The AIM2 inflammasome drives age-dependent cardiac dysfunction following ischemia-reperfusion in mice

Cardiac aging increases susceptibility to cardiovascular diseases (CVDs), particularly myocardial infarction. Although evidence suggest an association between activation of the absent in melanoma 2 (AIM2) inflammasome and CVDs, its contribution to age-related cardiac complications remains unknown. We investigated the role of the AIM2 inflammasome and the cardiac response to ischemia-reperfusion (I/R) injury in aged mice. Male wildtype (C57BL/6) and AIM2-deficient (AIM2-/-) mice were subjected to natural aging (21 months), using 3-month-old mice as controls, and human cardiomyocytes (AC16) were stressed by hydrogen peroxide to mimic senescent. AIM2 expression was up-regulated in the aged myocardium and senescence AC16 cells, coinciding with increased levels of cleaved caspase-1 (p20), IL-1β, and IL-18. Functional assays in Langendorff-perfused hearts revealed that AIM2 deficiency significantly attenuated post-I/R dysfunction in aged mice, restoring left ventricular developed pressure (LVDP) and pressure derivatives (+dP/dTmax and -dP/dTmin) toward pre-ischemic levels. While AIM2 absence did not alter age-associated hypertrophy, fibrosis, longevity, or senescence markers (p53 and p21), it reduced the baseline pro-inflammatory and pro-pyroptotic profile of the aged heart (IL-1β, IL-18, GSDMD-N, and ASC speck). In vitro, AIM2 activation using Poly(dA:dT) elevated IL-1β, GSDMD-N, ASC speck, and cell death in senescent cells, whereas pharmacological inhibition with A151 prevented these effects. Concurrently, age-dependent AIM2 up-regulation was confirmed in human cardiac datasets. Together, these findings suggest that age-dependent AIM2 induction primes a pro-inflammatory cardiac microenvironment, exacerbating post-I/R injury and highlighting this pathway for future investigation in the context of cardiac aging.