Takayama Ken-Ichi
Department of Functional Biogerontology, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan.
Department of Geriatric Medicine, Graduate School of Medicine, the University of Tokyo, Japan.
Endocr J. 2017 Oct 28;64(10):933-946. doi: 10.1507/endocrj.EJ17-0328. Epub 2017 Aug 19.
Hormonal alterations with aging contribute to the pathogenesis of several diseases. Androgens mediate their effects predominantly through binding to the androgen receptor (AR), a member of the ligand-dependent nuclear receptor superfamily. By androgen treatment, AR is recruited to specific genomic loci dependent on tissue specific pioneer factors to regulate target gene expression. Recent studies have revealed the epigenetic modulation by AR-associated histone modifiers and the roles of non-coding RNAs in AR signaling. Androgens are male sex hormone to induce differentiation of the male reproductive system required for the establishment of adult sexual function. As shown by several reports using AR knockout mouse models, androgens also have anabolic functions in several tissues such as bone, muscle and central nervous systems. Notably, AR has a central role in prostate cancer progression. Prostate cancer is the most frequently diagnosed cancer in men. Androgen-deprivation therapy for cancer patients and decline of serum androgen with aging promote several diseases associated with aging and quality of life of older men such as osteoporosis, sarcopenia and dementia. Thus, androgen replacement therapy for treating late onset hypogonadism (LOH) or new epigenetic regulators have the potential to overcome the symptoms caused by the low androgen, although adverse effects for cardiovascular diseases have been reported. Given the increasing longevity and consequent rise of age-related diseases and prostate cancer patients, a more understanding of the AR actions in male health remains a high research priority.
随着年龄增长的激素变化促成了多种疾病的发病机制。雄激素主要通过与雄激素受体（AR）结合来介导其作用，AR是配体依赖性核受体超家族的成员。通过雄激素治疗，AR会被招募到依赖于组织特异性先驱因子的特定基因组位点，以调节靶基因表达。最近的研究揭示了AR相关组蛋白修饰剂的表观遗传调控以及非编码RNA在AR信号传导中的作用。雄激素是诱导成年性功能建立所需的男性生殖系统分化的雄性激素。正如使用AR基因敲除小鼠模型的几份报告所示，雄激素在骨骼、肌肉和中枢神经系统等多个组织中也具有合成代谢功能。值得注意的是，AR在前列腺癌进展中起核心作用。前列腺癌是男性中最常被诊断出的癌症。癌症患者的雄激素剥夺疗法以及随着年龄增长血清雄激素的下降会引发与衰老相关的多种疾病以及老年男性的生活质量问题，如骨质疏松症、肌肉减少症和痴呆症。因此，用于治疗迟发性性腺功能减退（LOH）的雄激素替代疗法或新的表观遗传调节剂有可能克服低雄激素引起的症状，尽管已有关于心血管疾病不良反应的报道。鉴于寿命延长以及随之而来的与年龄相关疾病和前列腺癌患者数量的增加，更深入了解AR在男性健康中的作用仍然是一个高度优先的研究课题。
