Rosmarinic acid administration improves cognitive and emotional behaviour and brain anti-oxidant defences in a sex-dependent manner in C57BL/6N aged mice fed a Western diet

A growing body of research suggests that regular consumption of nutraceuticals might improve healthspan. However, a better understanding of their therapeutic efficacy, as well as their mechanism of action, is needed. We investigated the ability of the nutraceutical compound rosmarinic acid (RA) to counteract the negative effects of a Western Diet (WD, high in sugar and fat) in a murine model of aging. Male and female 22-month-old C57BL/6N mice received either RA (500 mg/kg daily) or vehicle (KH2PO4/K2HPO4) via drinking water. Two weeks later, all subjects received either WD or control diet for 28 days, and were tested for emotional (Elevated Plus Maze - EPM), cognitive (Morris Water Maze - MWM) and metabolic parameters. At sacrifice, brain areas were dissected and used for transcriptomic analyses. Results show that RA prevented the WD-induced increase in body weight in males, although it failed to counteract the deleterious effects observed on glucose metabolism. Moreover, RA improved learning abilities in the MWM and increased exploration in the EPM in females only. These behavioural effects were associated with increased hippocampal expression levels of NFE2L2/NRF2, a master transcription factor for regulating the expression of multiple antioxidant proteins involved in mitochondrial redox homeostasis. Overall, our data suggest that RA may promote healthy aging in a sex-dependent fashion, at least in part through its ability to boost the organisms’ anti-oxidant defences. A thorough analysis of the transcriptomic profile (in process) will help elucidating all the pathways affected by RA. Support: H2020 AwE (grant-N. 633589).