During the past years, several lines of evidence argued for an important role of RAS and especially angiotensin II in the development of aging lesions, especially in kidney and arteries12. Genetic disruption of the AT1a receptor prevented aging-related progression of cardiac hypertrophy and fibrosis, and extended mouse lifespan23. To a lesser extent, RAS pharmacological inhibition was also able to protect against aging related lesions in murine models24, 25. Interestingly, we observed that calpain inhibition decreased features of aging particularly in the kidney and the cardiovascular system. Specific calpain inhibition was associated to less cardiovascular hypertrophy and remodelling already present at one year, independently from changes in hemodynamic features and blood pressure at that time. Kidneys from CalpTG mice exhibited less fibrosis and less glomerular lesions. Senescence markers including p21 and beta-galactosidase activity were dramatically lower in CalpTG mice cells, indicating that oxidative stress was reduced. Genome-wide gene expression analyses in 2-years old mice highlighted that inflammation-related pathways differed dramatically between the 2 groups, particularly transcripts of genes involved in innate immunity, NLRP3 inflammasome formation and NF-κB activation. We confirmed that immune cell and especially macrophage infiltration was reduced in CalpTG mice kidneys. There was no difference in M1/M2 polarization, suggesting that inflammatory cell recruitment was influenced by the calpain system but not macrophage polarization.