Mechanisms of Aging in Senescence-Accelerated Mice. Mus musculus

Background: Progressive neurological dysfunction is a key aspect of human aging. Because of underlying differences in the aging of mice and humans, useful mouse models have been difficult to obtain and study. We have used gene-expression analysis and polymorphism screening to study molecular senescence of the retina and hippocampus in two rare inbred mouse models of accelerated neurological senescence (SAMP8 and SAMP10) that closely mimic human neurological aging, and in a related normal strain (SAMR1) and an unrelated normal strain (C57BL/6J). Results: The majority of age-related gene expression changes were strain-specific, with only a few common pathways found for normal and accelerated neurological aging. Polymorphism screening led to the identification of mutations that could have a direct impact on important disease processes, including a mutation in a fibroblast growth factor gene, Fgf1, and a mutation in and ectopic expression of the gene for the chemokine CCL19, which is involved in the inflammatory response. Conclusions: We show that combining the study of inbred mouse strains with interesting traits and gene-expression profiling can lead to the discovery of genes important for complex phenotypes. Furthermore, full-genome polymorphism detection, sequencing and gene-expression profiling of inbred mouse strains with interesting phenotypic differences may provide unique insights into the molecular genetics of late-manifesting complex diseases. Keywords: disease state analysis Overall design: Gene-expression profiling was performed on 3 month-old (young), 16 month-old (old) S8, S10 and SR1 mice. Two independent samples for each time point were used in gene-expression profiling for each strain. Because of greater replicate variability, three samples were used for hippocampus of 16-month SAM mice. A 10.0 ug sample of total RNA was used to generate labeled cRNA for each sample according to recommended protocols (Affymetrix). RNA from multiple animals was not pooled, except in the case of retina, where the retinas of two mice were combined to generate sufficient total RNA.

背景：进行性神经功能障碍是人类衰老的核心特征之一。由于小鼠与人类衰老过程存在本质差异，长期以来难以获取并研究理想的小鼠衰老模型。本研究采用基因表达分析（gene-expression analysis）与多态性筛选（polymorphism screening）技术，针对两种可精准模拟人类神经衰老进程的罕见加速神经衰老近交小鼠模型（SAMP8与SAMP10），以及相关正常品系SAMR1与无关正常品系C57BL/6J，对其视网膜与海马体的分子衰老特征开展研究。
结果：绝大多数年龄相关的基因表达变化具有品系特异性，仅在正常衰老与加速神经衰老中发现少量共通的信号通路。多态性筛选成功鉴定出可直接影响重要疾病进程的突变，包括成纤维细胞生长因子基因Fgf1的突变，以及趋化因子CCL19基因的突变与异位表达——该基因参与炎症应答过程。
结论：本研究证实，结合具有特殊表型的近交小鼠品系研究与基因表达谱分析（gene-expression profiling），可发现与复杂表型相关的关键基因。此外，对具有显著表型差异的近交小鼠品系开展全基因组多态性检测、测序及基因表达谱分析，可为迟发性复杂疾病的分子遗传学研究提供独特视角。
关键词：疾病状态分析（disease state analysis）
实验设计：针对3月龄（青年）、16月龄（老年）的S8（SAMP8）、S10（SAMP10）与SR1（SAMR1）小鼠开展基因表达谱分析。每个品系的每个时间点均设置两份独立样本用于基因表达谱分析。由于重复样本间变异度较高，16月龄SAM小鼠海马体样本采用了三份。每份样本取10.0 μg总RNA，按照官方推荐的实验流程（Affymetrix）制备标记cRNA。除视网膜样本外，其余样本均未混合多只动物的RNA；视网膜样本需将2只小鼠的视网膜合并，以获取足够的总RNA。