic acid (DNA) synthesis, loss of telomerase, loss of antioxidant mechanisms, and anti-apoptotic signals. [Table 3] shows various changes that take place in a white hair bulb during canities.
|Table 3: Various changes that take place in a white hair bulb during canities|
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The net result is that fewer melanosomes are incorporated into cortical keratinocytes of the hair shaft. Cessation of pigment production by melanocytes in the hair matrix area surrounding the dermal papilla is a slow process resulting in slow outgrowth of graying hair at the pace of normal hair growth. All hair bulbs do not decrease pigment incorporation in the growing hair at the same time giving “salt and pepper pattern” to the scalp hair.
It has been observed that hair graying pattern depends on gender, age of onset, and smoking habits, with smokers having higher chances of having canities. Temporal area is involved in males first while in females, it is the frontal area. Age of onset also affects the area of involvement; parietal and occipital areas are involved in patients of young age while frontal area is involved in late onset group.
| Why Does Premature Canities Occur?|| |
Premature canities is a common cause of referral to dermatologists. It occurs most commonly without any underlying pathology, but is said to be inherited in an autosomal dominant manner. It is different from poliosis which is circumscribed hypomelanosis of hair. The diseases associated with poliosis are given in [Table 4].
The pathogenesis of premature canities has not yet been clearly elucidated. A hypothesis that pH and cysteine level of melanosomes play critical roles in determining the course of mixed melanosomes leading to dark, light, or red hair phenotype has been proposed because of the diversity of human hair pigmentation. The role of pH in controlling mixed melanogenesis has attracted much attention as it is seen that tyrosinase activity is progressively suspended by lowering the pH, with a shift to more pheomelanin phenotype.,,, Concentration of cysteine in melanosomes is another control point in mixed melanogenesis. Chemical hair straightening is done by alkaline disruption of the disulphide bonds in the cortex of the hair shaft. It causes considerable damage to the hair because of the pH (9–12) of the chemicals leaving the hair dry and fragile. In a questionnaire-based study, Shetty et al. reported that 22% of the cases experienced graying of hair also.,
There is definitely a role of trace metal ions in hair pigmentation. Copper ions are required by tyrosinase at its active center; thus, it is likely that copper ions in melanocytes are necessary to maintain normal color. Fatemi Naieni et al. compared the mean copper concentration in patients with PHG and controls and found lower mean serum copper concentration in the cases.
Another trace metal, which has a role in pigmentation, is iron. A 15-year-old Japanese girl who had segmented heterochromic hair in association with iron deficiency anemia has been reported whose melanin content recovered after iron supplementation. Metal cations like iron, copper and zinc are required in the rearrangement of dopachrome to 5,6- dihydroxy indole-2- carboxylic acid (DHICA) and in the oxidative polymerization of DHICA to melanin pigments. There are reports that in tautomerization (a late stage reaction of melanin biosynthesis), the isomerization of dopachrome to dihydroxyindole-2-carboxylic acid DHICA occurs. This reaction is catalyzed by dopachrome tautomerase which is a metalloenzyme with ferrous ions in at its active site. Plonka et al. did a study on murine hair shafts and found that high dose of oral zinc cations is a potent downregulator of eumelanin content in vivo.
Although there are many studies investigating the hair metal ion contents in different hair colors with controversial results, there are only a few studies assessing the level of trace elements in the body. Sufficient supply with vitamin B12 and folic acid is also required for the cells of the hair follicle as they are rapidly dividing cells and their proliferation is dependent upon synthesis of DNA. Moreover, vitamin B12 is known to stabilize the initial anagen phase of the hair follicle and might decrease post-transplantational effluvium in hair restoration surgery.
Nowadays, the role of vitamin D3 is also being discussed in many diseases. Premature canities has also been linked to decreased bone mineral density, and calcium is also involved in some steps of melanogenesis. Bhat et al. found that vitamin D3 levels were either deficient or insufficient in all the individuals of case group indicating probably an important role in pigmentation of the hair. However, there is a paucity of studies related to the role of vitamin D3 in premature graying of hair.
