The role of telomerase in hair growth and relevant disorders: A review

Hair diseases may present with hair loss, hirsutism, hair melanin abnormalities and other manifestations. Hair follicles are known as mini‐organs that undergo periodic remodeling, and their constant regeneration in vivo reflects interesting anti‐aging functions. Telomerase prevents cellular senescence by maintaining telomere length, but its excessive proliferation in cancer cells may also induce cancer. However, the effects of telomerase in hair growth have rarely been reported.

or lengthened telomeres showed decreased or increased life spans, respectively. 5In 1985, Greider and Blackburn first discovered a novel enzymatic activity capable of adding tandem DNA repeats onto chromosome ends and extending telomere length, 7 which is now called telomerase, a cellular reverse transcriptase.It has also been indicated that aging can be reverted by telomerase activation. 5ch evidence shows that abnormal telomerase activation is associated with cancer development.Under normal physiological conditions, telomere shortening in human cells and eventual senescence will result in the restriction of cell division potential, and cells will finally die. 8However, by activating or upregulating telomerase, cancer cells can counteract telomere shortening and become immortality.
Telomerase is active in approximately 85% of cancer tumors 8 and almost all human cancers can use telomerase activation as a marker.
Telomerase acts as an intersection of cancer and aging, 9 so activating its antiaging effects on human cells may also come with the risk of triggering cancer.Thus, the concept of "telomerase restoration therapy" was proposed as a potential strategy.Through transient telomerase induction, telomere reserve and healing are restored while avoiding the possibility of cancer-fueling that may arise from constitutive telomerase activation. 6At present, there are many natural substances, including Centella asiatica, Astragalus, oleanolic acid, etc. which have been proven to be effective telomerase activators at cellular levels. 10[13][14][15] Most human somatic cells with limited replication capacity do not contain telomerase activity due to the repression of the TERT gene expression, but cells with strong proliferative abilities such as embryonic stem cells and germ line cells do 16 .Telomerase activity has also been found in human adult stem cells including hematopoietic and nonhematopoietic stem cells in the skin, intestinal crypt, and liver. 16And for hair, telomerase has also been shown to play a certain role in regeneration.Until now, few studies have been conducted on telomerase activity and trends in HFs.This article will focus on the role of telomerase in hair growth and related diseases.

| ANATOMY OF THE HF AND THE E XPRE SS I ON OF TELOMER A S E
Hair has two separate structures: the follicle in the skin and the hair shaft on the body surface. 17A human hair follicular unit usually consists of two-three hair shafts, there are also those with only one hair shaft or even four-five.The follicle is the essential structure and is in charge of hair growth.The outermost aspect of the HF can be divided into the outer hair root sheath (ORS) and the inner hair root sheath (IRS).The ORS has been identified as a reservoir of multipotent stem cells including keratinocyte and melanocyte stem cells.The ORS proliferates between the insertion of the arrector pili muscle and the sebaceous gland duct to form a pronounced bulge area, which is currently considered the main part where HF stem cells (HFSCs) are present. 17The IRS consisting of Henle's layer, Huxley's layer, and cuticle layer, separates the hair shaft from the ORS. 17The bottom of the follicle consists of the bulb area, the matrix, and the papilla, which is known as the most important signaling center in hair. 18The size of the papilla and the bulb in the anagen phase determine a hair's diameter.Telomerase can be detected in keratinocytes of the basal epidermis but not in skin fibroblasts. 19Early in 1997, telomerase activity was first discovered in human HFs.By detecting telomerase activity in dissected compartments of the anagen HF, Ruben found that the bulb area contained high levels of telomerase activity while the bulge area and gland-containing fragment contained low levels, and no activity was detectable in the hair shafts. 20Early studies have shown that telomerase activity does not vary significantly as a function of cell proliferation, but decreases definitely in quiescent cells. 21Most HFSCs at the HF bulge are undifferentiated and quiescent, which supports the result of low telomerase activity at this site.Additionally, in catagen HF, telomerase activity in all parts was quantitated to be significantly lower than that of the anagen HF. 20 No association was found between the above telomerase activity trends and increasing age, possibly because HFs are in a constantly renewed growth cycle.

