Cellular and molecular mechanisms of motor aging in Drosophila

根据全球人类预期寿命的增加，制定未来健康老龄化战略的先决条件是了解正常老龄化的生物学。尽管许多报道已经确定了人类和无脊椎动物模型系统中大脑功能随衰老而下降的分子原因和神经相关性，但将与年龄相关的表现缺陷的分子和神经原因精确映射到大脑中仍然是该领域的挑战。我们利用果蝇模型系统的实验优势，以确定与年龄相关的运动表现下降的分子球员和神经基板。首先，我们已经开始将与衰老相关的特定运动行为的丧失，即视觉诱导的逃避反应映射到神经系统中。当一只苍蝇在它的视野中检测到一个接近的威胁时，它会做出反应，先是逃跑，然后逃跑。潜在的神经回路是已知的，并且所有组成神经元在遗传和生理上都是可接近的。我们已经发现，这种行为是失去了在后期的生活，由于差分电路的脆弱性。感光器功能和突触传递到一阶视觉中间神经元，也没有运动神经元和信息传递到肌肉的影响，由老化，但我们已经映射的原因与年龄有关的行为损失，以少数确定的大脑中间神经元和突触。该项目的第一个目的是精确地查明正常衰老过程中功能回路衰退的神经原因。第二个目标是确定大脑老化的分子原因。我们已经确定爬升速度作为一种生物标志物，可以预测健康中年苍蝇的预期寿命长短。基于此，我们进行了转录组学研究，以确定大脑衰老的分子原因。现在，我们将验证选定的顶级候选因素的表达变化，并将这些全局映射到大脑中，特别是逃逸回路上。在第三个目标中，我们将操纵这些因素。将测试所有神经元的全局操纵对寿命和晚年生活质量的潜在积极影响。将测试逃逸回路特定神经元中的靶向操作是否有可能推迟或改善晚年运动表现缺陷。由于大多数动物的基本分子和细胞生物学原理高度保守，我们期望对正常脑老化的分子和细胞机制有新的见解。

A prerequisite toward developing future strategies for healthy aging in the light of globally increasing human life expectancy is to understand the biology of normal aging. Although numerous reports have identified molecular causes and neural correlates of functional brain decline with aging, both in humans and in invertebrate model systems, precise mapping of the molecular and neural causes of age-related performance defects into the brain remains a challenge in the field. We utilize experimental advantages of the Drosophila model system to identify molecular players and neural substrates that underlie age related decline of motor performance. First, we have started mapping the aging related loss of a specific motor behavior, the visually induced escape response, into the nervous system. When a fly detects an approaching threat in its visual field, it responds with escape jumping followed by flight. The underlying neural circuit is known and all component neurons are genetically and physiologically accessible. We have found that this behavior is lost during late life due to differential circuit vulnerability. Neither photoreceptor function and synaptic transmission to first order visual interneurons, nor motoneurons and information transmission to muscles are affected by aging, but we have mapped the cause of age-related behavioral loss to few identified brain interneurons and synapses. The first aim of this project is to precisely pinpoint the neural causes of functional circuit decline during normal aging. The second aim is to identify molecular causes of brain aging. We have identified climbing speed as a biomarker that predicts long versus short life expectancy already in healthy, mid aged flies. Based on this we have conducted transcriptomics to identify molecular causes of brain aging. We will now validate expressional changes of selected top candidate factors and map these globally into the brain and specifically onto the escape circuit. In the third aim, we will then manipulate these factors. Global manipulation in all neurons will be tested for potential positive effects on lifespan and on late life quality. Targeted manipulation in specific neurons of the escape circuit will be tested for the potential to postpone or ameliorate late-life motor performance deficits. Due to a high degree of conservation of basic molecular and cell biological principles in most animals we expect novel insights into the molecular and cellular mechanisms that underlie normal brain aging.