Towards a “free radical theory of graying”: melanocyte apoptosis in the aging human hair follicle is an indicator of oxidative stress induced tissue damage

Here we provide unique evidence for oxidative stress induced loss of melanocytes from the human hair follicle during aging. In detail, we show for the first time that:1)a decreased number of viable melanocytes in the aging hair follicle bulge and bulb and an increased incidence of hair bulb melanocyte apoptosis in aging individuals are associated with oxidative stress in the pigmentary unit;2)the aging hair follicle is characterized by the absence of oxidative stress-protectors, such as Bcl-2, and melanocyte growth factors, such as c-Kit;3)a higher frequency of oxidative stress associated mitochondrial DNA damage occurs in graying hair follicles, while unpigmented hair follicles prove to be not “older” than pigmented hair follicles;4)melanocytes of the pigmentary unit are highly and selectively susceptible to exogenous oxidative stress damage.One major route, by which oxidative stress leads to permanent melanocyte damage, appears to pass by the mitochondria, since their DNA is not so well protected as genomic DNA. The accumulation of mutations, therefore, correlates with age and is indicative of general exposure and generation of oxidative stress, (39⤻, 40)⤻caused for example by psychoemotional stress, inflammation, UV-light, and others. In summary, our findings support the proposed hypothesis of a “free radical theory of graying” and suggest that melanocytes in the hair follicle are highly susceptible to endogenous oxidative stress. Exogenous oxidative stress can trigger and hasten this process and provoke permanent damage selectively and prematurely in hair bulb melanocytes.

FGF5 is a crucial regulator of hair length in humans

Hair length varies dramatically on different body sites and also varies between individuals. Thus, hair length is a quantitative trait, suggesting inherited differences. In this study, we obtained DNA from families segregating excessively long eyelashes consistent with an autosomal recessive trait. We identified mutations in a single gene, fibroblast growth factor 5 (FGF5), which was homozygous in affected family members only. FGF5 has previously been implicated as a regulator of hair lengths in mammals, with mutations resulting in the well-described angoraphenotype. However, until now a human counterpart to this phenotype remained elusive. Here, we present, to our knowledge, the first human counterpart of the angoraphenotype, showing that FGF5 underlies trichomegaly and is a crucial regulator of hair growth in humans.

The impact of oxidative stress on hair

Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system’s ability to detoxify the reactive intermediates or to repair the resulting damage. Reactive oxygen species or free radicals are highly reactive molecules that can directly damage lipids, proteins, and DNA. They are generated by a multitude of endogenous and environmental challenges, while the body possesses endogenous defense mechanisms. With age, production of free radicals increases, while the endogenous defense mechanisms decrease. This imbalance leads to progressive damage of cellular structures, presumably resulting in the aging phenotype. While the role of oxidative stress has been widely discussed in skin aging, little focus has been placed on its impact on hair condition. Moreover, most literature on age‐related hair changes focuses on alopecia, but it is equally important that the hair fibers that emerge from the scalp exhibit significant age‐related changes that have equal impact on the overall cosmetic properties of hair. Sources of oxidative stress with impact on the pre‐emerging fiber include: oxidative metabolism, smoking, UVR, and inflammation from microbial, pollutant, or irritant origins. Sources of oxidative stress with impact on the post‐emerging fiber include: UVR (enhanced by copper), chemical insults, and oxidized scalp lipids. The role of the dermatologist is recognition and treatment of pre‐ and post‐emerging factors for lifetime scalp and hair health.

Repigmentation of hair following adalimumab therapy

Repigmentation of canities, or age-related grey or white hair, is a rare occurrence. Generalized repigmentation of grey-white hair has been reported following inflammatory processes,[1] and heterochromia (localized patches of hair repigmentation) is even more unusual, reported in association with medication use and malignancy.Tumor necrosis factor (TNF) inhibitors are increasingly utilized medications for inflammatory disorders, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. Hair loss, or alopecia, has been described among the side effects of these medications,[2] but changes in hair pigmentation in association with this class of drugs have not previously been reported. We describe a patient with hair repigmentation associated with adalimumab therapy.

A Comment on the Science of Hair Aging

In contrast to the skin, aging of the hair has seemingly only recently found the attention of dermatological meetings, mainly promoted by the cosmetic industry for marketing purposes. In fact, basic scientists interested in the biology of hair growth and pigmentation have for some time already exposed the hair follicle as a highly accessible model with unique opportunities for the study of age-related effects. As a result, the science of hair aging focuses on two main streams of interest: the esthetic problem of aging hair and its management, in terms of age-related effects on hair color, quantity, and quality; and the biological problem of aging hair, in terms of microscopic, biochemical, and molecular changes underlying the aging process. Ultimately, the aim of hair anti-aging is to delay, lessen, or reverse the effects of aging on hair. According to the complex nature of the aging process, the treatment for lifetime scalp and hair health has to be holistic to include the multitude of contributing factors in a polyhedral and patient-specific manner. It comprises both medical treatments and hair cosmetics. Accordingly, the discovery of pharmacological targets and the development of safe and effective drugs for treatment of hair loss indicate strategies of the drug industry for maintenance of hair growth and quantity, while the hair care industry has become capable of delivering active compounds directed toward meeting the consumer demand for maintenance of hair cosmesis and quality. “Where there’s life, there’s hope” (Ecclesiastes 9:3-5).

