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Skin and hair play a major role in a person’s appearance. The colour of human hair – such as black, brown, blonde etc. – depends on the type of melanin in human hair follicles and its transformation from melanocyte to keratinocyte i.e. melanogenesis[1]. As one grows older, melanocytes, the pigment cells in the hair follicles, die slowly; due to which, hair may not contain as much melanin as needed to maintain its color, and as a result, it turns grey, silver, or white. Greying of hair (also called canities) is no longer associated with age, and depends on several factors such as deficiency of vitamin B12[2], stress[3], smoking[4], genetics[5], and auto-immune diseases such as vitiligo and alopecia areata[6] etc. Reversal of greying of hair is now receiving the attention of researchers worldwide.


The process of hair growth consists of 3 phases;

  • Anagen, the active growth stage of the hair fiber
  • Catagen, wherein hair growth slows down
  • Telogen, wherein hair growth completely stops and the hair fiber falls off

When hair is formed, melanocytes inject melanin into cells containing keratin, the basic structural protein of hair fibre, resulting in hair retaining its original colour[7]. Melanogenesis, a process of melanin production and distribution, is reported to be controlled by neuroendocrine factors such as alpha melanocyte-stimulating hormone (α-MSH), adrenocorticotropic hormone (ACTH),grey-hair ß-endorphin, corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH)], and micropthalmia-associated transcription factor (MITF)[8]. Greying of hair is caused either by active hair growth; which induces oxidative or genotoxic stress in hair bulge, resulting in depletion of melanocyte stem cells (MSC); or dysfunction of melanocyte stem cells in the bulge, which in turn may be attributed to the generation of toxic reactive oxygen species (ROS) on melanocyte nuclei and mitochondria[9].

According to a study conducted by the University of Texas Southwestern Medical Center, certain proteins such as stem cell factor (SCF) in hair progenitor cells are responsible for hair pigmentation, and the scientists demonstrated using mouse models  that deletion of SCF gene in hair cells caused their hair to turn white[10]. Wood et al. used FT-Raman spectroscopy to show that accumulation of hydrogen peroxide (H2O2) in millimolar concentrations in human grey/white scalp hair shafts, along with absence of catalase, methionine sulfoxide reductase A and B protein expression and inhibition of function of tyrosinase enzyme, are the root causes of greying[11]. Ataxia Telangiectasia Mutated (ATM), a serine/threonine protein kinase within melanocytes in hair follicle bulbs, works as a primary sensor of ROS in human cells and

protects it from oxidative stress-induced greying of hair follicle[12]. Based on their findings from experiments on stem cells of mice, researchers from Harvard and the University of Sao Paulo concluded that stem cells are responsible for controlling the colour of hair and skin[13]. Under stressful conditions, the sympathetic nervous system releases a chemical called norepinephrine, which then flows through the stem up into the hair follicles and activates all the melanocyte stem cells. Stem cells migrate from their niche, and as a result, when new hair grows, there is no stem cell to make pigment cells. How stress affects depletion of melanocyte stem cells by sympathetic nerve activation is depicted in the accompanying figure[14].


Using confocal Raman microspectroscopy, French companies Silab and BioSpecT  investigated molecular signature such as lipid conformation (trans/gauche ratio) and protein secondary structure that cause greying hair shafts[15]. Smoking also causes generation of (ROS), which damages hair follicle melanocytes and accelerates greying of hair[16, 17].


Dyeing has always been considered as the ideal way to disguise grey hair permanently. Dyes of various compositions have been in commercial use for over 100 years. Due to the presence of paraphenylene-diamine, prolonged use of hair dye causes rhabdomyolysis, laryngeal edema, severe metabolic acidosis and acute renal failure[18]. Acute hair dye poisoning may cause swollen face and chocolate brown colour of urine[19], increase the risk of bladder cancer[20], induce non-Hodgkin lymphoma[21], systemic lupus erythematosus (SLE) and so on. Research is in progress to address the problems associated with phenylenediamine‐based dyes through the development of natural dyes. Natural dyes may include indigo carminecombined with other natural dyes[22], polymeric dyes from natural phenolic monomers derived from plant fibres such as lignin and tannin through the enzymatic route[23], pigments such as peridinin, 19-but-fucoxanthin, fucoxanthin, diadinoxanthin, violaxanthin, antheraxanthin, zeaxanthin and DV chlorophyll from six species of Thai plants[24] etc. Presence of harmful ingredients such as logwood, hematein and hematoxylin in natural dyes may cause harm when inhaled or absorbed through the skin, thus reducing the demand for natural dyes.


