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

Cardiac aging increases susceptibility to cardiovascular diseases, particularly myocardial infarction. Although evidence suggest association between activation of the AIM2 inflammasome and cardiovascular diseases, 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 upregulated in the aged myocardium and senescent 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 upregulation 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.