A BDNF-TrkB autocrine loop enhances senescent cell viability.
A BDNF-TrkB autocrine loop enhances senescent cell viability.
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DOI：
10.1038/s41467-022-33709-8
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发表时间：
2022-10-20
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
细胞衰老的特征在于细胞周期停滞、抗凋亡和衰老相关分泌表型（SASP），由此细胞分泌促炎因子和组织重塑因子。鉴于SASP加剧了与年龄相关的病理，一些衰老干预措施旨在选择性地消除衰老细胞。在这项研究中，药物库筛选发现TrkB（NTRK2）抑制剂能够触发几种衰老但不增殖的人类细胞的凋亡。衰老细胞表达高水平的TrkB，其支持衰老细胞活力，并分泌TrkB配体BDNF。在消除BDNF信号传导后衰老细胞的活力降低表明TrkB和BDNF的自分泌功能，其激活ERK 5并升高BCL 2L2水平，有利于衰老细胞存活。用TrkB抑制剂处理减少了衰老细胞在衰老小鼠器官中的积累。我们提出，SASP因子BDNF激活TrkB可促进细胞存活，并可用于治疗以减少衰老细胞负担。选择性消除衰老细胞是一种有望改善临床前模型中年龄相关病理的方法。在这里，作者报告说，BDNF通过培养细胞中的TrkB增强衰老细胞的活力，并且TrkB抑制可以减少衰老细胞在衰老小鼠器官中的积累。
Cellular senescence is characterized by cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP) whereby cells secrete pro-inflammatory and tissue-remodeling factors. Given that the SASP exacerbates age-associated pathologies, some aging interventions aim at selectively eliminating senescent cells. In this study, a drug library screen uncovered TrkB (NTRK2) inhibitors capable of triggering apoptosis of several senescent, but not proliferating, human cells. Senescent cells expressed high levels of TrkB, which supported senescent cell viability, and secreted the TrkB ligand BDNF. The reduced viability of senescent cells after ablating BDNF signaling suggested an autocrine function for TrkB and BDNF, which activated ERK5 and elevated BCL2L2 levels, favoring senescent cell survival. Treatment with TrkB inhibitors reduced the accumulation of senescent cells in aged mouse organs. We propose that the activation of TrkB by SASP factor BDNF promotes cell survival and could be exploited therapeutically to reduce the senescent-cell burden. Selective elimination of senescent cells is an approach that has shown promise to ameliorate age-associated pathologies in preclinical models. Here the authors report that BDNF enhances senescent cell viability via TrkB in cultured cells, and that TrkB inhibition can reduce the accumulation of senescent cells in aged mouse organs.
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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
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
14.9
作者：
Casella, Gabriel;Munk, Rachel;Gorospe, Myriam
通讯作者：
Gorospe, Myriam
影响因子：
5.2
作者：
Idda, M. Laura;McClusky, Waverly G.;Gorospe, Myriam
通讯作者：
Gorospe, Myriam
影响因子：
13.6
作者：
Anerillas C;Herman AB;Rossi M;Munk R;Lehrmann E;Martindale JL;Cui CY;Abdelmohsen K;De S;Gorospe M
通讯作者：
Gorospe M