Hair greying in castrated mice

Introduction

Hair greying is a common and ubiquitous feature of human aging.¹ Although the rate of hair greying varies among individuals, almost all males and females experience depigmentation of hair shafts with age. Because the color in hair shafts is provided by melanin granules, which are supplied to the trichocytes of growing hair shafts by melanocytes,² age-related hair greying is thought to involve some dysfunction to these processes.³

In contrast to humans, mice do not show any obvious hair greying, probably because they have a much shorter lifespan. However, hair greying in mice is experimentally inducible by genetic manipulation³ or ionizing radiation,⁴ suggesting that hair greying in humans may also involve genetic variation and genomic damage. Very recently, a report demonstrated that strong acute stress leads to hair greying in mice through depletion of melanocyte stem cells.⁵ Consistent with this, another report indicated that hair greying in humans likely occurs in parallel with psychological stressors.⁶ Given that genomic damage and psychological stress are likely to accumulate with age, these factors may explain the mechanism of age-related hair greying in humans. However, the true mechanism remains unclear due to the lack of direct evidence for this hypothesis and the presence of multiple other factors related to aging that may be involved in human hair greying.

Many previous studies have demonstrated a relationship between sex hormones and hair physiology and drastic changes in the secretion of sex hormones with age.^7,8 Therefore, in this study, we focused on the causal link between sex hormone secretion and hair greying.

Methods

Results and discussion

Intact male and female C57BL6 mice did not show any visibly obvious signs of hair greying over their lifetime, probably because their lifespan was too short for depigmentation to begin in the hair shaft. Based on a previous report demonstrating that repetitive shaving or plucking accelerates hair greying,⁹ we applied this method to increase the susceptibility of hair shafts to greying in response to experimental intervention. As expected, neither a single shaving nor waxing session to pluck hair shafts from the back was sufficient to induce hair greying (shaving, 16-week-old males (n = 12) and females (n = 12); plucking, 16-week-old males (n = 52) and females (n = 12)). Next, to simply and directly test the involvement of androgen in hair greying, we examined whether or not a single session of plucking hair shafts from the back caused hair to grey in castrated male mice (Figure 1a). We found that while sham-operated mice did not show any visible signs of greying, one-third of castrated mice showed hair greying in a small area on the surface of the back (16-week-old sham-operated (n = 12) and castrated males (n = 18)). A Fisher’s exact test showed that there was a significant difference in the incidence of hair greying between sham-operated and castrated males (0 out of 12 sham-operated versus 6 out of 18 castrated males, P < 0.01). Taken together, these results suggest that loss of androgen substantially accelerates hair greying. Grey hair shafts were still present after more than 100 days post-hair plucking (Figure 1b). Given that the length of each hair cycle in mice is about 25 days,¹⁰ this result indicates that hair greying continued across at least four hair cycles. Therefore, just a single session of hair plucking in castrated mice caused long-lasting damage to the pigmentation of hair shafts.

Figure 1. Long-lasting hair greying in castrated mice subjected to a single session of hair plucking.

(a) Representative images of the back of sham-operated and castrated male mice 24 days after hair plucking. The operation and waxing were performed when mice were 5 and 16 weeks old, respectively. Hair shafts were removed from almost the entire area of the back in the image. The area containing greying hairs is enlarged two-fold and shown at the bottom.

(b) An image showing the back of a castrated mouse with greying hair 103 days after hair plucking. The animal in this image is the same as that shown in the rightmost image in (a).

Considering that androgen secretion decreases with age in both male and female humans,⁸ a possible interpretation of the present findings is that this decrease contributes to age-related hair greying in humans. While it is well known that androgen is involved in the pathogenesis of androgenetic alopecia,¹¹ the present study is the first to show that androgen is also involved in hair greying. Further studies are required to elucidate the mechanism underlying how loss of androgen causes depigmentation of hair shafts.

A potential limitation of the present study is that our experimental results may not directly explain age-related hair greying in humans because hair greying in mice was induced by hair plucking. However, it is difficult to overcome this technical limitation in animal experiments due to the creatures’ short lifespan, thus, unavoidably requiring some artificial induction of hair greying. Another potential limitation is that we cannot currently explain why a single session of hair plucking causes hair to grey in only about 33% but not all castrated mice, and in just a small area but not the entire surface of the back.

The present method may be useful for generating a new mouse model of hair greying that differs from most previous models in that it does not require genetic manipulations. However, our experimental procedure needs to be modified to improve the success rate and increase the body surface across which hair greying is induced. It is possible that a second session of hair plucking may overcome these limitations. Successful modification of the procedure for hair greying will provide a useful mouse model for studying the mechanism and prevention of human hair greying.

Data availability

All data underlying the results are available as part of the article and no additional source data are required.

Author contributions

A.M., J.K. and N.K. performed experiments. K.N. provided a wide range of general support. M.A. conceived and supervised the project and wrote the manuscript.