We have previously described that CalpTG mice were protected against inflammation in models of glomerulonephritis, sepsis or allograft rejection but this is the first demonstration that blunting calpain activity protects against inflammaging2, 3, 11. Interestingly, calpain-induced inflammatory processes and classical inflammaging features share similarities. Inflammaging is characterized by a low grade of chronic and systemic inflammation in aging, in the absence of systemic infection or inflammatory disease15. One of the main mechanisms involved in inflammaging onset is the NLRP3 inflammasome activation by mitochondrial reactive oxygen species. NLRP3 is a multiproteic complex activating caspase 1, IL-1α, IL-1β and IL-18 processing and synthesis26. The synthesis of IL-1α and IL-1β mRNA in response to various NLRP3 inflammasome activators were reduced in CalpTG macrophages. Of notice, the production of IL-1α protein was impacted by calpain inhibition in response to the particulate inflammasome activators (MSU and silica) but much lower in response to ATP or nigericin. This observation is in accordance with the observation by Gross et al. that particulate activators, but not nigericin and ATP, are able to induce IL-1α secretion in a way partly independent of the inflammasome, but involving calcium influx and calpain activation27.