PDF(Pubmed)
Abstract：
Cognitive decline is a significant health concern in our aging society. Here, we used the model organism C. elegans to investigate the impact of the IIS/FOXO pathway on age-related cognitive decline. The daf-2 Insulin/IGF-1 receptor mutant exhibits a significant extension of learning and memory span with age compared to wild-type worms, an effect that is dependent on the DAF-16 transcription factor. To identify possible mechanisms by which aging daf-2 mutants maintain learning and memory with age while wild-type worms lose neuronal function, we carried out neuron-specific transcriptomic analysis in aged animals. We observed downregulation of neuronal genes and upregulation of transcriptional regulation genes in aging wild-type neurons. By contrast, IIS/FOXO pathway mutants exhibit distinct neuronal transcriptomic alterations in response to cognitive aging, including upregulation of stress response genes and downregulation of specific insulin signaling genes. We tested the roles of significantly transcriptionally-changed genes in regulating cognitive functions, identifying novel regulators of learning and memory. In addition to other mechanistic insights, a comparison of the aged vs young daf-2 neuronal transcriptome revealed that a new set of potentially neuroprotective genes is upregulated; instead of simply mimicking a young state, daf-2 may enhance neuronal resilience to accumulation of harm and take a more active approach to combat aging. These findings suggest a potential mechanism for regulating cognitive function with age and offer insights into novel therapeutic targets for age-related cognitive decline.
摘要：
认知下降是我们老龄化社会的一个重要健康问题。这里,我们使用模型生物C.elegans研究IIS/FOXO通路对年龄相关认知功能下降的影响.与野生型蠕虫相比，daf-2胰岛素/IGF-1受体突变体随着年龄的增长，学习和记忆跨度显着延长，依赖于DAF-16转录因子的作用。为了确定老化的daf-2突变体随着年龄的增长而保持学习和记忆的可能机制，而野生型蠕虫失去神经元功能，我们在老年动物中进行了神经元特异性转录组分析。我们观察到老化的野生型神经元中神经元基因的下调和转录调节基因的上调。相比之下,IIS/FOXO通路突变体表现出不同的神经元转录组改变，以响应认知老化，包括应激反应基因的上调和特定胰岛素信号基因的下调。我们测试了显著转录改变的基因在调节认知功能中的作用，识别学习和记忆的新型调节因子。除了其他机械见解，对老年和年轻daf-2神经元转录组的比较表明，一组新的潜在神经保护基因被上调；而不是简单地模仿年轻状态，daf-2可能会增强神经元对伤害积累的抵抗力，并采取更积极的方法来对抗衰老。这些发现表明了随着年龄的增长调节认知功能的潜在机制，并为与年龄相关的认知衰退提供了新的治疗目标。
