Therapeutic effect of androgen therapy in a mouse model of aplastic anemia produced by short telomeres

Bär, Christian; Huber, Nicolas; Beier, Fabian; Blasco, Marı́a A.

doi:10.3324/haematol.2015.129239

Cited by 71 publications

(45 citation statements)

References 39 publications

(44 reference statements)

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“…The mechanisms by which the high-intensity exercise training results in telomere preservation in master sprinters need to be investigated. On the other hand, studies conducted with individuals other than middle-aged sprinters indicate that an improved antioxidant status, a decreased oxidative stress and reduced inflammation [27], as well as lower levels of stress hormones with a better autonomic balance [3], and perhaps a preservation of the hypothalamic-pituitary-gonadal axis function during aging [2], may be involved in lower telomere attrition and higher telomerase activity leading to TL preservation). Future investigations regarding these possible mechanisms in master sprinters should also include endurance master athletes (whose training is performed at higher volume and lower intensity) for comparison, in order to verify if both training regimens are equally beneficial and if protective mechanisms of TL during aging are the same.…”

Section: Non-athletes (N = 10)mentioning

confidence: 99%

Longer Telomere Length in Elite Master Sprinters: Relationship to Performance and Body Composition

et al. 2017

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Emergent evidence suggests that the long-term healthy lifestyle of master athletes may attenuate aging. We compared telomere length (TL) of high-level master sprinters and non-athlete age-matched controls, and analyzed the relationships of TL with performance and body fat. Elite master sprinters (n=11; aged 50.1±9.2yrs) and healthy untrained controls (n=10; aged 45.4±10.9yrs) had blood samples collected for biochemical and biomolecular analyses. Master sprinters had longer TL, lower body fat and BMI, and a better lipid profile than age-matched controls (p<0.05). A large effect size was verified comparing TL between athletes vs. controls (Cohen's d=1.039), with a significant negative correlation between TL and performance decline per decade (r=-0.624, p<0.01) and a positive correlation of TL and actual performance level (r=0.641, p<0.01). In conclusion, TL of elite master sprinters was longer than their untrained peers, and seems to be not only a marker of health status, but also an indicator of sports longevity since both actual performance level and its decrease over years were related to TL. Further research might assess the TL of elite master endurance athletes for comparison with sprinters, and also investigate the underlying mechanisms by which the attenuation of telomere shortening occurs in master athletes.

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Section: Non-athletes (N = 10)mentioning

confidence: 99%

Longer Telomere Length in Elite Master Sprinters: Relationship to Performance and Body Composition

et al. 2017

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“…It has been widely hypothesized that enhancing telomerase expression and activity may provide a therapeutic intervention for individuals diagnosed with telomeropathies (Holohan et al, 2014) and may even avert age-related conditions and increase longevity (Bar et al, 2015; Bernardes de Jesus et al, 2012; de Jesus, 2011). Further, preliminary evidence has demonstrated that sex steroid hormones may increase telomerase activity in certain cell lines and tissue types (Calado et al, 2009; Kyo et al, 1999; Nanni et al, 2002; Nourbakhsh et al, 2010; Sato et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Associations between circulating sex steroid hormones and leukocyte telomere length in men in the National Health and Nutrition Examination Survey

et al. 2018

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Preliminary evidence suggests that sex steroid hormones, such as danazol (a synthetic sex steroid hormone), may be involved in enhancing telomerase activity. Elucidating underlying mechanisms of telomerase activity may further therapeutic options for individuals with telomeropathies and potentially avert certain age-related conditions. Therefore, we conducted a cross-sectional study to investigate the relationship between circulating sex steroid hormones and SHBG with leukocyte telomere length among 499 males in NHANES (1999-2002 surveys). Sample-weighted linear regression analyses were conducted to assess age-adjusted and multivariable-adjusted estimates of associations. Estimates were rescaled to represent telomere length change in base pairs per half the value of the interquartile range of the independent variable. Estradiol and free estradiol were significantly inversely associated with leukocyte telomere length (β = -61, p = 0.04; free estradiol β = -67, p = 0.03). Testosterone, free testosterone, androstanediol glucuronide, and SHBG were not associated with leukocyte telomere length. The inverse association seen in this study indicates that a danazol-induced hypoestrogenic state could partly underlie the previously observed association between danazol therapy and increased leukocyte telomere length.

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“…15 Recently, treatment with male hormones was shown to lead to hematologic improvement and telomere elongation in a mouse model of telomere dysfunction. 16 In a large epidemiologic study, metabolites of testosterone and genetic polymorphisms affecting hormone exposure were each linked to leukocyte telomere length in almost 1000 healthy men. 17 Here, we report the results of a study that was designed to assess retardation of telomere loss with androgen therapy in patients with a variety of telomere diseases and the effect of androgen therapy in improving blood counts.…”

mentioning

confidence: 99%

Danazol Treatment for Telomere Diseases

Townsley¹,

Dumitriu²,

Liu³

et al. 2016

N Engl J Med

326

247

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BACKGROUND Genetic defects in telomere maintenance and repair cause bone marrow failure, liver cirrhosis, and pulmonary fibrosis, and they increase susceptibility to cancer. Historically, androgens have been useful as treatment for marrow failure syndromes. In tissue culture and animal models, sex hormones regulate expression of the telomerase gene. METHODS In a phase 1–2 prospective study involving patients with telomere diseases, we administered the synthetic sex hormone danazol orally at a dose of 800 mg per day for a total of 24 months. The goal of treatment was the attenuation of accelerated telomere attrition, and the primary efficacy end point was a 20% reduction in the annual rate of telomere attrition measured at 24 months. The occurrence of toxic effects of treatment was the primary safety end point. Hematologic response to treatment at various time points was the secondary efficacy end point. RESULTS After 27 patients were enrolled, the study was halted early, because telomere attrition was reduced in all 12 patients who could be evaluated for the primary end point; in the intention-to-treat analysis, 12 of 27 patients (44%; 95% confidence interval [CI], 26 to 64) met the primary efficacy end point. Unexpectedly, almost all the patients (11 of 12, 92%) had a gain in telomere length at 24 months as compared with baseline (mean increase, 386 bp [95% CI, 178 to 593]); in exploratory analyses, similar increases were observed at 6 months (16 of 21 patients; mean increase, 175 bp [95% CI, 79 to 271]) and 12 months (16 of 18 patients; mean increase, 360 bp [95% CI, 209 to 512]). Hematologic responses occurred in 19 of 24 patients (79%) who could be evaluated at 3 months and in 10 of 12 patients (83%) who could be evaluated at 24 months. Known adverse effects of danazol — elevated liver-enzyme levels and muscle cramps — of grade 2 or less occurred in 41% and 33% of the patients, respectively. CONCLUSIONS In our study, treatment with danazol led to telomere elongation in patients with telomere diseases. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01441037.)

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Therapeutic effect of androgen therapy in a mouse model of aplastic anemia produced by short telomeres

Cited by 71 publications

References 39 publications

Longer Telomere Length in Elite Master Sprinters: Relationship to Performance and Body Composition

Longer Telomere Length in Elite Master Sprinters: Relationship to Performance and Body Composition

Associations between circulating sex steroid hormones and leukocyte telomere length in men in the National Health and Nutrition Examination Survey

Danazol Treatment for Telomere Diseases

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