Hair graying—also known as gray hair, white hair, or achromotrichia—is considered one of the earliest normal signs of aging. It usually appears around 34 years of age in Caucasians and 43 years in individuals of African descent.1 However, it is defined as premature graying (PG) when at least 5 gray hairs appear before the age of 20 years in Europeans, 25 gray hairs in Asians, and before 30 years of age in Africans.2

Hair symbolizes well-being and health and plays an important role in social communication, self-perception, self-esteem, and body Image.3 Recently, the treatment of premature graying has been increasingly studied due to its psychological consequences and its possible association with metabolic diseases.4,5

Hair follicle melanocytes are categorized into subpopulations according to their function, degree of differentiation, and location.

The first location is in the hair bulb during the anagen phase, in the upper region of the dermal papilla. Bulbar melanocytes are the only cells that contribute to hair pigmentation. They express active tyrosinase and dihydroxyphenylalanine (DOPA) and are considered part of the hair follicle pigmentary unit, along with keratinocytes.6

Melanogenesis occurs within specialized lysosomes called melanosomes, which are transferred to keratinocytes via dendrites and filopodia. This process occurs exclusively during the anagen phase, ceases during catagen, and remains inactive during telogen. Melanosomes transfer melanin primarily to the hair cortex, to a lesser extent to the medulla, and only occasionally to the cuticle.7

Unlike epidermal melanocytes, the hair bulb contains approximately 1 melanocyte for every 5 keratinocytes, and hair follicle melanocytes have longer and more numerous dendrites.8

The second melanocyte location within the hair follicle is the bulge area. These melanocytes are immature and inactive, do not express melanogenic enzymes such as tyrosinase or tyrosinase-related protein 1 (TRP-1), and serve as precursor cells. They proliferate, mature, and migrate to the bulb during anagen.9

Melanocytes have also been identified in the infundibulum, similar to epidermal melanocytes, and in sebaceous glands6 (Table 1).

The hair follicle pigmentary unit reaches its maximum melanin production during adolescence, followed by a gradual decline over the years.

Repigmentation and reconstruction of the pigmentary unit are lost with each hair cycle and can only be achieved for 7 to 15 cycles, corresponding to approximately 40–45 years of age, resulting in reduced pigment production. Another contributing factor is the prolongation of the telogen phase that occurs with aging10 (Fig. 1).

Fig. 1.

Etiopathogenic process of hair graying across phases.

Pigment loss in the hair shaft is associated with reduced melanin content and a decrease in bulbar melanocytes. When hair becomes gray, few melanocytes remain, but they still express tyrosinase and continue melanin transfer to keratinocytes. In contrast, white hair lacks melanocytes in the bulb altogether.1

The exact etiopathogenesis of premature graying has not yet been fully elucidated. It may be associated with autosomal genetic disorders, premature aging syndromes such as progeria and pangeria, oxidative stress resulting from ultraviolet radiation, pollution, and emotional factors, as well as inflammatory causes. Several studies have also reported associations with deficiencies of vitamin B12, vitamin D, iron, calcium, ferritin, copper, and zinc, as well as with thyroid hormone deficiency and drugs that reduce melanogenesis.2

Oxidative stress plays a significant role in melanogenesis. Melanin synthesis generates hydrogen peroxide (H2O2), superoxide (O2−), and hydroxyl free radicals. Compared with keratinocytes, melanocytes are more vulnerable to oxidative stress.11

Defense mechanisms against oxidative stress include antioxidants such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). However, their activity decreases with aging, creating an imbalance between oxidative damage and repair mechanisms.12

Excessive accumulation of reactive oxygen species (ROS) within hair follicle melanocytes leads to cellular damage through lipid peroxidation, DNA strand breaks, mutations, and protein and enzyme denaturation. Damage to the cell membrane generates arachidonic acid, followed by the formation of aldehydes such as malondialdehyde (MDA) and 4-hydroxynonenal. MDA crosses the cell membrane into the extracellular compartment; therefore, its serum concentration represents a sensitive marker of oxidative stress. Collectively, this damage results in decreased melanocyte pigment-forming capacity and may even induce apoptosis through activation of inflammatory pathways such as the MAPK and p53 pathways.13

Saxena et al. evaluated serum levels of MDA, reduced glutathione, and SOD in patients with premature graying and found significantly higher MDA levels vs controls. SOD levels were also lower in premature graying cases, reinforcing the role of oxidative stress in PG.14

Numerous genes and signaling pathways involved in premature graying have been identified. Bian et al. reported reduced expression of genes responsible for melanin synthesis in the hair follicle—such as TYR, melan-A (MLANA), premelanosome protein (PMEL), TYRP1, SLC45A2, KIT, G protein–coupled receptor 143 (GPR143), and OCA2—in patients with premature graying.15

UV radiation plays an important role in hair graying by stimulating the production of free radicals. UVA radiation can cause hair color changes by penetrating deeply into the cortex and inducing biochemical damage, whereas UVB radiation leads to protein depletion and structural damage to the cuticle.16,17

Smoking is associated with hair graying through increased free radical production. Shin et al. found a statistically significant association between smoking and premature graying, consistent with former studies.18,19

The mechanism linking graying and stress is not yet fully understood.

Animal studies suggest that stress can accelerate hair graying. Sharma et al. evaluated stress levels in patients with PG using the Perceived Stress Scale (PSS) and found significantly higher stress scores in patients with PG vs controls.20

Zhang et al. demonstrated that acute stress can cause irreversible depletion of somatic stem cells via activation of the sympathetic nervous system, resulting in permanent tissue damage and hair graying.21

Hair follicles are innervated by sympathetic nerves; under stress conditions, they release norepinephrine, inducing proliferation of melanocyte stem cells that differentiate and migrate out of the bulge.10 This leads to depletion of melanocyte stem cells without replacement. Without melanocytic cells to provide pigment during the next anagen phase, hair appears white10,22 (Fig. 2).

