Flor Stefano, Dost Thomas, Haase Madlen, Simon Rowena, Ederer Simone, Samer Kadibalban A, Taubenheim Jan, Olecka Maja, Walker Alesia, Zimmermann Johannes, Marinos Georgios, Franzenburg Sören, Schmitt-Kopplin Philippe, Baines John, Riege Konstantin, Hoffmann Steve, Best Lena, Frahm Christiane, Kaleta Christoph
Research Group Medical Systems Biology, Institute of Experimental Medicine, Christian Albrechts University of Kiel and University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
Department of Neurology, Jena University Hospital, Jena, Germany.
bioRxiv. 2025 Jul 14:2025.07.13.662751. doi: 10.1101/2025.07.13.662751.
Aging-related cognitive decline is associated with changes across different tissues and the gut microbiome, including dysfunction of the gut-brain axis. However, only few studies have linked multi-organ alterations to cognitive decline during aging. Here we report a multi-omics analysis integrating metabolomics, transcriptomics, DNA methylation, and metagenomics data from hippocampus, liver, colon, and fecal samples of mice, correlated with cognitive performance in the Barnes Maze spatial learning task across different age groups. We identified 734 molecular features associated with cognitive rank within individual data layers, of which 227 features remain when integrating all data layers with each other. Among the single-layer predictors, several host and microbial features were highlighted, with host-associated markers being predominant. Host features associated with cognitive function mainly belong to innate and adaptive inflammatory activity (inflammaging) and developmental processes. Our findings suggest that cognitive decline in aging is tightly coupled to systemic, age-associated inflammation, potentially initiated by microbiome-driven gastrointestinal inflammatory activity, emphasizing a link between peripheral tissue alterations and brain function.
衰老相关的认知衰退与不同组织以及肠道微生物群的变化有关，包括肠-脑轴功能障碍。然而，只有少数研究将多器官改变与衰老过程中的认知衰退联系起来。在此，我们报告了一项多组学分析，整合了来自小鼠海马体、肝脏、结肠和粪便样本的代谢组学、转录组学、DNA甲基化和宏基因组学数据，并将其与不同年龄组在巴恩斯迷宫空间学习任务中的认知表现相关联。我们在各个数据层中确定了734个与认知排名相关的分子特征，当将所有数据层相互整合时，其中227个特征仍然存在。在单层预测因子中，突出了几个宿主和微生物特征，其中宿主相关标记占主导地位。与认知功能相关的宿主特征主要属于先天性和适应性炎症活动（炎症衰老）以及发育过程。我们的研究结果表明，衰老过程中的认知衰退与全身性、年龄相关的炎症密切相关，可能由微生物群驱动的胃肠道炎症活动引发，强调了外周组织改变与脑功能之间的联系。
