Ann Dermatol.  2018 Aug;30(4):397-401. 10.5021/ad.2018.30.4.397.

Three Streams for the Mechanism of Hair Graying

• Jo SK
• Lee JY
• Lee Y
• Kim CD
• Lee JH
• Lee YH

• KMID: 2457515
• DOI: http://doi.org/10.5021/ad.2018.30.4.397

Abstract

Hair graying is an obvious sign of human aging. Although graying has been investigated extensively, the mechanism remains unclear. Here, we reviewed previous studies on the mechanism of graying and seek to offer some new insights. The traditional view is that hair graying is caused by exhaustion of the pigmentary potential of the melanocytes of hair bulbs. Melanocyte dysfunction may be attributable to the effects of toxic reactive oxygen species on melanocyte nuclei and mitochondria. A recent study suggests that bulge melanocyte stem cells (MSCs) are the key cells in play. Graying may be caused by defective MSC self-maintenance, not by any deficiency in bulbar melanocytes. Our previous study suggested that graying may be principally attributable to active hair growth. Active hair growth may produce oxidative or genotoxic stress in hair bulge. These internal stress may cause eventually depletion of MSC in the hair follicles. Taken together, hair graying may be caused by MSC depletion by genotoxic stress in the hair bulge. Hair graying may also be sometimes caused by dysfunction of the melanocytes by oxidative stress in the hair bulb. In addition, hair graying may be attributable to MSC depletion by active hair growth.

Keyword

Hair bulb; Hair bulge; Hair graying; Hair growth; Melanocyte stem cell; Melanocytes

MeSH Terms

Aging
DNA Damage
Hair Follicle
Hair*
Humans
Melanocytes
Mitochondria
Oxidative Stress
Reactive Oxygen Species
Rivers*
Stem Cells
Reactive Oxygen Species

Figure

• 

  Fig. 1 Hair graying may be caused by (1) depletion or dysfunction of melanocytes producing melanin in the hair matrix near the dermal papilla of the hair follicle (the theory of Tobin and Paus), (2) defective hair bulge MSC self-maintenance via genotoxic stress (the theory of Fisher and Nishimura), and/or (3) oxidative or genotoxic stress associated with active hair growth (the theory of Lee et al.).

Reference

1. Keogh EV, Walsh RJ. Rate of greying of human hair. Nature. 1965; 207:877–878.

2. Panhard S, Lozano I, Loussouarn G. Greying of the human hair: a worldwide survey, revisiting the ‘50’ rule of thumb. Br J Dermatol. 2012; 167:865–873.

3. Lison M, Kornbrut B, Feinstein A, Hiss Y, Boichis H, Goodman RM. Progressive spastic paraparesis, vitiligo, premature graying, and distinct facial appearance: a new genetic syndrome in 3 sibs. Am J Med Genet. 1981; 9:351–357.

4. Shin H, Ryu HH, Yoon J, Jo S, Jang S, Choi M, et al. Association of premature hair graying with family history, smoking, and obesity: a cross-sectional study. J Am Acad Dermatol. 2015; 72:321–327.

5. Tobin DJ, Paus R. Graying: gerontobiology of the hair follicle pigmentary unit. Exp Gerontol. 2001; 36:29–54.

6. Trüeb RM, Tobin DJ. Aging hair. Hedelberg: Springer;2010. p. 77–89.

7. Doubaj Y, De Sandre-Giovannoli A, Vera EV, Navarro CL, Elalaoui SC, Tajir M, et al. An inherited LMNA gene mutation in atypical Progeria syndrome. Am J Med Genet A. 2012; 158A:2881–2887.

8. Di Giacomo TB, Valente NY, Nico MM. Chloroquine - induced hair depigmentation. Lupus. 2009; 18:264–266.

9. Donovan JC, Price VH. Images in clinical medicine. Chloroquine-induced hair hypopigmentation. N Engl J Med. 2010; 363:372.

10. Chakrabarty S, Krishnappa PG, Gowda DG, Hiremath J. Factors associated with premature hair graying in a young Indian population. Int J Trichology. 2016; 8:11–14.

