Plant Extracts and ω-3 Improve Short-Term Memory and Modulate the Microbiota-Gut-Brain Axis in D-galactose Model Mice

Background: Aging, characterized by a slow and progressive alteration of cognitive functions, is associated with gut microbiota dysbiosis, low-grade chronic inflammation, as well as increased oxidative stress and neurofunctional alterations. Some nutrients, such as polyphenols, carotenoids, and omega (co)-3 (n-3), are good candidates to prevent age-related cognitive decline, because of their immunomodulatory, antioxidant, and neuroprotective properties. Objectives: The objective of this study was to demonstrate the preventive effect of a combination of plant extracts (PE) containing MemophenolTM (grapes and blueberries polyphenols) and a patented saffron extract (saffron carotenoids and safranal) and co-3 on cognitive function in a mouse model of accelerated aging and to understand the biological mechanisms involved. Methods: We used an accelerated-aging model by injecting 3-mo-old male C57Bl6/J mice with D-galactose for 8 wk, during which they were fed with a balanced control diet and supplemented or not with PE and/or co-3 (n 1/4 15-16/group). Short-term memory was evaluated by Y-maze test, following analyses of hippocampal and intestinal RNA expressions, brain fatty acid and oxylipin amounts, and gut microbiota composition (16S rRNA gene sequencing). Statistical analyses were performed (t test, analysis of variance, and Pearson Results: Our results showed that oral administration of PE, co-3, or both (mix) prevented hippocampus-dependent short-term memory deficits induced by D-galactose (P < 0.05). This effect was accompanied by the modulation of gut microbiota, altered by the treatment. PE and the mix increased the expression of antioxidative and neurogenesis markers, such as catalase and doublecortin, in hippocampus (P < 0.05 for both). Moreover, co-3 and the mix showed a higher co-3 amounts (P < 0.05) and EPA-derived 18- hydroxyeicosapentaenoic acid (P < 0.001) in prefrontal cortex. These changes may contribute to the improvement in memory. Conclusions: These results suggest that the mix of PE and co-3 could be more efficient at attenuating age-related cognitive decline than individual supplementations because it targeted, in mice, the different pathways impaired with aging.