Regional metabolic heterogeneity of the hippocampus is nonuniformly impacted by age and caloric restriction.
Regional metabolic heterogeneity of the hippocampus is nonuniformly impacted by age and caloric restriction.
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DOI：
10.1111/acel.12418
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发表时间：
2016-02
期刊：
影响因子：
7.8
通讯作者：
Anderson RM
中科院分区：
文献类型：
--
作者：
Martin SA;DeMuth TM;Miller KN;Pugh TD;Polewski MA;Colman RJ;Eliceiri KW;Beasley TM;Johnson SC;Anderson RM
海马体对于认知和记忆形成至关重要，并且容易发生与年龄相关的萎缩和功能丧失。这些表型被热量限制（CR）减弱，这是一种延迟衰老的饮食干预。在这里，我们显示了海马能量代谢的显着区域效应，对年龄和CR作出反应，涉及神经元保护的代谢途径。原位线粒体细胞色素c氧化酶活性具有区域特异性，老年小鼠较低，年龄的影响具有区域特异性。多光子激光扫描显微镜显示烟酰胺腺嘌呤二核苷酸（NAD）衍生代谢辅因子的区域和年龄特异性差异。代谢参数的年龄相关变化在时间上是分开的，对年龄的代谢反应有早期和晚期事件。年龄对较低水平的PGC-1α（一种主要的线粒体调节因子）有显著的区域影响。CR没有逆转年龄的影响，而是诱导了一种独特的代谢状态，细胞色素c氧化酶活性降低，NAD（P）H水平升高。海马PGC-1α的水平随着CR而降低，GSK 3 β的水平也是如此，GSK 3 β是PGC-1α转换和活性的关键调节因子。PGC-1α和GSK 3 β在小鼠海马中的区域分布和共定位在猴中相似。此外，CR对较低水平的PGC-1α和GSK 3 β的影响也是保守的。这些研究证实了海马是一个高度变化的代谢环境，揭示了对年龄和CR延迟衰老的代谢反应的细胞类型和区域特异性，并表明PGC-1α和GSK 3 β在实施CR诱导的神经保护程序中发挥作用。
The hippocampus is critical for cognition and memory formation and is vulnerable to age‐related atrophy and loss of function. These phenotypes are attenuated by caloric restriction (CR), a dietary intervention that delays aging. Here, we show significant regional effects in hippocampal energy metabolism that are responsive to age and CR, implicating metabolic pathways in neuronal protection. In situ mitochondrial cytochrome c oxidase activity was region specific and lower in aged mice, and the impact of age was region specific. Multiphoton laser scanning microscopy revealed region‐ and age‐specific differences in nicotinamide adenine dinucleotide (NAD)‐derived metabolic cofactors. Age‐related changes in metabolic parameters were temporally separated, with early and late events in the metabolic response to age. There was a significant regional impact of age to lower levels of PGC‐1α, a master mitochondrial regulator. Rather than reversing the impact of age, CR induced a distinct metabolic state with decreased cytochrome c oxidase activity and increased levels of NAD(P)H. Levels of hippocampal PGC‐1α were lower with CR, as were levels of GSK3β, a key regulator of PGC‐1α turnover and activity. Regional distribution and colocalization of PGC‐1α and GSK3β in mouse hippocampus was similar in monkeys. Furthermore, the impact of CR to lower levels of both PGC‐1α and GSK3β was also conserved. The studies presented here establish the hippocampus as a highly varied metabolic environment, reveal cell‐type and regional specificity in the metabolic response to age and delayed aging by CR, and suggest that PGC‐1α and GSK3β play a role in implementing the neuroprotective program induced by CR.