11. Seiberg M. Age-induced hair greying - the multiple effects of oxidative stress. Int J Cosmet Sci. 2013; 35:532–538.

12. Commo S, Gaillard O, Bernard BA. Human hair greying is linked to a specific depletion of hair follicle melanocytes affecting both the bulb and the outer root sheath. Br J Dermatol. 2004; 150:435–443.

13. Arck PC, Overall R, Spatz K, Liezman C, Handjiski B, Klapp BF, et al. Towards a “free radical theory of graying”: melanocyte apoptosis in the aging human hair follicle is an indicator of oxidative stress induced tissue damage. FASEB J. 2006; 20:1567–1569.

14. Wood JM, Decker H, Hartmann H, Chavan B, Rokos H, Spencer JD, et al. Senile hair graying: H2O2-mediated oxidative stress affects human hair color by blunting methionine sulfoxide repair. FASEB J. 2009; 23:2065–2075.

15. Slominski A, Wortsman J, Plonka PM, Schallreuter KU, Paus R, Tobin DJ. Hair follicle pigmentation. J Invest Dermatol. 2005; 124:13–21.

16. Seiberg M. Keratinocyte-melanocyte interactions during melanosome transfer. Pigment Cell Res. 2001; 14:236–242.

17. Joshi PG, Nair N, Begum G, Joshi NB, Sinkar VP, Vora S. Melanocyte-keratinocyte interaction induces calcium signalling and melanin transfer to keratinocytes. Pigment Cell Res. 2007; 20:380–384.

18. Nagl W. Different growth rates of pigmented and white hair in the beard: differentiation vs. proliferation? Br J Dermatol. 1995; 132:94–97.

19. Slominski A, Paus R. Melanogenesis is coupled to murine anagen: toward new concepts for the role of melanocytes and the regulation of melanogenesis in hair growth. J Invest Dermatol. 1993; 101:1 Suppl. 90S–97S.

20. Slominski A, Paus R, Schadendorf D. Melanocytes as “sensory” and regulatory cells in the epidermis. J Theor Biol. 1993; 164:103–120.

21. Slominski A. Neuroendocrine system of the skin. Dermatology. 2005; 211:199–208.

22. Ito N, Ito T, Kromminga A, Bettermann A, Takigawa M, Kees F, et al. Human hair follicles display a functional equivalent of the hypothalamic-pituitary-adrenal axis and synthesize cortisol. FASEB J. 2005; 19:1332–1334.

23. Kauser S, Thody AJ, Schallreuter KU, Gummer CL, Tobin DJ. A fully functional proopiomelanocortin/melanocortin-1 receptor system regulates the differentiation of human scalp hair follicle melanocytes. Endocrinology. 2005; 146:532–543.

24. Kauser S, Slominski A, Wei ET, Tobin DJ. Modulation of the human hair follicle pigmentary unit by corticotropin-releasing hormone and urocortin peptides. FASEB J. 2006; 20:882–895.

25. Tobin DJ, Kauser S. Hair melanocytes as neuro-endocrine sensors--pigments for our imagination. Mol Cell Endocrinol. 2005; 243:1–11.

26. Schneider MR, Schmidt-Ullrich R, Paus R. The hair follicle as a dynamic miniorgan. Curr Biol. 2009; 19:R132–R142.

27. Meyer KC, Brzoska T, Abels C, Paus R. The alpha-melanocyte stimulating hormone-related tripeptide K(D)PT stimulates human hair follicle pigmentation in situ under proinflammatory conditions. Br J Dermatol. 2009; 160:433–437.

28. Paus R, Arck P. Neuroendocrine perspectives in alopecia areata: does stress play a role? J Invest Dermatol. 2009; 129:1324–1326.

29. Paus R. A neuroendocrinological perspective on human hair follicle pigmentation. Pigment Cell Melanoma Res. 2011; 24:89–106.

30. Takada K, Sugiyama K, Yamamoto I, Oba K, Takeuchi T. Presence of amelanotic melanocytes within the outer root sheath in senile white hair. J Invest Dermatol. 1992; 99:629–633.

