Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan.
Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan.
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DOI：
10.1038/nature16932
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发表时间：
2016-02-11
期刊：
影响因子：
64.8
通讯作者：
van Deursen JM
中科院分区：
文献类型：
--
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
细胞衰老是一种应激诱导的不可逆生长停滞，其特征通常为p16 Ink 4a表达和独特的分泌表型，可防止癌前细胞的增殖，并在胚胎发生和伤口愈合期间的组织重塑中具有有益作用。随着时间的推移，衰老细胞在各种组织和器官中积累，并被推测在衰老中发挥作用。为了探索自然发生的衰老细胞的生理相关性和后果，我们使用先前建立的转基因INK-ATTAC，通过从一岁开始每周两次注射AP 20187来诱导野生型小鼠p16 Ink 4a表达细胞的凋亡。在这里，我们表明，与单独使用溶剂相比，AP 20187治疗延长了两种不同遗传背景的雄性和雌性小鼠的中位寿命。p16 Ink 4a阳性细胞的清除延迟了肿瘤发生，并减弱了几个器官的年龄相关性恶化，而没有明显的副作用，包括肾脏，心脏和脂肪，其中清除分别保留了肾小球，心脏保护性KATP通道和脂肪细胞的功能。因此，在成年期积累的p16 Ink 4a阳性细胞会对寿命产生负面影响，并促进多个器官的年龄依赖性变化，而去除它们可能是延长健康寿命的一种有吸引力的方法。
Cellular senescence, a stress-induced irreversible growth arrest often characterized by p16Ink4a expression and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time and have been speculated to play a role in aging. To explore the physiological relevance and consequences of naturally occurring senescent cells, we used a previously established transgene, INK-ATTAC, to induce apoptosis in p16Ink4a-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. Here we show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. Clearance of p16Ink4a-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels, and adipocytes, respectively. Thus, p16Ink4a-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in multiple organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.