Three Streams for the Mechanism of Hair Graying

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.

Pharmacologic interventions in aging hair

The appearance of hair plays an important role in people’s overall physical appearance and self-perception. With today’s increasing life-expectations, the desire to look youthful plays a bigger role than ever. The hair care industry has become aware of this and is delivering active products directed towards meeting this consumer demand. The discovery of pharmacological targets and the development of safe and effective drugs also indicate strategies of the drug industry for maintenance of healthy and beautiful hair. Hair aging comprises weathering of the hair shaft, decrease of melanocyte function, and decrease in hair production. The scalp is subject to intrinsic and extrinsic aging. Intrinsic factors are related to individual genetic and epigenetic mechanisms with interindividual variation: prototypes are familial premature graying, and androgenetic alopecia. Currently available pharmacologic treatment modalities with proven efficacy for treatment of androgenetic alopecia are topical minoxidil and oral finasteride. Extrinsic factors include ultraviolet radiation and air pollution. Experimental evidence supports the hypothesis that oxidative stress also plays a role in hair aging. Topical anti-aging compounds include photoprotectors and antioxidants. In the absence of another way to reverse hair graying, hair colorants remain the mainstay of recovering lost hair color. Topical liposome targeting for melanins, genes, and proteins selectively to hair follicles are currently under investigation.

Histopathology of aging of the hair follicle

Hair follicles experience several changes with aging, the most noticeable of which is graying of the hair shaft due to loss of melanin. Additional changes in the diameter and length of the hair have contributed to the concept of senescent alopecia, which is different from androgenetic alopecia according to most. Graying happens in most individuals, although in different grades and starting at different ages. It is related to a decrease in the number and activity of the melanocytes of the hair bulb, which eventually completely disappear from the bulb of the white hair. Residual non‐active melanocytes remain in the outer root sheath and in the bulge, which allows for repigmentation of the hair under certain stimuli or conditions.

A review of the etiologies, clinical characteristics, and treatment of grey hair

Hair pigmentation is regulated by follicular melanogenesis, in which the process consists of melanin formation and transfer to keratinocytes in the hair shaft. Human hair follicles contain two types of melanin: the brown‐black eumelanin and yellow‐red pheomelanin. Eumelanin is commonly present in black and brown hair while pheomelanin is found in auburn and blonde hair. Hair follicle melanogenesis is under cyclical control and is concurrently coupled to hair growth. Many factors including intrinsic and extrinsic factors affect the follicular melanogenesis. Though many studies have been conducted to identify the pathogenesis and regulation of hair pigmentation, the etiology of canities and hair pigmentation is still unclear. The pathogenesis of canities or gray hair is believed to occur either from insufficient melanin formation due to melanocyte degeneration or a defect in melanosomal transfer. Canities is an aging sign which often interferes with one’s socio‐cultural adjustment. On the other hand, premature canities correlate with diseases such as osteopenia and cardiovascular disease. Risk factors associated with canities are not only genetic but also external causes. For example, smoking, alcohol consumption, and stress are among the most common factors. Camouflage techniques are still used as the primary treatment of canities. Further treatments for canities are being developed to achieve the true reversal of hair pigmentation.

Aging of the Hair Follicle Pigmentation System

Skin and hair phenotypes are powerful cues in human communication. They impart much information, not least about our racial, ethnic, health, gender and age status. In the case of the latter parameter, we experience significant change in pigmentation in our journey from birth to puberty and through to young adulthood, middle age and beyond. The hair follicle pigmentary unit is perhaps one of our most visible, accessible and potent aging sensors, with marked dilution of pigment intensity occurring long before even subtle changes are seen in the epidermis. This dichotomy is of interest as both skin compartments contain melanocyte subpopulations of similar embryologic (i.e., neural crest) origin. Research groups are actively pursuing the study of the differential aging of melanocytes in the hair bulb versus the epidermis and in particular are examining whether this is in part linked to the stringent coupling of follicular melanocytes to the hair growth cycle. Whether some follicular melanocyte subpopulations are affected, like epidermal melanocytes, by UV irradiation is not yet clear. A particular target of research into hair graying or canities is the nature of the melanocyte stem compartment and whether this is depleted due to reactive oxygen species-associated damage, coupled with an impaired antioxidant status, and a failure of melanocyte stem cell renewal. Over the last few years, we and others have developed advanced in vitro models and assay systems for isolated hair follicle melanocytes and for intact anagen hair follicle organ culture which may provide research tools to elucidate the regulatory mechanisms of hair follicle pigmentation. Long term, it may be feasible to develop strategies to modulate some of these aging-associated changes in the hair follicle that impinge particularly on the melanocyte populations.

Dihydrotestosterone-inducible IL-6 inhibits elongation of human hair shafts by suppressing matrix cell proliferation and promotes regression of hair follicles in mice.

Cytokines and Other Mediators in Alopecia Areata

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