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32]

Review Article

Biology of hair pigmentation and its role in premature

canities
ABSTRACT
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

INTRODUCTION BIOLOGY OF HAIR PIGMENTATION

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.[1]
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.
MANU SEHRAWAT, SURABHI SINHA, NEHA MEENA, PRAFULLA K.
SHARMA
Department of Dermatology, PGIMER, Dr. Ram Manohar Lohia
Hospital, New Delhi, India
Address for correspondence: Dr. Surabhi Sinha, M.D D.N.B M.N.
A.M.S Specialist, C 403, Sabka Ghar C.G.H.S Plot 23, Sector 6,
Dwarka, New Delhi, Delhi - 110 075, India.
E-mail: surabhi2310@gmail.com

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DOI:
10.4103/2349-5847.208297 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.

© 2017 Pigment International | Published by Wolters Kluwer - Medknow 7

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Sehrawat et al.: Premature canities

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].[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 melan-
ogenesis. 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.[3] 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.
This compartmentalization of follicular melanocyte sub-
populations 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.[3] 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).

Table 1: Diseases associated with premature canities

Inherited causes Fanconi syndrome, Book syndrome, Down syndrome,
Hallermann–Streiff syndrome, Treacher-Collins
syndrome, prolidase deficiency
Chronic protein Kwashiorkor, nephrosis, ulcerative colitis,
deficiency malabsorption, etc.
Vitamin B12
deficiency
Hyperthyroidism Figure 1: Fate of melanoblasts with and without expression of KIT
Drugs Tyrosine kinase inhibitors and antimalarials (receptor for SCF) on their surface
(chloroquine > hydroxychloroquine)

Table 2: The Fischer–Saller scale to determine the shades of

hair color
Category Colour of hair
A Very light blond
B–E Light blond
F–L Blond
M–O Dark blond
P–T Light brown to brown
U–Y Dark brown/black
Roman numerals I–IV Red
Figure 2: Fate of DOPA oxidase +ve or DOPA oxidase −ve follicular
V–VI Red blond
melanocytes

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Sehrawat et al.: Premature canities
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.[4]
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.[5]
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.[6] Temporal area is
Table 3: Various changes that take place in a white hair bulb
during canities
Melanocytes turn DOPA −ve (= no tyrosinase activity)
Defective transfer of melanosomes to keratinocytes (probably due to
decreased dendrites)
Melanocytes contain melanin debris in autophagolysosomes (suggesting
defective melanogensisis probably containing reactive melanin metabolites)
Melanocytes become vacuolated (suggesting high oxidative stress and
supporting the aforementioned point)
Melanocyte apoptosis occurs
Pigment International | Volume 4 | Issue 1 | January-June 2017
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.[6]
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.[7] 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.[8] 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.[8-11] Concentration of cysteine in melanosomes
is another control point in mixed melanogenesis.[7] 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.[8,12]
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.[7] 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.[13]
Another trace metal, which has a role in pigmentation, is
iron. A 15-year-old Japanese girl who had segmented
Table 4: Diseases associated with poliosis
Inflammatory/ Vitiligo, halo nevus, alopecia areata, post-inflammatory
autoimmune (e.g., DLE), Vogt–Kayanagi–Harada syndrome and
Alezzandrini syndrome
Inherited disorders Tuberous sclerosis, piebaldism (midline frontal
forelock), Waardenburg syndrome (primarily midline
frontal), isolated white forelock, isolated occipital
white forelock (XLR), white forelock with osteopathia
striata and white forelock with multiple malformations
Others Post-traumatic
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Sehrawat et al.: Premature canities
heterochromic hair in association with iron deficiency
anemia has been reported whose melanin content
recovered after iron supplementation.[14] 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.[15]
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.[16]
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.[7] 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.[7]
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.[7]
Data suggest that oxidative stress can also play a major role
in the premature aging of skin and hair.[5] 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.[5]
10 Pigment International | Volume 4 | Issue 1 | January-June 2017
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.[17] Evidence from studies on epidermal
melanocyte aging suggests that ROS damages both
nuclear and mitochondrial DNA, which may lead to
mutations in bulbar melanocytes.[18] 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.[19]
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.[4]
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.[20]
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
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Sehrawat et al.: Premature canities
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.[21] 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.[22] Calcium pantothenate
has also been used successfully in dosage of 200 mg/day.[4]
It has been found that hair dyes may protect hair against
photo-damage.[22] 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,[23]
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).[24]
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
Pigment International | Volume 4 | Issue 1 | January-June 2017
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.[25] Use of l-methionine to suppress
methionine oxidation and restore the methionine-sulfoxide
repair mechanism, and thus prevent graying of hair needs
further exploration.[4] A new type of compounds (SkQs; Sk is
for penetrating cation (“Skulachev ion”) and Q is for
plastoquinone)[26] 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.[25] These have been shown to inhibit
development of age-related diseases and traits such as
cataract, retinopathy, glaucoma, balding, canities, and
osteoporosis in animals.[25]
Human skin and hair follicles have a melatonergic enzyme
system, which expresses the specific enzymes necessary for
melatonin biosynthesis.[27] Melatonin acts as a potent
antioxidant, direct radical scavenger, and anti-aging factor
and protects against damage caused by UV rays.[5]
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.[25] 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
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Sehrawat et al.: Premature canities
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.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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