Data suggest that oxidative stress can also play a major role in the premature aging of skin and hair. This theory has been widely accepted these days. Reactive oxygen species (ROS) or free radicals, generated by a variety of internal and environmental factors may result in direct damage to various cellular structural membranes, lipids, proteins, and DNA. To combat these free radicals, our body has endogenous defense mechanisms such as antioxidative enzymes which include superoxide dismutase, catalase, glutathione peroxidase as well as non-enzymatic antioxidative molecules like vitamin E, vitamin C, glutathione, and ubiquinone. The production of these endogenous defense mechanisms decreases while that of free radical increases, resulting in aging.
Other causes that are implicated in premature canities are stress (both emotional and inflammatory stress), pesticides, drugs, and ultraviolet (UV) light. Pesticides are known to produce ROS in the human body. A recent study done in Malwa district of Punjab reported that premature canities was present in both males and females of that region. Evidence from studies on epidermal melanocyte aging suggests that ROS damages both nuclear and mitochondrial DNA, which may lead to mutations in bulbar melanocytes. Nishimura et al. reported that defective self-maintenance of melanocyte stem cells due to exposure to environmental toxicants as one of the possible cause of change in hair color.
A number of drugs trigger premature graying like chloroquine, mephensin, phenylthiourea, triparanol, fluorobutyrophenone, dixyrazine, epidermal growth factor receptor inhibitor − imatinib, and interferon-alpha, as well as use of certain topical chemicals − diathranol, chrysarobin, and prostaglandin F2 alpha analogues.
Ultraviolet A (UVA) spectrum of radiation induces degradation of hair pigment by producing free radicals. Superoxide radicals generated by interaction of UVA light with topically applied psoralen have recently been shown to induce graying of hair in mice. This photosensitization induced graying was, however, averted by pre-treatment with superoxide dismutase gel on opposite side.
| Approach to management of premature canities|| |
On the basis of the possible etiologies, various investigations might help in assessing the cause of premature canities. The proposed investigations include complete blood count, liver function tests, kidney function tests, serum antinuclear antibody (ANA), rheumatoid factor, anti streptolysin O (ASO) titres, C reactive protein (CRP) levels, serum iron profile, serum folic acid, serum vitamin B12, and others − vitamin D3, serum calcium, total protein, albumin and globulin.
There is an increased awareness and demand for treatment, but disappointingly we have very limited treatment options to offer and there are no standard guidelines for evaluation of its extent and severity. Various means of scoring that have been used previously have numerous drawbacks. They are not standardized, may not be reproducible, and might have observer bias. They are chosen randomly and according to convenience, and entire scalp is not assessed. In the self-reported estimation, there might be inter-individual variation, as it is difficult for an individual to examine his/her own scalp. Futher, it is the perception of reporting person regarding the severity and involved area that is taken into account.
Recently, a novel severity score, named Graying Severity Score (GSS) by Singal et al., has been proposed which is numeric, objective, and reproducible method for
assessment of severity of premature canities. The data can be maintained in the form of photographic record and can be helpful in therapeutic trials with pre- and post-treatment score. In this method, the entire scalp surface is divided into five zones, that is, frontal region, vertex, right and left temporal regions, and the occipital. In each of these zones, representative areas showing maximum graying are identified, photographed, and projected onto computer screens where a count of the white and black hair is done. The GSS is finally calculated for each patient by taking a sum of the scores at the five representative sites. The maximum attainable score for a patient is 15 (3 × 5).
The objective scores are further graded as mild (a score of 0–5), moderate (score of 6–10), and severe (score of 11–15). With some treatment options being tried out in premature canities, this score could prove useful in objective evaluation of improvement.
The management options are limited and mostly of unproven efficacy. Among the earliest options, P-aminobenzoic acid was tried by Sieve as early as 1941 with a dose of 100 mg thrice daily in 460 patients of gray hair with a response rate of 82% but the graying reverted back again in 2–4 weeks after stopping the treatment. The mechanism of action was unclear with frequent side effects especially gastrointestinal upset. Calcium pantothenate has also been used successfully in dosage of 200 mg/day.
