Increased gene dosage of Ink4/Arf and p53 delays age-associated central nervous system functional decline
Increased gene dosage of Ink4/Arf and p53 delays age-associated central nervous system functional decline
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DOI：
10.1111/acel.12343
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发表时间：
2015-08-01
期刊：
影响因子：
7.8
通讯作者：
Matheu, Ander
中科院分区：
文献类型：
--
作者：
Carrasco-Garcia, Estefania;Arrizabalaga, Olatz;Matheu, Ander
大脑活动的损害是衰老的主要特征，这与神经干细胞功能的减少相一致。我们以前已经表明，在s-Ink 4/Arf/p53小鼠中，额外的受调节的Ink 4/Arf和p53活性拷贝延长寿命并延缓衰老。在这项工作中，我们研究了s-Ink 4/Arf/p53大脑衰老的生理学，重点是神经干细胞（NSC）群体。我们发现，与野生型对照相比，来自老年s-Ink 4/Arf/p53小鼠的细胞显示出增强的神经球形成和自我更新活性。这与室管膜下区（SVZ）和齿状回（DG）小生境的颗粒下区中Sox 2、Sox 9、Glast、Ascl 1和Ars 2 NSC标记物的增强表达相关。此外，老年s-Ink 4/Arf/p53小鼠在嗅球（OB）和DG中表达更高水平的Doublecortin和PSA-NCAM（成神经细胞）和NeuN（神经元），表明体内神经发生增加。最后，老年s-Ink 4/Arf/p53小鼠表现出增强的行为和神经肌肉协调活动。总之，这些发现表明，增加但调节的Ink 4/Arf和p53活性改善了维持干细胞库所需的中枢神经系统活性的年龄相关性恶化，不仅为延长寿命而且为这些小鼠的健康寿命提供了机制。
The impairment of the activity of the brain is a major feature of aging, which coincides with a decrease in the function of neural stem cells. We have previously shown that an extra copy of regulated Ink4/Arf and p53 activity, in s-Ink4/Arf/p53 mice, elongates lifespan and delays aging. In this work, we examined the physiology of the s-Ink4/Arf/p53 brain with aging, focusing on the neural stem cell (NSC) population. We show that cells derived from old s-Ink4/Arf/p53 mice display enhanced neurosphere formation and self-renewal activity compared with wt controls. This correlates with augmented expression of Sox2, Sox9, Glast, Ascl1, and Ars2 NSC markers in the subventricular zone (SVZ) and in the subgranular zone of the dentate gyrus (DG) niches. Furthermore, aged s-Ink4/Arf/p53 mice express higher levels of Doublecortin and PSA-NCAM (neuroblasts) and NeuN (neurons) in the olfactory bulbs (OB) and DG, indicating increased neurogenesis invivo. Finally, aged s-Ink4/Arf/p53 mice present enhanced behavioral and neuromuscular coordination activity. Together, these findings demonstrate that increased but regulated Ink4/Arf and p53 activity ameliorates age-related deterioration of the central nervous system activity required to maintain the stem cell pool, providing a mechanism not only for the extended lifespan but also for the health span of these mice.