Senescent Cell Depletion Through Targeting BCL-Family Proteins and Mitochondria.
Senescent Cell Depletion Through Targeting BCL-Family Proteins and Mitochondria.
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通过靶向 BCL 家族蛋白和线粒体来消除衰老细胞
DOI：
10.3389/fphys.2020.593630
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发表时间：
2020
影响因子：
4
通讯作者：
Shao L
中科院分区：
文献类型：
--
作者：
Fan Y;Cheng J;Zeng H;Shao L
在基因毒性、氧化性和致癌应激过程中可产生具有复制停滞的衰老细胞。由于bcl家族蛋白的高表达，衰老细胞长期滞留在体内，主要通过衰老相关分泌表型（SASP）慢性损伤组织。已有文献证明，衰老细胞的积累有助于慢性疾病和与衰老有关的疾病。尽管没有独特的标记物可用于识别衰老细胞，但p16INK4a表达的增加一直被用作衰老细胞的体外和体内标记物。我们回顾了五种现有的p16INK4a报告小鼠模型，以检测、分离和耗尽衰老细胞。与正常细胞相比，衰老细胞表达高水平的抗凋亡和促凋亡基因。因此，破坏抗凋亡和促凋亡基因（如ABT-263和ABT-737）表达之间的平衡，可以激活凋亡信号通路，去除衰老细胞。还讨论了衰老细胞中的线粒体异常，例如线粒体DNA突变积累，线粒体自噬功能障碍和线粒体未折叠蛋白反应（mtUPR）。线粒体靶向的他莫昔芬，米托坦，由于其在衰老细胞中抑制呼吸复合体I和降低腺嘌呤核苷酸转位酶2 （ANT2）的表达，可以有效地去除衰老细胞。因此，衰老细胞可以通过各种策略去除，从而延缓慢性和衰老相关疾病，延长寿命和身体健康状况。
Senescent cells with replicative arrest can be generated during genotoxic, oxidative, and oncogenic stress. Long-term retention of senescent cells in the body, which is attributed to highly expressed BCL-family proteins, chronically damages tissues mainly through a senescence-associated secretory phenotype (SASP). It has been documented that accumulation of senescent cells contributes to chronic diseases and aging-related diseases. Despite the fact that no unique marker is available to identify senescent cells, increased p16INK4a expression has long been used as an in vitro and in vivo marker of senescent cells. We reviewed five existing p16INK4a reporter mouse models to detect, isolate, and deplete senescent cells. Senescent cells express high levels of anti-apoptotic and pro-apoptotic genes compared to normal cells. Thus, disrupting the balance between anti-apoptotic and pro-apoptotic gene expression, such as ABT-263 and ABT-737, can activate the apoptotic signaling pathway and remove senescent cells. Mitochondrial abnormalities in senescent cells were also discussed, for example mitochondrial DNA mutation accumulation, dysfunctional mitophagy, and mitochondrial unfolded protein response (mtUPR). The mitochondrial-targeted tamoxifen, MitoTam, can efficiently remove senescent cells due to its inhibition of respiratory complex I and low expression of adenine nucleotide translocase-2 (ANT2) in senescent cells. Therefore, senescent cells can be removed by various strategies, which delays chronic and aging-related diseases and enhances lifespan and healthy conditions in the body.
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影响因子：
64.5
作者：
Burd CE;Sorrentino JA;Clark KS;Darr DB;Krishnamurthy J;Deal AM;Bardeesy N;Castrillon DH;Beach DH;Sharpless NE
通讯作者：
Sharpless NE
影响因子：
82.9
作者：
Farr JN;Xu M;Weivoda MM;Monroe DG;Fraser DG;Onken JL;Negley BA;Sfeir JG;Ogrodnik MB;Hachfeld CM;LeBrasseur NK;Drake MT;Pignolo RJ;Pirtskhalava T;Tchkonia T;Oursler MJ;Kirkland JL;Khosla S
通讯作者：
Khosla S
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：
16.6
作者：
Fuhrmann-Stroissnigg H;Ling YY;Zhao J;McGowan SJ;Zhu Y;Brooks RW;Grassi D;Gregg SQ;Stripay JL;Dorronsoro A;Corbo L;Tang P;Bukata C;Ring N;Giacca M;Li X;Tchkonia T;Kirkland JL;Niedernhofer LJ;Robbins PD
通讯作者：
Robbins PD
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