It has been found that hair dyes may protect hair against photo-damage. Recent experimental work indicates that cinnamidopropyltrimonium chloride, a quaternized UV absorber, delivered from a shampoo system, is suitable for photoprotection of hair, while simultaneously providing an additional conditional benefit on hair, Solid lipid nanoparticles have been developed as novel carriers of UV blockers for use on skin and hair, offering photoprotection on their own too by reacting and scattering ultraviolet radiation (UVR).
Recent advances in the management of aging hair and scalp are anti-aging compounds. Shampoos are largely ineffective as anti-aging agents due to water dilution and short contact time, and antioxidants such as vitamin C and E in these preparations protect fatty substances in the shampoo from oxidation, and not the hair. Topical anti-aging compounds of current interest are green tea polyphenols, selenium, copper, phytoestrogens, melatonin, and as yet unidentified substances from traditional Chinese medicine and Ayurvedic medicine. Use of hormonal anti-aging protocols containing recombinant human growth hormone has resulted in improvement of hair thickness, hair growth, and in some cases darkening of hair. Use of l-methionine to suppress methionine oxidation and restore the methionine-sulfoxide repair mechanism, and thus prevent graying of hair needs further exploration. A new type of compounds (SkQs; Sk is for penetrating cation (“Skulachev ion”) and Q is for plastoquinone) comprising plastoquinone (an antioxidant moiety), a penetrating cation, and a decane or pentane linker has been synthesized that specifically target mitochondria and act as rechargeable antioxidants. These have been shown to inhibit development of age-related diseases and traits such as cataract, retinopathy, glaucoma, balding, canities, and osteoporosis in animals.
Human skin and hair follicles have a melatonergic enzyme system, which expresses the specific enzymes necessary for melatonin biosynthesis. Melatonin acts as a potent antioxidant, direct radical scavenger, and anti-aging factor and protects against damage caused by UV rays.
Melitane, a biomimetic peptide agonist of α-MSH, stimulates melanin synthesis, inducing skin pigmentation via the activation of its receptor MC1-R. Melitane has a preventive action on DNA damage induced by UVA or (UVB) radiations and reduces the number of sunburn cells attesting a DNA repair action, for maximal anti-aging benefits. Before applying melitane, scalp should either be washed with a mild shampoo or cleaned with a wet towel. Required dose of 1 ml/day can be applied by using spray or dropper. There is no need to rinse off the solution post-application, as it gets completely absorbed in the scalp. Therapy should be continued for at least 6 months. It is recommended for premature canities between 8 and 25 years of age only.
Various topical preparations containing phytic acid, amino acids, peptides and acetyl hexapeptide-1, melitane, capixyl, pea proteins, etc. are available in market. Phytic acid, amino acids, peptides and acetyl hexapeptide-1 are marketed by some pharmaceutical companies currently. Approximately 2ml is applied. It usually takes a minimum of 3 months of continuous application on hair for a visible change. On discontinuation however, premature canities will most likely restart and be visible again after 4–6 weeks. Hence, prolonged treatment would be necessary. Further studies are required for validation of these products.
In the future, there might be a possibility that hair follicular route for delivery of active compounds affecting hair would be used. Currently, research is focusing on topical liposome targeting melanins, genes, and proteins selectively to hair follicles for therapeutic and cosmetic modification of hair.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Tobin DJ, Paus R. Graying: Gerontobiology of the hair follicle pigmentary unit. Exp Gerontol 2001;36:29-54.
Suter D. Hair colour in the Faroe and Orkney Islands. Ann Hum Biol 1979;6:89-93.
Tobin DJ. Aging of the hair follicle pigmentation system. Int J Trichol 2009;1:83-93.
] [Full text]
Pandhi D, Khanna D. Premature graying of hair. Indian J Dermatol Leprol 2013;79:641-53.
Trüeb RM. Oxidative stress in ageing of hair. Int J Trichol 2009;1:6-14.
Jo JS, Paik SH, Choi JW, Lee JH, Cho S, Kim KH et al.
Hair graying pattern depends on gender, onset age and smoking habits. Acta Derm Venereol 2012;92:160-1.