31. Horikawa T, Norris DA, Johnson TW, Zekman T, Dunscomb N, Bennion SD, et al. DOPA-negative melanocytes in the outer root sheath of human hair follicles express premelanosomal antigens but not a melanosomal antigen or the melanosome-associated glycoproteins tyrosinase, TRP-1, and TRP-2. J Invest Dermatol. 1996; 106:28–35.

32. Nishimura EK, Granter SR, Fisher DE. Mechanisms of hair graying: incomplete melanocyte stem cell maintenance in the niche. Science. 2005; 307:720–724.

33. Nishimura EK, Suzuki M, Igras V, Du J, Lonning S, Miyachi Y, et al. Key roles for transforming growth factor beta in melanocyte stem cell maintenance. Cell Stem Cell. 2010; 6:130–140.

34. Nishimura EK. Melanocyte stem cells: a melanocyte reservoir in hair follicles for hair and skin pigmentation. Pigment Cell Melanoma Res. 2011; 24:401–410.

35. Tanimura S, Tadokoro Y, Inomata K, Binh NT, Nishie W, Yamazaki S, et al. Hair follicle stem cells provide a functional niche for melanocyte stem cells. Cell Stem Cell. 2011; 8:177–187.

36. Inomata K, Aoto T, Binh NT, Okamoto N, Tanimura S, Wakayama T, et al. Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation. Cell. 2009; 137:1088–1099.

37. Valluet A, Druillennec S, Barbotin C, Dorard C, Monsoro-Burq AH, Larcher M, et al. B-Raf and C-Raf are required for melanocyte stem cell self-maintenance. Cell Rep. 2012; 2:774–780.

38. Lee JH, Fisher DE. Melanocyte stem cells as potential therapeutics in skin disorders. Expert Opin Biol Ther. 2014; 14:1569–1579.

39. Choi YJ, Yoon TJ, Lee YH. Changing expression of the genes related to human hair graying. Eur J Dermatol. 2008; 18:397–399.

40. Van Neste D. Thickness, medullation and growth rate of female scalp hair are subject to significant variation according to pigmentation and scalp location during ageing. Eur J Dermatol. 2004; 14:28–32.

41. Choi HI, Choi GI, Kim EK, Choi YJ, Sohn KC, Lee Y, et al. Hair greying is associated with active hair growth. Br J Dermatol. 2011; 165:1183–1189.

42. Shimomura Y, Aoki N, Rogers MA, Langbein L, Schweizer J, Ito M. Characterization of human keratin-associated protein 1 family members. J Investig Dermatol Symp Proc. 2003; 8:96–99.

43. Schweizer J, Langbein L, Rogers MA, Winter H. Hair follicle-specific keratins and their diseases. Exp Cell Res. 2007; 313:2010–2020.

44. Ota Y, Saitoh Y, Suzuki S, Ozawa K, Kawano M, Imamura T. Fibroblast growth factor 5 inhibits hair growth by blocking dermal papilla cell activation. Biochem Biophys Res Commun. 2002; 290:169–176.

45. Drögemüller C, Rüfenacht S, Wichert B, Leeb T. Mutations within the FGF5 gene are associated with hair length in cats. Anim Genet. 2007; 38:218–221.

46. Danilenko DM, Ring BD, Yanagihara D, Benson W, Wiemann B, Starnes CO, et al. Keratinocyte growth factor is an important endogenous mediator of hair follicle growth, development, and differentiation. Normalization of the nu/nu follicular differentiation defect and amelioration of chemotherapy-induced alopecia. Am J Pathol. 1995; 147:145–154.

47. Guo L, Degenstein L, Fuchs E. Keratinocyte growth factor is required for hair development but not for wound healing. Genes Dev. 1996; 10:165–175.

48. Mizuno S, Iijima S, Okano T, Kajiwara N, Kunita S, Sugiyama F, et al. Retrotransposon-mediated Fgf5(go-Utr) mutant mice with long pelage hair. Exp Anim. 2011; 60:161–167.