Age is an important risk factor for cardiovascular diseases (CVD) and associated with a systemic, low-grade inflammation, so called "inflammaging". We aimed to investigate the impact of age and sex on the inflammatory markers S100A9 and components of the NLRP3 inflammasome at an early stage in the aging process, using mature adult and middle-aged/perimenopausal mice. Given the importance of the cardiosplenic axis in heart failure, the spleen was analyzed in addition to the left ventricle and cardiac fibroblasts. Using immunohistochemistry, flow cytometry and gene expression analysis, our study demonstrates a higher inflammatory state of the spleen in perimenopausal versus age-matched males and 3-months old female mice, whereas aging is associated with higher left ventricular gene expression of S100A9 and NLRP3 inflammasome components independent of sex. In conclusion, our data indicate that inflammatory signatures in the spleen and left ventricle already differ in middle-aged mice and are partly sex-dependent.