The specific inhibition of calpains by calpastatin overexpression protected CalpTG mice against aging-related lesions, especially vascular and kidney lesions. Calpain inhibition reduced kidney inflammaging as evidenced by RNAseq analyses, tissular flow cytometry, immunohistochemistry and complementary in vitro and in vivo models. To our knowledge, this study is the first to identify calpains as a potent inflammaging mediator.