Persistent metabolic remodeling after dietary salt reduction reveals sex differences in the adaptation to chronic high-salt intake

Background Excessive salt intake is a risk factor for cardiovascular disease, yet its systemic metabolic consequences and its relationship to differential cardiovascular adaptations in males and females remain poorly understood. Here, we performed plasma metabolite profiling in male and female mice subjected to long-term high-salt diet (HSD) exposure during aging. Methods Mice were fed HSD (8.6% NaCl) or low-salt normal diet (ND; 0.6% NaCl) from 9 to 23 months of age, with a subset of mice undergoing diet reversal to ND after 7 months of HSD. Plasma metabolites were analyzed using gas chromatography/mass spectrometry and related to previously reported measurements of arterial blood pressure and cardiac function. Results Female mice developed salt-sensitive hypertension driven by vascular dysfunction, whereas male mice exhibited cardiac and vascular remodeling independent of blood pressure. Among 48 measured metabolites, HSD induced substantial alterations in levels of glucose, glycerol, glycerol phosphates, and fatty acids. Males showed a near-complete normalization of metabolite profiles following 7 months of salt reduction, whereas females retained a metabolomic signature different from ND despite normalization of blood pressure. In particular, metabolites related to energy metabolism, lipid handling, and osmotic balance were influenced by both diet and sex, with linoleate showing a significant sex-diet interaction. Correlation analyses demonstrated associations between metabolite profiles and cardiovascular parameters with different patterns in males and females. Conclusion Our findings demonstrate that chronic high-salt consumption induces persistent plasma metabolite alterations displaying different patterns in male and female mice that are not fully reversed by a salt-lowering dietary intervention. The dissociation between physiological recovery and metabolic normalization, particularly in females, suggests that metabolic alterations may represent an additional layer of cardiovascular risk beyond blood pressure control in mice.