Hair Pigmentation

Biology of hair pigmentation

Melanin is produced in the hair follicle pigmentary unit (HFPU) by specialised cells called melanocytes through a process called melanogenesis (where the oxidation of tyrosine by tyrosinase (TYR) is followed by polymerization). Melanogenesis occurs within unique lysosome-derived, membrane-bound organelles termed ‘melanosomes’ that are transferred to the surrounding keratinocytes of the hair shaft. The colour of hair is determined by ratios of different types of melanin such as brown eumelanin, black eumelanin and the red-yellow pheomelanin.

Melanogenesis in skin melanocytes is responsible for skin colour. Melanosomes from melanocytes of fair-skinned individuals are more acidic and display low TYR activity, whereas melanosomes in dark skin are more neutral and present higher levels of TYR activity. Eye color is controlled by the amount and ratio of eumelanin and pheomelanin production by melanocytes in the iris. However, unlike skin and hair, in the iris melanosomes containing pigment are retained within the melanocytes. Blue and green eyes have a larger ratio of pheomelanin to eumelanin (∼14:1), while brown eyes contain similar amounts of each pigment. A wide range of genetic polymorphisms responsible for skin, hair and eye colour have been found and all of these traits are highly heritable1.

There are also melanocyte stem cells (MSCs) located in the bulge which are un-pigmented, containing few dendrites and low/no expression of glycoprotein 100.

HF pigmentation is strictly coupled to the hair cycle. In early anagen (I–II) no pigment is produced as the HF grows and differentiates following telogen. Subsequently, pigmentation is initiated during anagen III, and reaches its maximum in anagen VI HFs. In catagen, most HFPU melanocytes undergo apoptosis, while bulge MSCs survive.

The prevailing view is that follicular MSCs that survive catagen contribute immature progenitors to replenish bulbar melanogenic melanocytes at the start of each new anagen phase. There are also melanocyte progenitor cells located in the matrix of human HFs that could represent an alternative, bulge-MSC independent melanoblast pool. This remains an open question of hair biology.

Biology of hair greying

The biology of hair greying has been extensively described by O’Sullivan et al2 in more detail and eloquence than I could manage, so I will simply provide a short summary. All references for the below (and above) information can be found in this paper.

Melanocyte pathology

Melanocyte sub-populations across the HF appear to be differentially lost during ageing:

• Grey HFs contain a reduced number of differentiated, i.e. melanogenically active, bulbar melanocytes. Eventually, ‘white’ HFs exhibit a complete loss of melanin transfer to the hair shaft, usually accompanied by the corresponding loss of all bulbar melanocytes. However, even optically white HFs may still contain a few hair bulb melanocytes, some of which may engage in residual melanogenesis despite a lack of transfer of melanin to the hair shaft.

• Amelanotic melanocytes present in the bulge, outer root sheath and matrix may persist for longer, but also gradually deplete over time.

• MSCs in the bulge region, which remain unaffected for a long time after hair greying has already affected the HFPU, are the last to be lost.

There is still little evidence that MSCs play any major role in the initiation of hair greying and, in light of the above evidence, the causes for greying initiation in humans must be sought within the HFPU, and possibly intra-bulbar melanocyte progenitor cells, but not the bulge. Nonetheless, depletion of bulge MSCs does play a part in the long-term irreversible process of human hair greying.

Genetics

The role of genes in human greying remains poorly understood, but there are clear links. Mutations in genes encoding enzymes involved in melanogenesis certainly affect hair pigmentation. The age of greying onset is linked to geographic ancestry, and greying is considered premature when it occurs before 20 in Caucasians, before 25 is Asians and before 30 in Africans. In a twin-controlled study of heritability within Danish and British Caucasians, the onset of greying was highly heritable.

Underlying mechanisms

The primary mechanisms underlying hair greying include oxidative stress, accumulation of DNA damage and mitochondrial dysfunction. Interestingly, these are also some of the predominant paradigms in aging research and in this way HFs provide highly useful platforms for investigation of aging mechanisms, as they are both easy to collect from patients using biopsies and to study in vitro. Progeroid syndromes (effectively accelerated ageing) are caused by defective DNA repair mechanisms and exhibit accelerated greying of hair.

Within melanocytes, tyrosine hydroxylation and DOPA-to-melanin oxidation in the melanogenesis pathway lead to high levels of ROS (reactive oxygen species), which are managed by antioxidants including catalase, methionine sulfoxide reductase, eumelanin itself as well as various other enzymes. Impaired antioxidant systems and overaccumulation of ROS cause melanocyte damage during ageing, with external stimuli [inflammation, ultraviolet (UV), smoking and oxidizing agents] also contributing to the loss of redox balance.

This is supported by findings that the HFPU is damaged following exposing of HFs by H2O2 or ROS-generating cytotoxic agents that induce lipid peroxidation, mitochondrial DNA (mtDNA) deletion and cell death. Greying hair bulbs often display vacuolated melanocytes, a common cellular response to oxidative stress. There is also evidence to support that human HF melanocytes, compared to epidermal melanocytes, are more susceptible to chronological ageing.

The Met374 residue of tyrosinase, the rate-limiting enzyme of melanogenesis, constitutes a prime target for H2O2-mediated oxidation; reduced catalase activity could therefore directly damage the HFPU’s enzymatic melanin synthesis and its capacity to protect itself from oxidative damage by melanin production, resulting in an oxidative feedback loop. Melanogenesis itself generates substantial amounts of the superoxide radical. If the ROS-generating enzymatic cascade culminating in melanin synthesis is stimulated, but the ROS-scavenging end-product eumelanin is insufficiently synthesized, this could result in major oxidative damage to the HFPU.

