FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice
FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice
复制标题
FOXO4-DRI 通过靶向衰老小鼠的衰老 Leydig 细胞来缓解与年龄相关的睾酮分泌不足。
DOI：
10.18632/aging.102682
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发表时间：
2020-01
期刊：
影响因子：
5.2
通讯作者：
Liu Guihua
中科院分区：
文献类型：
--
作者：
Zhang Chi;Xie Yun;Chen Haicheng;Lv Linyan;Yao Jiahui;Zhang Min;Xia Kai;Feng Xin;Li Yanqing;Liang Xiaoyan;Sun Xiangzhou;Deng Chunhua;Liu Guihua
男性迟发性性腺功能减退症是一种与年龄相关的疾病，其核心机制是衰老的间质细胞功能障碍。最近的研究表明，消除衰老细胞可以恢复衰老组织的适当稳态。在本研究中，我们发现叉头盒O（FOXO）转录因子FOXO4在人类Leydig细胞中特异表达，并且其易位至老年人的细胞核与睾酮合成减少有关。使用过氧化氢诱导的衰老 TM3 Leydig 细胞作为体外模型，我们观察到 FOXO4 维持衰老 Leydig 细胞的活力并抑制其凋亡。通过破坏 FOXO4-p53 相互作用，FOXO4-DRI（一种特定的 FOXO4 阻断剂）选择性诱导衰老 Leydig 细胞中的 p53 核排斥和细胞凋亡。在自然衰老的小鼠中，FOXO4-DRI 改善了睾丸微环境并缓解了与年龄相关的睾酮分泌不足。这些发现揭示了 FOXO4-DRI 治疗男性迟发性性腺功能减退症的治疗潜力。
Male late-onset hypogonadism is an age-related disease, the core mechanism of which is dysfunction of senescent Leydig cells. Recent studies have shown that elimination of senescent cells can restore proper homeostasis to aging tissue. In the present study, we found that the fork head box O (FOXO) transcription factor FOXO4 was specially expressed in human Leydig cells and that its translocation to the nucleus in the elderly was related to decreased testosterone synthesis. Using hydrogen peroxide-induced senescent TM3 Leydig cells as an in vitro model, we observed that FOXO4 maintains the viability of senescent Leydig cells and suppresses their apoptosis. By disrupting the FOXO4-p53 interaction, FOXO4-DRI, a specific FOXO4 blocker, selectively induced p53 nuclear exclusion and apoptosis in senescent Leydig cells. In naturally aged mice, FOXO4-DRI improved the testicular microenvironment and alleviated age-related testosterone secretion insufficiency. These findings reveal the therapeutic potential of FOXO4-DRI for the treatment of male late-onset hypogonadism.
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影响因子：
7.8
作者：
Zhu Y;Tchkonia T;Pirtskhalava T;Gower AC;Ding H;Giorgadze N;Palmer AK;Ikeno Y;Hubbard GB;Lenburg M;O'Hara SP;LaRusso NF;Miller JD;Roos CM;Verzosa GC;LeBrasseur NK;Wren JD;Farr JN;Khosla S;Stout MB;McGowan SJ;Fuhrmann-Stroissnigg H;Gurkar AU;Zhao J;Colangelo D;Dorronsoro A;Ling YY;Barghouthy AS;Navarro DC;Sano T;Robbins PD;Niedernhofer LJ;Kirkland JL
通讯作者：
Kirkland JL
血浆睾丸激素水平的个体变异来源。
DOI：
10.1098/rstb.2007.0001
发表时间：
2008-05-12
影响因子：
6.3
作者：
Kempenaers, Bart;Peters, Anne;Foerster, Katharina
通讯作者：
Foerster, Katharina
影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
影响因子：
64.8
作者：
Conboy, IM;Conboy, MJ;Rando, TA
通讯作者：
Rando, TA
影响因子：
2.6
作者：
Erenpreiss, Juris;Fodina, Violeta;Pozarskis, Anatolijs
通讯作者：
Pozarskis, Anatolijs