Carrasco-Garcia Estefania, Arrizabalaga Olatz, Serrano Manuel, Lovell-Badge Robin, Matheu Ander
Neuro-Oncology Group, Biodonostia Institute, Paseo Dr. Beguiristain s/n, San Sebastian, 20014, Spain.
Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), 3 Melchor Fernandez Almagro st, Madrid, 28029, Spain.
Aging Cell. 2015 Aug;14(4):710-4. doi: 10.1111/acel.12343. Epub 2015 May 20.
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 in vivo. 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.
大脑活动的损伤是衰老的一个主要特征，这与神经干细胞功能的下降相吻合。我们之前已经表明，在s-Ink4/Arf/p53小鼠中，额外拷贝调控的Ink4/Arf和p53活性可延长寿命并延缓衰老。在这项工作中，我们研究了衰老过程中s-Ink4/Arf/p53大脑的生理学，重点关注神经干细胞（NSC）群体。我们发现，与野生型对照相比，来自老年s-Ink4/Arf/p53小鼠的细胞表现出增强的神经球形成和自我更新活性。这与室下区（SVZ）和齿状回（DG）龛的颗粒下区中Sox2、Sox9、Glast、Ascl1和Ars2神经干细胞标志物的表达增加相关。此外，老年s-Ink4/Arf/p53小鼠在嗅球（OB）和DG中表达更高水平的双皮质素和PSA-NCAM（神经母细胞）以及NeuN（神经元），表明体内神经发生增加。最后，老年s-Ink4/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，增加但受调控的Ink4/Arf和p53活性可改善与年龄相关的维持干细胞池所需的中枢神经系统活动的衰退，这不仅为这些小鼠的寿命延长提供了一种机制，也为其健康寿命提供了一种机制。
