The Resilient Brain. Imaging Biomarkers of Brain Metabolic Reserve

该提案旨在验证两种创新的大脑抗衰老生物标志物。生物标志物使用两种众所周知且广泛可用的成像技术，即目前用于动物和人类的磁共振成像（MRI）和正电子发射断层扫描（PET）。寻找衰老的生物标志物是一件困难的事情，因为它们的必要要求是预测能力-理想情况下，当研究旨在调节衰老过程的干预措施时，我们希望尽快了解其对衰老轨迹的影响，而不必等待衰老过程最终发生。以大脑为例，如果我们能够测量它的恢复能力，就可以实现这一点--而决定其抑制细胞病变能力的一个相关生物学参数是它的代谢储备。在普通成年人中，大脑约占总体重的2%，但它占所有能量消耗的20%，是其重量预测的10倍。需要注意的是，这种非常高的能量消耗率仅在休息状态下才需要，而与任何精神活动相关的额外能量非常小，通常不到基线的5%。在这个高能量器官中，代谢储备是脑细胞仍然可以用来对抗所有我们称之为衰老的病理现象的能量储备。大的代谢储备将意味着对衰老的巨大适应力，差或没有储备意味着很少或没有适应力。当测量能量储备时，我们希望以称为线粒体的小细胞器的功能为目标。关于线粒体有两个关键的观察结果。1)它们是进行有氧呼吸的细胞机器的基本元素，例如使用氧气氧化葡萄糖产物并将其转化为能量。2)线粒体维持的过程是高度动态的，这些成分不断更新，特别是较老和受损的成分。我们关注线粒体功能的这两个关键方面，并设计了两种测量方法。1）测量1 -我们希望通过在用亚甲蓝（MB）激发之前和之后用MRI测量氧细胞代谢来测量线粒体呼吸储备能力。亚甲基溴是一种化合物，已被批准用于人类，可诱导细胞呼吸大幅增加（>40%）。使用MB，我们可以将线粒体的能力扩展到极限，远远超过使用任何需要很少增量能量的脑力任务，并且在实验或临床环境中更不可控。2)测量2 -我们希望测量一种特定线粒体蛋白的表达水平，称为18 Kd转运蛋白或TSPO。TSPO调节线粒体周转，并作为质量控制器驱动在损伤或应激后去除有缺陷的线粒体的过程。重要的是，TSPO水平可以通过PET在动物和人类中体内测量。我们将通过跟踪两组大鼠的时间来验证这些措施。其中一组大鼠将接受一种干预措施，这种干预措施有助于大脑衰老过程，特别是线粒体功能。治疗将包括环境富集和饮食限制，我们将模仿人类健康的生活方式。在他们的一生中，我们将使用适当的测试持续监测他们的认知能力，我们将验证我们早期采取的措施是否能预测他们的智力衰退。一旦得到验证，这些措施将成为老龄化研究的极其强大的工具。它们将缩短实验环境中的时间，并允许最佳使用动物，因为它们不需要动物牺牲。它们将立即转化为人类，因为所使用的成像技术和药理学挑战均已单独验证并授权用于人类。

This proposal aims to validate two innovative biomarkers of brain resilience to ageing. The biomarkers use two well-known and widely available imaging technologies, magnetic resonance imaging (MRI) and positron emission tomography (PET) that are presently used both in animals and humans. The quest for biomarkers of ageing is a difficult one as their necessary requirement is prediction power - ideally, when studying an intervention aimed at modulating the ageing process, we would like to know its effect on the ageing trajectory as soon as possible without having to wait for the ageing process to eventually happen. In the case of brain, this can be achieved if we can measure its resilience - and the one relevant biological parameter determining the ability to withhold cellular pathology is its metabolic reserve.Why metabolism? In the average adult human, the brain represents about 2% of the total body weight yet it accounts for 20% of all the energy consumed, 10 times that predicted by its weight alone. Note that this very high rate of energy consumption is required only by its resting state while the additional energy associated with any mental activity is remarkably small, often less than 5% of the baseline.In this highly energetic organ, metabolic reserve is the amount of energy reserve that brain cells can still use to fight all those pathological phenomena that we call ageing. Big metabolic reserve will then mean great resilience to ageing, poor or no reserve means little or no resilience.When measuring energy reserve we wish to target the functioning of small cellular organelles called mitochondria. There are two key observations about mitochondria. 1)They are the fundamental elements of the cellular machine performing aerobic respiration e.g. using oxygen to oxidise the products of glucose and convert them into energy. 2) The process of mitochondria maintenance is highly dynamic with a constant turnover of these components particularly the older and damaged ones.We have focused on these two key aspects of mitochondrial function and devised two measures.1) MEASURE 1 - We wish to measure mitochondrial respiratory reserve capacity by measuring oxygen cellular metabolism with MRI before and after a challenge with Methylene Blue (MB). MB is a compound, already authorized for human use, that induces substantial increases (>40%) in cell respiration. Using MB we can expand mitochondrial capacity to its limit, far more than using any mental task that requires very little incremental energy and is far less controllable in an experimental or clinical setting. 2) MEASURE 2 - We wish to measure the level of expression of one particular mitochondrial protein, called the 18Kd translocator protein or TSPO. TSPO regulates mitochondrial turnover and acts as a quality controller driving the process that removes defective mitochondria following damage or stress. Importantly TSPO levels can be measured in-vivo by PET in both animals and humans. We will validate these measures by following through time two groups of rats. One group of rats will be submitted to an intervention which is known to benefit the brain ageing process and mitochondria function in particular. The treatment will consist in environmental enrichment and dietary restriction by which we will mimic human healthy lifestyle. During their lifetime, we will continuously monitor their cognitive ability using appropriate tests and we will verify whether our measures, taken early on, predict their mental decline. Once validated, these measures will be extremely powerful tools for ageing research. They will shorten timings in experimental settings and will allow an optimal use of animals as they do not require animal sacrifice. They will be immediately translated to humans as both imaging technologies and the pharmacological challenge used have been separately validated and authorized for human use.