**Author details**

span and delay the onset of age-related diseases, these findings suggest a possibility of

Androgen has been used to treat bone mallow failure and aplastic anemia with the anabolic effect on bone marrow [87], although precise mechanisms have not been fully understood. It has been reported that telomere diseases with mutations in genes responsible for telomere maintenance and repair lead to bone mallow failure [88]. Interestingly, considerable evidence suggests that androgen directly regulates telomerase activity [89]. Recently, it has been reported that the treatment with androgen leads to telomere elongation in a mouse model of telomerase dysfunction [90]. In addition, serum dihydrotestosterone and estradiol levels and aromatase gene polymorphisms were associated with telomere length [91]. Very recently, Townsley et al. reported that danazol, the synthetic sex hormone, which has androgen activity, was efficacious to elongate the telomere length in bone marrow cells [92]. Patients with mutations in the genes related to the telomere maintenance or repairment, such as *TERT*, *TERC*, and *DKC1*, were enrolled and orally administered danazol at a dose of 800 mg/day for a total of 24 months. Surprisingly, almost all the patients (11 of 12) had a substantial gain in telomere length at 24 months when compared with baseline. Hematologic responses were also observed in 10 of 12 patients at 24 months. As an underlying mechanism, *in vitro* study showed a direct effect of androgen on telomerase activity by upregulation of *TERT* expression [93]. Although whether androgen is also effective to subjects without gene mutations in telomererelated genes is still unclear, there is a possibility that pharmacological intervention for

telomere elongation may be applicable for the treatment of age-related disease.

In summary, telomere length assessed in peripheral leukocytes is associated with various metabolic and endocrine diseases **Figure 2A**. In addition, recent studies suggest that shortened telomeres may have a causal role in the pathophysiology of age-related diseases, such as T2DM, metabolic syndrome, and cardiovascular disease **Figure 2B** [70,94]. However, it has not yet been elucidated that how shortened telomeres cause these age-related diseases. One possible explanation is SASP. Shortened telomeres activate DDR pathway, which results in apoptosis and/or cell cycle arrest, and cellular senescence. Recently, it has emerged that cellular senescence and the related SASP play important roles in the development of age-related diseases [8,9,95,96]. In conclusion, although there is a strong association between telomere shortening and metabolic and endocrine diseases, further studies are needed to understand the mechanisms underlying these associations. Also, it is suggested that interventions that restore telomere length may be a potential therapeutic target for age-related disease **Figure 2C**.

telomere/telomerase as a therapeutic target for preventing aging.

**6.2. Danazol**

152 Telomere - A Complex End of a Chromosome

**7. Conclusion**

Ryusaku Matsumoto and Yutaka Takahashi\*

\*Address all correspondence to: takahash@med.kobe-u.ac.jp

Division of Diabetes Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
