A Systematic Investigation into Aging Related Genes in Brain and Their Relationship with Alzheimer’s Disease

Aging, as a complex biological process, is accompanied by the accumulation of functional loses at different levels, which makes age to be the biggest risk factor to many neurological diseases. Even following decades of investigation, the process of aging is still far from being fully understood, especially at a systematic level. In this study, we identified aging related genes in brain by collecting the ones with sustained and consistent gene expression or DNA methylation changes in the aging process. Functional analysis with Gene Ontology to these genes suggested transcriptional regulators to be the most affected genes in the aging process. Transcription regulation analysis found some transcription factors, especially Specificity Protein 1 (SP1), to play important roles in regulating aging related gene expression. Module-based functional analysis indicated these genes to be associated with many well-known aging related pathways, supporting the validity of our approach to select aging related genes. Finally, we investigated the roles of aging related genes on Alzheimer’s Disease (AD). We found that aging and AD related genes both involved some common pathways, which provided a possible explanation why aging made the brain more vulnerable to Alzheimer’s Disease.

衰老是一种复杂的生物学过程，伴随不同层级的生理功能衰退累积，而年龄也因此成为诸多神经系统疾病的首要风险因素。即便经过数十年研究，人们对衰老过程的认知仍不够全面，尤其是在系统层面上。本研究通过收集衰老过程中呈现持续且稳定的基因表达或DNA甲基化（DNA methylation）改变的基因，筛选出大脑内的衰老相关基因。对这些基因开展基因本体论（Gene Ontology, GO）功能富集分析后发现，转录调控因子是衰老过程中受影响最显著的一类基因。转录调控分析显示，部分转录因子——尤其是特异性蛋白1（SP1）——在调控衰老相关基因表达中发挥关键作用。基于模块的功能分析结果表明，这些基因与诸多经典衰老相关通路存在关联，验证了本研究筛选衰老相关基因方法的有效性。最后，本研究探讨了衰老相关基因在阿尔茨海默病（Alzheimer’s Disease, AD）中的作用。研究发现，衰老相关基因与阿尔茨海默病相关基因共享部分通路，这为解释衰老为何会使大脑更易罹患阿尔茨海默病提供了潜在依据。