Bhat RM, Sharma R, Pinto AC, Dandekeri S, Martis J. Epidemiological and investigative study of premature graying of hair in higher secondary and pre-university school children. Int J Trichol 2013;5:17-21.
] [Full text]
Ancans J, Tobin DJ, Hoogduijn MJ, Smit NP, Wakamatsu K, Thody AJ. Melanosomal pH controls rate of melanogenesis, eumelanin/phaeomelanin ratio and melanosome maturation in melanocytes and melanoma cells. Exp Cell Res 2001;268:26-35.
Ito S, Wakamatsu K. Human hair melanins: What we have learned and have not learned from mouse coat color pigmentation. Pigment Cell Melanoma Res 2011;24:63-74.
Smith DR, Spaulding DT, Glenn HM, Fuller BB. The relationship between Na(+)/H(+) exchanger expression and tyrosinase activity in human melanocytes. Exp Cell Res 2004;298:521-34.
Cheli Y, Luciani F, Khaled M, Beuret L, Bille K, Gounon P et al.
α-MSH and cyclic AMP elevating agents control melanosome pH through a protein kinase A-independent mechanism. J Biol Chem 2009;284:18699-706.
Shetty VH, Shetty NJ, Nair DG. Chemical hair relaxers have adverse effects a myth or reality. Int J Trichol 2013;5:26-8.
] [Full text]
Fatemi Naieni F, Ebrahimi B, Vakilian HR, Shahmoradi Z. Serum iron, zinc, and copper concentration in premature graying of hair. Biol Trace Elem Res 2012;146:30-4.
Sato S, Jitsukawa K, Sato H, Yoshino M, Seta S, Ito S et al.
Segmented heterochromia in black scalp hair associated with iron-deficiency anemia. Canities segmentata sideropaenica. Arch Dermatol 1989;125:531-5.
Chakraborty AK, Orlow SJ, Pawelek JM. Evidence that dopachrome tautomerase is a ferrous iron-binding glycoprotein. FEBS Lett 1992;302:126-8.
Plonka PM, Handjiski B, Michalczyk D, Popik M, Paus R. Oral zinc sulphate causes murine hair hypopigmentation and is a potent inhibitor of eumelanogenesis in vivo. Br J Dermatol 2006;155:39-49.
Mittal S, Kaur G, Vishwakarma GS. Effects of environmental pesticides on the health of rural communities in the Malwa region of Punjab, India: A review. Hum Ecol Risk Assess: Int J 2014;20:366-87.
Van Neste D, Tobin DJ. Hair cycle and hair pigmentation: Dynamic interactions and changes associated with aging. Micron 2004;35:193-200.
Nishimura EK, Granter SR, Fisher DE. Mechanisms of hair graying: Incomplete melanocyte stem cell maintenance in the niche. Science 2005;307:720-4.
Emerit I, Filipe P, Freitas J, Vassy J. Protective effect of superoxide dismutase against hair graying in a mouse model. Photochem Photobiol 2004;80:579-82.
Singal A, Daulatabad D, Grover C. Graying severity score: A useful tool for evaluation of premature canities. Indian Dematol Online J 2016;7:164-7.
Pande CM, Albrecht L, Yang B. Hair photoprotection by dyes. J Cosmet Sci 2001;52:377-89.
Gao T, Bedell A. Ultraviolet damage on natural gray hair and its photoprotection. J Cosmet Sci 2001;52:103-18.
Wissing SA, Müller RH. Solid lipid nanoparticles (SLN) − A novel carrier for UV blockers. Pharmazie 2001;56:783-6.
Trüeb RM. Pharmacologic interventions in aging hair. Clin Interv Aging 2006;1:121-9.
Skulachev VP, Anisimov VN, Antonenko YN, Bakeeva LE, Chernyak BV, Erichev VP et al.
An attempt to prevent senescence: A mitochondrial approach. Biochim Biophys Acta 2009;1787:437-61.
Fischer TW, Trüeb RM, Hänggi G, Innocenti M, Elsner P. Topical melatonin for treatment of androgenetic alopecia. Int J Trichol 2012; 4: 236-45.
] [Full text]
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]