Fig. 2.

Etiopathogenic mechanism of stress-induced hair graying.

Various stressors—including nociception-induced stress, chronic stress, and restraint stress—have been shown to cause melanocyte stem cell loss and hair graying through immunological mechanisms, corticosterone, and norepinephrine.22,23

Melanocyte stem cells express β2-adrenergic receptors, which respond to norepinephrine. Loss of this receptor completely blocks stress-induced hair graying.23 Other stress-related mediators include calcitonin gene-related peptide, which maintains immune privilege and induces catagen while promoting melanogenesis; substance P, which downregulates growth, induces apoptosis, and increases free radical production; and vasoactive intestinal peptide, which prevents follicular collapse.24,25

Adipose tissue surrounding hair follicles is rich in growth factors that regulate stem cell activation and regeneration and repress Wnt signaling.22,24

Hair may exhibit reversible hypopigmentation due to nutritional deficiencies. Daulatabad et al. found lower vitamin B12 levels in patients with PG vs controls, with greater deficiency associated with increased severity. They also found lower folic acid levels but no differences in biotin levels.26

Sharma et al. reported lower serum calcium and ferritin, lower HDL cholesterol, and higher LDL cholesterol levels in patients with PG vs controls.20 Premature graying has been linked to early cardiovascular disease, and dyslipidemia may serve as a connecting factor.5

Furthermore, lower vitamin D levels have been reported in patients with PG, although without statistically significant associations.20,27 Regarding copper, lower levels have been observed in PG patients vs controls, but without statistical significance.28,29

Several studies have reported a higher prevalence of atopic diathesis in patients with PG.20,26,30 Das et al. conducted a study in patients with PG and found higher levels of blood pressure, glucose, insulin, C-reactive protein, and HOMA index, as well as elevated IL-6 levels, compared with controls. These findings suggest an increased cardiovascular risk, leading the authors to propose screening for cardiovascular risk factors in patients with PG.5

Chandran et al. measured thyroid hormone levels in patients with PG and found higher anti-thyroid peroxidase (TPO) antibody levels vs controls; however, no differences were observed in T3, T4, or TSH levels.31

An increased risk of osteopenia—up to fourfold higher—has been reported in patients with PG vs individuals without gray hair.32 Nevertheless, more recent studies failed to confirm this association.33

In cases of PG, a laboratory work-up may be necessary, including iron studies, vitamin B12, folic acid, 25-hydroxyvitamin D, thyroid profile, and antithyroid antibodies.31–33

Gray hair primarily results from an optical phenomenon. The pale yellow keratin of non-pigmented hair appears white due to light refraction or reflection.34 Compared with pigmented hair, gray hair is thicker, stiffer, and more difficult to manage, grows faster, and is more susceptible to UV radiation damage, requiring greater protection.35 Alterations in hair fiber make it more difficult to maintain artificial color, leading many individuals to undergo repeated dyeing procedures, which may result in toxicity from artificial hair dyes.36

There are no sex-related differences in the prevalence of premature graying.37

In women, gray hair usually begins along the hairline, whereas in men it typically starts in the temporal region and sideburns. Graying first affects the scalp, followed by the facial area, and finally body hair.

There is no standardized scale for classifying graying. Several have been proposed; one of the most widely used is the Hair Whitening Score (HWS), which is based on the percentage of affected hair38:

• •

  Trace: <25%

• •

  Mild: 25–50%

• •

  Moderate: 50–75%

• •

  Marked: 75–100%

• •

  Complete: 100%

It is necessary to distinguish graying from other conditions that cause localized or diffuse hair hypopigmentation (Table 2).

There are reports of abrupt overnight graying, known as sudden canities or Marie Antoinette syndrome, which is related to diffuse alopecia areata. In this condition, pigmented hair is preferentially shed, leaving only hypopigmented hair.39,40

Despite extensive research into the pathophysiology of graying, no satisfactory treatments currently exist (Table 3). Due to high patient demand, vitamin supplements, antioxidants, and minerals such as biotin, zinc, copper, selenium, and calcium pantothenate are frequently used, although their efficacy has not been demonstrated. If deficiencies of vitamin B12, folic acid, vitamin D, or thyroid hormone abnormalities are detected, specific treatment is recommended.

Palmitoyl tetrapeptide-20 and melitane are biomimetic peptides that act as agonists of α-melanocyte-stimulating hormone (α-MSH) and, together with its melanocortin-1 receptor (MC1R), regulate pigment production in hair. Palmitoyl tetrapeptide-20 has been studied in vitro and in 15 men with premature graying, inducing hair pigmentation after 3 months.44 The use of melitane plus oral supplements has been reported in a 14-year-old woman, with favorable results observed after 6 months.45

Latanoprost has been studied in animal models, demonstrating increased follicular melanogenesis and hair growth.46

Hair disorders have a significant impact on quality of life, and PG is no exception. Daulatabad et al. assessed quality of life using the Dermatology Life Quality Index (DLQI) in 57 patients with PG, finding that 65.4% had a significant impact and 19.23% had an extremely significant impact, with high levels of guilt and mood changes.53 Mathias et al. reported that among 100 patients with PG, 49% had a significant impact and 22% an extremely significant impact on quality of life.54 Parihar et al. assessed body image in 295 patients with PG and found poor body image in 54%.55

The authors declare that they have no conflict of interest.

43.