Keeping in mind the adverse effects of dying grey hair, researchers are focusing on re-pigmentation or reversal of grey hair. Topical application of Thyroid hormones (T3 and T4) was observed to induce hair follicles to enter the anagen phase from telogen phase, and showed proliferation of hair matrix keratinocytes[25, 26]. Two patients diagnosed with myxedema coma and iatrogenic hyperthyroidism were given intravenous 0.5 mg ofL-thyroxine and 0.2 mg/d of L-thyroxine respectively, and during the treatment with thyroid hormone, both patients were observed to have experienced re-pigmentation of grey hair[25]. ‘Rise-N-Shine’, a nutritional supplement company has developed an all-natural pill in shampoo-and-conditioner form that replaces the lost catalase and prevents formation of peroxide, which reverses and prevents grey hair without the use of colourants[27]. According to a team of researchers from the Netherlands, Germany and the U.K., an inside-out bleaching or greying process can be cured with a proprietary treatment described as a topical, sunlight-activated compound made into a ‘modified pseudocatalase”. The study also shows that the same treatment works for vitiligo, grey-haira skin condition that causes de-pigmentation of sections of skin[28]. An agonist of α‐melanocyte‐stimulating hormone (α‐MSH), a biomimetic peptide (palmitoyl tetrapeptide‐20, PTP20) was developed by Scalvino et al. and was found to enhance hair pigmentation, and retard hair-greying process[29]. Redenhair in Spain has developed Greyverse, which is an α-MSH analogue capable of binding to MC1-R, a transmembrane receptor located on the surface of the melanocytes and causing stimulation of melanogenesis process. It reduces the accumulation of H2O2 responsible for accelerating the grey hair formation process[30]. Experimental results showed that only 0.5% of Greyverse™ increased the melanin synthesis by 19%.

A case report from Mount Sinai Hospital, Canada, has revealed that a woman patient aged 75 years who was having grey hair during the diagnosis of multiple myeloma observed that her hair had become darker over the years while she was under long-term medication of Thalidomide[31]. Hair re-pigmentation associated with use of thalidomide was further supported by a review paper on hair re-pigmentation following the use of anti-inflammatory drugs, stimulants of melanogenesis, vitamin supplements and certain drugs that bioaccumulate in tissues or those whose mechanistic pathway is not well known[32].

Silab, a French manufacturer of biological active ingredients, has developed a re-pigmentation agent called AGREYNIST® by combining the efficacies of black oat and spiny restharrow.  It inhibits the generation of free radicals, considered pro-pigmenting active ingredients and reduces oxidative stress[33].The technology is presented in  US20210259948A1.


Phyto RE30 revives the natural pigment at the root of the hair while protecting it from future depigmentation. It contains approximately 98% of natural ingredients. It acts upon the roots in two stages, that is, by boosting pigmentation and protecting it against depigmentation[34].

grey-hairFor natural and permanent reversal of grey hair, Reparex has introduced products that can restore the original colour of hair from the inside. Reparex removes the accumulated oxygen from the hair by using an enzyme called G-reductase, which binds to silver nitrate. This will restore the melanin’s natural colour over time[35].


Just for Men has launched ControlGX, a shampoo that restores pigments to grey hair. The hair pigments entrapped between shampoo and conditioner molecules are released once the shampoo is massaged into the hair and keeps the original colour of the hair[36].

