Western diet-induced cognitive and metabolic dysfunctions in aged mice are prevented by rosmarinic acid in a sex-dependent fashion

Unhealthy lifestyles, and in particular chronic consumption of Western Diet (WD), has been associated with an increased incidence of cognitive dysfunctions during aging. By contrast, regular consumption of nutraceuticals may promote brain and metabolic health. Although the mechanisms of action and sex/gender specificity are still unclear, it is possible that these compounds might counteract the low-grade inflammation and oxidative stress (OS) characterizing the aging brain that is sustained by WD. We investigated whether oral administration of the polyphenol rosmarinic acid (RA, 500 mg/kg) might protect aged male and female C57BL/6N mice from cognitive decline and metabolic derangements upon WD (5.28 kcal/g) feeding. A thorough characterization of both the cognitive/emotional and metabolic profile was carried-out in addition to the analysis of hippocampal gene expression through RNAseq. In males, WD resulted in a condition of insulin resistance as revealed by HOMA-IR index, while females showed a generalized increase in emotionality. RA prevented these effects and was able to protect both male and female mice from WD-dependent cognitive dysfunction, as assessed in a spatial memory task. RNAseq analysis revealed that RA might mediate its effects by modulating OS in males and immune-related and sex hormones signalling cascades specifically in females (Lhb and Lhcgr genes). RA led to an overall upregulation of Glp1r, a gene recently identified as promising target to prevent metabolic derangements during aging, suggesting a possible mechanism of action of this and other nutraceutical compounds worth of further investigation. Taken together our results provides evidence for oral RA supplementation to promote brain and metabolic health during aging with its mechanisms of action being finely modulated according to sex. Moreover, the use of RA might be considered in the context of health conditions involving metabolic derangements when specific dietary regimes are needed but the compliance is poor.