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

Unhealthy lifestyles, such as chronic consumption of a Western Diet (WD), have been associated with increased systemic inflammation and oxidative stress (OS), a condition that may favour cognitive dysfunctions during aging. Polyphenols, such as rosmarinic acid (RA) may buffer low-grade inflammation and OS, characterizing the aging brain that is sustained by WD, promoting healthspan. The aim of this study was to evaluate the ability of RA to prevent cognitive decline in a mouse model of WD-driven unhealthy aging and to gain knowledge on the specific molecular pathways modulated within the brain. Aged male and female C57Bl/6N mice were supplemented either with RA or vehicle for 6 weeks. Following 2 weeks on RA they started being administered either with WD or control diet (CD). Successively all mice were tested for cognitive abilities in the Morris water maze (MWM) and emotionality in the elevated plus maze (EPM). Glucose and lipid homeostasis were assessed in trunk blood while the hippocampus was dissected out for RNAseq transcriptomic analysis. RA prevented insulin resistance in males while protecting both males and females from WD-dependent memory impairment. In the hippocampus, RA modulated OS pathways in males and immune- and sex hormones-related signalling cascades ( Lhb and Lhcgr genes) in females. Moreover, RA overall resulted in an upregulation of Glp1r, recently identified as a promising target to prevent metabolic derangements. In addition, we also found an RA-dependent enrichment in nuclear transcription factors, such as NF-κB, GR and STAT3, that have been recently suggested to promote healthspan and longevity by modulating inflammatory and cell survival pathways. Oral RA supplementation may promote brain and metabolic plasticity during aging through antioxidant and immune-modulating properties possibly affecting the post-reproductive hormonal milieu in a sex-dependent fashion. Thus, its supplementation should be considered in the context of precision medicine as a possible strategy to preserve cognitive functions and to counteract metabolic derangements. Graphical abstract . Chronic consumption of Western Diet (WD) may negatively affect the aging process precipitating cognitive decline by sustaining the systemic low-grade inflammatory state and pro-oxidant environment characterizing this life stage. The hippocampus (marked in red in the brain) is a preferential target for the negative effects of WD-like patterns. The resulting effect is an increased cognitive decline and the development of metabolic dysfunctions (metabolic syndrome) that might reinforce one another in a vicious cycle. Regular consumption of polyphenols may promote healthspan by counteracting the low-grade inflammation and oxidative stress. In our WD-induced mouse model of unhealthy aging (light green square on the right), oral supplementation with rosmarinic acid (RA) prevented WD-mediated metabolic impairments specifically in males and reduced age-related anxiety-like behaviours in females while enhancing cognitive abilities in all subjects by specific changes in hippocampal gene expression. In particular, RA modulated Glp1r, Lhb, Lhcgr genes and enriched NF-κB, GR and STAT3 nuclear transcription factors. These findings shed light on the beneficial preventive effects of nutraceuticals in promoting healthy aging by affecting metabolic, inflammatory and cell survival pathways in a sex-dependent fashion. • Western diet (WD) precipitates aging in mice in a sex-dependent manner. • Rosmarinic acid (RA) prevents WD-mediated metabolic derangements in males. • RA decreases anxiety and enhances cognition in both sexes. • RA modulates oxidative stress, immune- and sex hormones-related pathways in the hippocampus. • RA supplementation could be a feasible strategy to promote healthspan.