Givaudan has launched Darkenyl™,  a combination of molecules, namely Taxifolin glucoside, a unique stabilised plant polyphenol, and-acetyl-tyrosine, a soluble precursor of melanin synthesis. Darkenyl™’s melanin synthesis precursor reactivates the melanogenesis pathway protecting hair follicle melanocytes from ROS. It also activates bulge stem cells enabling the production of new melanocytes. Its antioxidant properties reduce free radical damage in hair follicles, thus protecting existing melanocytes[37].

grey-hairPeople suffering from premature greying have a reduced level of copper in their blood serum which, in turn, reduces the activity of tyrosinase and hence, reduces pigment production. Based on this, scientists at Oxford Biolabs have developed Melaniq®, which includes copper, a necessary component of the biosynthesis of melanin[38].


grey-hairDSM has developed a patented salt of steviol or isosteviol for topical cosmetic and non-therapeutic use in hair for restoring hair color (EP2595598B1). It delays the onset of greyness in hair by increasing the total number of melanocytes in hair follicles, and increases the differentiation and migration of melanocytes from the hair sheath to the hair matrix. In an experiment, hair follicles in anagen phase were isolated from scalp skin and kept in a petri dish containing culture. Sphingosyl phosphorylcholine at 1 µM and steviol at 0.625 and 1.25 µM were added in the culture medium and hair follicle pigmentation was noted with + sign as a score, as shown in the figure. After 7 days, the hair follicles were stored at -80 °C. An improvement in hair pigmentation was achieved through the use of steviol. At 0.625 µM, Steviol showed better pigmentation as compared to other control studies.

ISP Investments Inc., in its patent US8188050B2, claims a cosmetic or pharmaceutical composition comprising a peptide fragment of protein SLC24A5, which can restore the synthesis of melanin in the melanocytes of the epidermis or pilar bulb.

grey-hairL’Oreal, in its patent US8895037B2, discloses that Ellagic acid and its derivatives are effective in treating canities by increasing the level of GSH in the melanocytes, thereby helping in the restoration of hair pigmentation.

Protection of melanocytes by Ellagic acid was demonstrated wherein normal human melanocytes (NHMs) were inoculated with 2′,7′-Dichlorodihydrofluorescein diacetate H2DCFDA (10 µM in PBS) first, and then in Ellagic acid culture medium as such or in the presence of H2O2. The fluorescence was measured after 15 minutes, using a fluoroscan imaging tool (excitation: 485 nm, emission: 538 nm), and it was observed that ellagic acid reduces the effect of ROS. Amorepacific Corp., in its patent US20220226220A1 has disclosed that the production of melanin in melanocytes can be promoted by administering a composition containing fructose 1,6-bisphosphate its derivatives. (US20220226220A1)

Leidos Inc., in its patent WO2022081426A1, has disclosed a pharmaceutical composition containing a peptide that shows re-pigmentation effect in hair.

Asma Mirza, an independent inventor, has disclosed a dietary supplement containing black beans, black seeds, walnuts and flaxseeds in US8512772B1. The use of this dietary supplement can retard, prevent, suppress, and even reverse the greying of hair due to the antioxidant properties of the ingredients.


A multi-vitamin nutraceutical was designed by GetawayGrey to reverse and prevent grey hair. GetAwayGrey is a supplement that replicates the Catalase enzyme, the lack of which causes grey hair, and stops the chemical chain reaction that causes hair to bleach itself from the inside out. According to Karin Schallreuter, Professor of clinical and experimental dermatology at the University of Bradford,  UK, replacing Catalase could have great implications in human hair turning grey. Several thousand people tried the product and obtained desired results within as early as eight weeks[39].

Rivertown Therapeutics, Inc., a New York-based start-up, has developed a topical medication to reverse grey hair. The topical compound RT1640 was developed by combining three drugs, cyclosporin, minoxidil and a new molecule that is said to cause hair regrowth. The stem cell migration induces hair to grow with its original color.

Full scale FDA clinical trials will be necessary before it is available in the market[40].


Hair cosmetics is currently entering a new era of gene modulation. Designer drugs, natural compounds, siRNAs, bioactive macromolecules etc., in association with polymeric nanoparticles, liposomes and lipid nanoparticles, are being used to modulate the expression or function of desired genes that are responsible for natural colour modulation in hair[41]. This will indeed create a whole portfolio of hair care products.




  • This document has been created for educational and instructional purposes only
  • Copyrighted materials used have been specifically acknowledged
  • We claim the right of fair use as ascertained by the author

Posted Date: August, 2022


Dr.Baisali Sarkar
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