Department of Molecular Biology and Biochemistry, Nelson Biological Laboratories, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
J Neurosci. 2012 Jun 27;32(26):8778-90. doi: 10.1523/JNEUROSCI.1494-11.2012.
Caenorhabditis elegans is a powerful model for analysis of the conserved mechanisms that modulate healthy aging. In the aging nematode nervous system, neuronal death and/or detectable loss of processes are not readily apparent, but because dendrite restructuring and loss of synaptic integrity are hypothesized to contribute to human brain decline and dysfunction, we combined fluorescence microscopy and electron microscopy (EM) to screen at high resolution for nervous system changes. We report two major components of morphological change in the aging C. elegans nervous system: (1) accumulation of novel outgrowths from specific neurons, and (2) physical decline in synaptic integrity. Novel outgrowth phenotypes, including branching from the main dendrite or new growth from somata, appear at a high frequency in some aging neurons, but not all. Mitochondria are often associated with age-associated branch sites. Lowered insulin signaling confers some maintenance of ALM and PLM neuron structural integrity into old age, and both DAF-16/FOXO and heat shock factor transcription factor HSF-1 exert neuroprotective functions. hsf-1 can act cell autonomously in this capacity. EM evaluation in synapse-rich regions reveals a striking decline in synaptic vesicle numbers and a diminution of presynaptic density size. Interestingly, old animals that maintain locomotory prowess exhibit less synaptic decline than same-age decrepit animals, suggesting that synaptic integrity correlates with locomotory healthspan. Our data reveal similarities between the aging C. elegans nervous system and mammalian brain, suggesting conserved neuronal responses to age. Dissection of neuronal aging mechanisms in C. elegans may thus influence the development of brain healthspan-extending therapies.
秀丽隐杆线虫是分析调节健康衰老的保守机制的强大模型。在衰老线虫的神经系统中，神经元死亡和/或可检测到的过程损失并不明显，但由于树突重构和突触完整性的丧失被假设为导致人类大脑衰退和功能障碍的原因，我们结合荧光显微镜和电子显微镜（EM）以高分辨率筛选神经系统变化。我们报告了衰老秀丽隐杆线虫神经系统中两种主要形态变化成分：（1）特定神经元中新型突起的积累，以及（2）突触完整性的物理下降。在一些衰老神经元中，新的生长表型，包括从主树突分支或从体节新生长，以高频率出现，但并非所有神经元都如此。线粒体通常与与年龄相关的分支部位有关。降低胰岛素信号传导会在老年时赋予 ALM 和 PLM 神经元结构完整性的一些维持，并且 DAF-16/FOXO 和热休克因子转录因子 HSF-1 发挥神经保护功能。hsf-1 可以在这种能力上自主发挥作用。在富含突触的区域进行 EM 评估揭示了突触囊泡数量的惊人下降和突触前密度大小的减小。有趣的是，保持运动能力的老年动物比同龄的衰弱动物表现出较少的突触下降，这表明突触完整性与运动健康寿命相关。我们的数据揭示了衰老秀丽隐杆线虫神经系统与哺乳动物大脑之间的相似性，表明神经元对年龄的反应具有保守性。秀丽隐杆线虫中神经元衰老机制的剖析可能会影响大脑健康寿命延长疗法的发展。
