Figure 2A. Experimental design of the water maze experiment. At 12 months of age, male mice were subjected to the water-maze training protocol in order to habituate the animals to the procedure. Subsequently, mice were subjected to water maze training followed by a probe test at 13.5, 15 and 16.5 months of age. The platform position was altered during each training procedure. Blood was collected upon completion of each water maze procedure. A visual cued test was performed after the first and after the last blood collection when mice were 12 and 16.5 months of age respectively. B. Escape latency during water maze training when mice were 13.5, 15 or 16.5 months of age (n = 10 each group). Two-way ANOVA followed by Tukey´s multiple comparisons test revealed significant effects of training trials (p value < 0.0001) and age (***p value 0.0004) on the performance. On day one and two, there was a significant (p value < 0.05) difference between mice at 13.5 vs. 16.5 months and 15 vs. 16.5 months of age (n = 10 each group). On the 5th day of training there was a significant difference observed between 15 and 16.5 months of age. Density plot (Right) shows the occupancy pattern of mice at different time points of aging. Occupancy signal on the platform was the least at 16.5 months, suggesting mice at the given age failed to locate the platform. C. Analysis of the different search strategies during the water training sessions. Note that especially at 16.5 months of age mice adopt hippocampal independent search strategies indicative of impaired cognitive function. D. The cumulative cognitive score calculated for each day on the basis of hippocampal dependent strategies was significantly impaired when comparing mice at 16.5 month of age to their performance at 15 or 13.5 months of age. Data is normalized to 13.5 month group (Ordinary One-way ANOVA, Tukey`s multiple comparison test). N = 10 mice/group, **P<0.01. E. Heat map showing the expression pattern of 55 aging responsive microRNAs significantly deregulated during the course of aging. All data is shown in comparison to the expression level at 12 month of age. All microRNAs having at least 100 reads in 50% of the samples were filtered prior to differential expression analysis. F. Expressions of these 55 microRNAs and cognitive performances along aging were used to identify microRNA features linked to cognition. Three independent approaches [e.g. random forests (RF) with leave one out cross validation, RF with multivariate bootstrapping and support vector machine (SVM)] find seven common microRNAs that explain cognitive variability assayed in the water maze test. G. Color map showing that the 7 microRNAs identified in (F) are present in the co-expression modules significantly linked to cognition in healthy humans as described in Fig 1. H. Heat map showing the enrichment of mRNA targets of the 7 microRNAs shown in (G) with a gene-set identified by GWAS studies linking genes to cognition in healthy humans (Davies G, 2018). Note that target genes of miR-181a-5p, miR-148a-3p and miR-146a-5p are significantly overlapped in a hypergeometric test (Fold enrichment > 1.5 and FDR<0.05). *P = 0.02, **P = 0.0008, ***P = 2.267e-05. I. Gene ontology analyses of miR-181a-5p, miR-148a-3p and miR-146a-5p predicted targets reveal top significant processes linked to neuronal function and inflammation. Heatmap represents the top 5 significant biological processes. Color code represents adjusted p value.