Therapeutic perspectives

A myriad of cases in the medical literature have documented the reversibility of hair greying3.

However, it should be noted that the reversibility of hair greying has only been seen within the duration of anagen during which greying started (i.e. 2–6 years in human terminal scalp HFs), meaning a short window for potential therapeutic options. Indeed, considering the complex mechanisms underlying greying and their resemblance to a general process of “accumulative-oxidative-stress mediated aging” it is not so surprising that an adequate treatment option does not really exist.

Grey hair can look beautiful too! If a patient is upset with the greying of their hair then my condolences :( . Probably the best and most affordable approach to combating grey hair is simply to dye it.

Consequently it is preferable to avoiding the greying of hair in the first place…

Preventative measures

Hair greying can be indicated by vitamin B12 deficiency4 or hypothyroidism5, and more generally speaking it is a bad idea to be deficient in these.

Certain chemotherapeutic drugs678 and antimalarials such as chloroquine9 might induce hair greying as well so caution is advised when taking these.

As mentioned previously, certain factors contribute significantly to oxidative stress and can cause accelerated greying. Smoking has a significant correlation with premature hair greying (PHG)101112, with one study estimating that smokers are 2.5 times more likely to develop PHG than non-smokers13. Another paper found significant correlations between PHG and male gender, vegetarianism, alcohol consumption, BMI, and family history of greying14. Indeed alcohol is known to increase oxidative stress throughout the body15. Another paper found correlations between PHG and alcohol consumption, emotional stress and chronic diseases16. Diseases in general cause an inflammatory response that increases oxidative stress and ROS throughout the body, so... you should avoid being diseased :)

One study showed a link between stress and an increase in oxidative stress and telomere shortening17. Another study demonstrated the correlation between perceived workload, stress and increased oxidative DNA damage18. Individuals who suffer from anxiety disorders exhibit higher oxidative stress1920 and some degree of correlation between anxiety and PHG has been found21. The same study found a lower average income and living conditions.

It should be noted that some of the same metrics did not show correlation with PHG in other studies and this is often down to the sampled population, for example:

…alcohol consumption was lower in participants with HG in our study. This result may be related to low alcohol consumption in the especially elderly Turkish population in living rural areas…

Nonetheless the general takeaway is that stress, overworking, obesity, smoking and alcohol are all reasonably likely to contribute to PHG and should be avoided where possible, while a balanced diet and a healthy lifestyle is encouraged22.

Hair dyeing

Hair dyes23 come in two forms: oxidative and nonoxidative (semi-permanent and temporary). Permanent hair dyes are not easily removable by shampooing. In contrast, temporary dyes are easily washed out in one shampoo rinse, while semi-permanent dyes are removed in 4 to 12 shampoos.

Oxidative dyes consist of primary intermediates (e.g., p-phenylenediamines (PPDs) and p-aminophenols) and couplers (e.g., m-aminophenols and m-hydroxyphenols) in the presence of peroxide and ammonia. The combination of oxidizing and alkaline agents causes swelling of the hair cuticle. Swelling facilitates diffusion of the colorless precursor into the hair cortex, which bleaches the natural melanin pigment. Dye precursors penetrate into the cortex and undergo oxidation to form large colored molecules that tend to remain within the cortex with the least possibility of diffusion.

However, the hair shaft can sustain oxidative damage with permanent hair dye use. The damage is accentuated with the use of dark-colored dyes because darker shades need higher concentrations of precursors. The destructive nature of permanent hair dyes, especially dark-colored dyes, is reflected in the epidemiological evidence, demonstrating its potential association to human malignancy. Increased developer concentration increases the amount of sulfur that is removed from the hair, causing hardening of the hair.

Paraphenylenediamine (PPD) is one of the most widely used chemical substances for permanent hair dye, although ~5% of people exhibit allergic reactions (some of which can be really bad, so do a patch test!). Paratoluenediamine sulfate (PTDS) has been used as a replacement and is tolerated by about 50% of people who are allergic to PPD.

A number of components contained in hair dye products are suspected to cause cancer, although none are yet specifically identified in that respect. The use of hair dyes has been suggested as a risk factor for several types of cancer in some epidemiologic studies, although no strong link has been found and data is variable.

An excellent toxicological report on the safety profile of hair dye constituents has recently been published by He et al.24 which I would recommend taking a closer look at if you are interested.

Nonoxidative dyes include colored compounds that stain hair directly. The larger molecules of temporary hair dyes are unable to penetrate into the cortex; on the other hand, the smaller molecules of semi-permanent hair dyes easily penetrate into the cortex but diffuse out easily in subsequent washes. Semi-permanent dyes may also contain an alkaline agent other than ammonia (e.g., ethanolamine and sodium carbonate) with a low level of hydrogen peroxide. Overall these dyes are less harmful to damaged or fragile hair.

Colour depositing shampoo and conditioner products contain pigments and while they aren’t as strong as hair coloring products, they can help replenish color that you lose over time from washing, styling, and heat treatment.

UV light damages hair tissues while visible light causes the photodegradation of melanin, both of which cause subsequent lightening of the hair25. Citric acid, a natural bleaching agent and constituent of lemon juice, encourages hair cuticles to open and melanin to degrade, further accelerating the photobleaching of hair.

I have read that chlorine-treated water and saltwater may strip hair dyes faster but haven’t found any reliable sources for this claim.

Notes