| TELOMER A S E AC TIVATI ON P OS ITIVELY PROMOTE S HAIR G ROW TH
The protein component of telomerase is called telomerase reverse transcriptase (TERT), which keeps telomeres long and stable enough to prevent the adverse consequences of dysfunctional telomeres on cell viability and chromosomal stability. 22Telomerase is primarily functioned by TERT, and TERT quantification can represent the level of telomerase activity.Given the complexity of the study and testing, the vast majority of data and valid conclusions of the telomerase's function in HFs are mainly based on mice models.As early as 2006, Sarin reported the conditioned transgenic induction of TERT in the skin epithelium of mice caused a rapid transition from the telogen phase to the anagen phase, thereby promoting robust hair growth. 22 not only confirmed the role of TERT in promoting hair growth but also verified that this is due to its ability to activate quiescent HFSCs. 22The longest telomeres are present in HF epithelial stem cells in mice. 23Masahiro ameliorates hair inductive activity by introducing the TERT gene into murine dermal papilla cells (DPCs). 24ter being infected with cytomegalovirus (CMV) with exogenous TERT, the mice experienced longer life spans, improved hair loss, overweigh, and other biomarkers associated with healthy aging without leading to cancer. 25In the studies of human histology, Mayumi showed that overexpression of TERT in human DPCs can promote hair growth, prolong HF life span, and maintain hair growth ability. 26 comparing existing hair growth gene databases, Choi concluded that TERT activates the expression of hair growth genes and inhibits the expression of antihair growth genes.What is more, these gene expression changes are directly related to changes in TERT levels. 27sed on the above experiments, the role of telomerase in promoting the growth of hair follicles can certainly be confirmed.But how exactly does it cause hair follicle regeneration?In fact, telomere shortening impairs the mobilization and proliferation of HFSCs, exhibiting a follicle aging phenotype of thinner hair, hair loss, or gray hair, 28  to the in vivo condition. 30This suggests that TERT can enhance the proliferative capacity of DPCs without impairing their hair inductivity.The IDPCs introduced of TERT could retain the activity of alkaline phosphatase, 31 and were confirmed by Fukuda to be free from cellular senescence. 32A variety of receptors including androgen receptors were stably and continuously expressed by transfected TERT-induced IDPCs, which helped to provide a stable source of cells for basic medical experiments. 32

| Telomerase in androgenetic alopecia
Although Ramirez reported no significant differences in telomerase activity levels among different types of male pattern baldness, 20 a regulatory relationship between TERT and androgens has been gradually demonstrated.Androgens, the key players in androgenetic alopecia (AGA), 33 can stimulate TERT gene expression and telomerase activity in human cells. 34Dihydrotestosterone, which is considered a major contributor to AGA, has been shown to regulate hTERT transcription and telomerase activity in vitro. 35This suggests that telomerase may play a temporarily unknown role in the development of AGA.Augmentation of TERT is likely to become a novel target for AGA treatment distinct from finasteride and minoxidil.

| Telomerase in chemotherapy-induced alopecia
One of the most serious and significant side effects of chemotherapy is hair loss, approximately 65% of patients receiving chemotherapy experience chemotherapy-induced alopecia (CIA). 36And to make matters worse, a small number of CIA is irreversible, and some patients even refuse chemotherapy for fear of CIA.The emergence of the CIA may be related to the suppression of telomere function by chemotherapy drugs exerting anticancer effects.According to similar speculation, Stone published the idea that pretreatment around HFs with topically applied telomerase activity inducers may represent a new strategy to reduce the risk of CIA. 37

| Telomerase in gray hair
Gray hair may be related to shortened telomeres.Blasco reported that the telomerase-knockout mice had dramatically more gray hair than control mice. 38The formation of gray hair is mainly due to a reduction in the active melanocyte population, which is probably caused by reactive oxygen species (ROS) damage.ROSs are preferentially attracted to the 5-terminal "GGG" sequences of telomeres, so long telomeres prevent the destruction of other fragments in the DNA.As telomeres shorten, this protection is lost and stressinduced premature senescence or apoptosis of melanocytes, 39 eventually manifests as gray hair.

| Telomerase in hirsutism
No study has confirmed whether telomerase levels in HFs of hirsutism are altered.However, Stone et al. proposed that inhibiting hTERT expression and/or telomerase activity by topical telomerase inhibitors could constitute a new therapeutic principle for hirsutism and hypertrichosis. 37

| Telomerase in cicatricial alopecia
In cicatricial or scarring alopecia, irreversible damage to HFs may be due to extremely short telomeres of HFSCs at the bulb, causing aging and apoptosis, and the lack of progenitor cells and transientamplifying cells leading to irreversible cessation of hair growth. 37ditionally, there still exist other types of hair disorders not be mentioned.Common as alopecia areata (AA), as we all know, is an autoimmune disease, part of which is self-limited.Its pathogenesis, currently considered to be related to immunity, genetics, oxidative stress, allergies, etc. 40 However, no studies have reported the relationship between AA and telomerase or cellular senescence, and this maybe a potential research direction.

| CON CLUS I ON S AND FUTURE DIREC TIONS
Telomerase, mainly distributed at the bottom bulb area of anagen HFs, positively promotes hair growth by enhancing cell proliferation and facilitating HF growth cycle transition (catagen to anagen).

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which may be due to the corresponding negative effects on DPCs and HF melanocytes.Overexpression of TERT or reintroduction of telomerase can reverse this defect, activate quiescent HFSCs and melanocyte stem cells, fight HF aging, and facilitate HF regeneration.IMMORTALIZED DP C S CONS TRUC TED BY TR AN S FEC TI ON OF H UMAN TERT The isolation and culture of DPCs in vitro are tedious and difficult, so the establishment of immortalized DPCs has brought great convenience to relevant researchers.The simultaneous introduction of human TERT (hTERT) and simian virus 40 large T antigen (SV40T-Ag) into very early passaged human scalp DPCs successfully established immortalized DPCs, which still retain responses to androgen, Wnt/β-catenin, and BMP signaling pathways, similar