Aging Impairs Mitochondrial Function and Mitophagy and Elevates Interleukin 6 Within the Cerebral Vasculature.
Aging Impairs Mitochondrial Function and Mitophagy and Elevates Interleukin 6 Within the Cerebral Vasculature.
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DOI：
10.1161/jaha.120.017820
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发表时间：
2020-12
影响因子：
5.4
通讯作者：
Goldstein DR
中科院分区：
文献类型：
--
作者：
Tyrrell DJ;Blin MG;Song J;Wood SC;Goldstein DR
血脑屏障（BBB）对脑血管健康至关重要。尽管衰老会损害血脑屏障的完整性，但这一现象背后的机制尚不清楚。随着线粒体功能失调，线粒体成分激活炎症，我们研究了衰老如何影响脑血管线粒体功能、线粒体自噬和炎症信号；以及这些变化是否与血脑屏障功能有关。我们分离了幼龄（2-3个月大）和老年（18-19个月大）小鼠的脑血管，发现衰老导致细胞周期蛋白依赖性激酶抑制剂1衰老标志物的增加，线粒体功能受损，与老年小鼠相比，老年小鼠的血脑屏障泄漏增加。随着年龄的增长，脑血管中有丝分裂蛋白Parkin和Nix的表达也有所增加。使用线粒体自噬报告者（mtKeima）小鼠，我们发现鱼藤酮治疗后脑血管内从基线增加线粒体自噬的能力随着年龄的增长而降低。脑血管内的衰老也导致干扰素基因刺激因子的上调和白细胞介素6 （IL - 6）的增加，白细胞介素6是一种改变线粒体功能的细胞因子。重要的是，外源性IL - 6对年轻脑血管的处理上调了线粒体自噬和Parkin并损害了线粒体功能；而在老年脑血管中抑制IL - 6可降低Parkin表达并增加线粒体功能。此外，用线粒体N -甲酰基肽处理年轻小鼠的脑血管可上调IL - 6，增加Parkin，并降低Claudin - 5（一种与血脑屏障完整性相关的紧密连接蛋白）。衰老改变脑血管系统，损害线粒体功能和线粒体自噬，增加IL - 6水平。这些改变可能损害血脑屏障的完整性，并可能随着年龄的增长而降低脑血管健康。
The blood‐brain barrier (BBB) is critical for cerebrovascular health. Although aging impairs the integrity of the BBB, the mechanisms behind this phenomenon are not clear. As mitochondrial components activate inflammation as mitochondria become dysfunctional, we examined how aging impacts cerebrovascular mitochondrial function, mitophagy, and inflammatory signaling; and whether any alterations correlate with BBB function. We isolated cerebral vessels from young (2–3 months of age) and aged (18–19 months of age) mice and found that aging led to increases in the cyclin‐dependent kinase inhibitor 1 senescence marker with impaired mitochondrial function, which correlated with aged mice exhibiting increased BBB leak compared with young mice. Cerebral vessels also exhibited increased expression of mitophagy proteins Parkin and Nix with aging. Using mitophagy reporter (mtKeima) mice, we found that the capacity to increase mitophagy from baseline within the cerebral vessels on rotenone treatment was reduced with aging. Aging within the cerebral vessels also led to the upregulation of the stimulator of interferon genes and increased interleukin 6 (IL‐6), a cytokine that alters mitochondrial function. Importantly, exogenous IL‐6 treatment of young cerebral vessels upregulated mitophagy and Parkin and impaired mitochondrial function; whereas inhibiting IL‐6 in aged cerebral vessels reduced Parkin expression and increased mitochondrial function. Furthermore, treating cerebral vessels of young mice with mitochondrial N‐formyl peptides upregulated IL‐6, increased Parkin, and reduced Claudin‐5, a tight junction protein integral to BBB integrity. Aging alters the cerebral vasculature to impair mitochondrial function and mitophagy and increase IL‐6 levels. These alterations may impair BBB integrity and potentially reduce cerebrovascular health with aging.