Transcriptomic and metabolomic changes might predict frailty in SAMP8 mice

Frailty is a geriatric multi-dimensional syndrome which reflects multisystem physiological change and is a transversal measure of reduced resilience to negative events. It is characterized by weakness, frequent falls, cognitive decline, increased hospitalization and dead, and represents a risk factor for the development of Alzheimers disease (AD). The fact that frailty is recognized as a reversible condition, encourages the identification of earlier biomarkers to timely predict and prevent its occurrence. SAMP8 (Senescence-Accelerated Mouse Prone-8) mice represent the most appropriate preclinical model to this aim and were used in this study to carry transcriptional and metabolic analyses in the brain and plasma respectively, upon a characterization at cognitive, motor, structural and neuropathological level at 2.5, 6 and 9 months of age. At 2.5 months SAMP8 mice started displaying memory deficits, muscle weakness and motor impairment. Functional alterations were associated with a neurodevelopment deficiency associated with reduced neuronal density and glial cell loss. Through transcriptomics we identified specific genetic signatures well distinguishing SAMP8 mice at 6 months and correlating with motor and cognitive dysfunction, whereas plasma metabolomics allowed to segregate SAMP8 mice from SAMR1 already at 2.5 months of age by detecting constitutively lower levels of acylcarnitines and lipids in SAMP8 at all ages investigated. Our findings suggest that specific genetic alterations at central level, as well as metabolomic changes in plasma, might allow to early assess a frail condition leading to dementia development, which paves the foundation for future investigation in a clinical setting. Comparative gene expression profiling analysis of RNA-seq data for SAMP8 with respect to SAMR1 mice in frailty衰弱（Frailty）是一种老年多维度综合征，反映多系统生理变化，是衡量机体对不良事件应对韧性下降的横向评估指标。其特征表现为肌力减退、频繁跌倒、认知衰退、住院率升高及死亡风险上升，同时也是阿尔茨海默病（Alzheimer's Disease, AD）发生的风险因素。鉴于衰弱被证实为可逆状态，这推动了早期生物标志物的发掘，以实现对其发生的及时预测与预防。 衰老加速易感小鼠8型（Senescence-Accelerated Mouse Prone-8, SAMP8）是实现这一目标的最优临床前模型，本研究以其为对象，分别在脑与血浆中开展转录组与代谢组分析，此前已在2.5、6及9月龄时对其开展认知、运动、结构及神经病理层面的表型鉴定。2.5月龄时，SAMP8小鼠即开始出现记忆缺陷、肌力减退与运动功能受损。上述功能异常与神经发育缺陷相关，后者表现为神经元密度降低与胶质细胞丢失。 通过转录组学分析，我们鉴定出可有效区分6月龄SAMP8小鼠的特异性基因特征，且该特征与运动及认知功能障碍存在关联；而血浆代谢组学分析则可在2.5月龄时即区分SAMP8与衰老加速抵抗小鼠（SAMR1），其机制为在所有检测月龄中，SAMP8小鼠的酰基肉碱与脂质水平均持续处于较低水平。本研究结果表明，中枢神经系统的特异性遗传改变与血浆代谢组变化，或可实现对导致痴呆发生的衰弱状态的早期评估，这为未来临床场景下的相关研究奠定了基础。本研究针对衰弱状态下SAMP8与SAMR1小鼠的RNA测序（RNA-seq）数据开展了比较基因表达谱分析。