Elderly people without atrial fibrillation (AF) still have a high incidence of cardioembolic stroke, suggesting that thrombus formation within the left atrial appendage (LAA) may also occur in an AF-independent manner. In the present study, we explored the potential mechanisms for aging-induced LAA thrombus formation and stroke in mice. We monitored stroke events in 180 aging male mice (14–24 months) and assessed left atrium (LA) remodeling by echocardiography at different ages. Mice that had stroke were implanted with telemeters to confirm AF. Histological features of LA and LAA thrombi were examined, as well as collagen content, expression of matrix metalloproteinases (MMPs), and leukocyte density in the atria at different ages, in mice with or without stroke. Also, the effects of MMP inhibition on stroke incidence and atrial inflammation were tested. We detected 20 mice (11 %) with stroke, 60 % of which were within 18–19 months of age. Although we did not detect AF in mice with stroke, we detected the presence of LAA thrombi, suggesting that stroke originated from the hearts of these mice. Compared with 18-month-old mice without stroke, 18-month-old stroke mice had enlarged LA with a very thin endocardium, that was associated with less collagen and heightened MMP expression in the atria. During aging, we found that the expression of mRNAs for atrial MMP7, MMP8, and MMP9 peaked at 18 months, which closely correlated with reductions in collagen content and the time-window for cardioembolic stroke in these mice. Treatment of mice with an MMP inhibitor at 17–18 months of age reduced atrial inflammation and remodeling, and stroke incidence. Taken together, our study demonstrates that aging-induced LAA thrombus formation occurs through a mechanism involving upregulation of MMPs and breakdown of collagen, and that treatment with an MMP inhibitor may be effective as a treatment strategy for this heart condition. Possible mechanisms of left atrial appendage (LAA) thrombus formation in aging mice Normal mice (2-month-old) display intact and thick connective tissue in the atrial endocardium. During 18–19 months of age, increased infiltration of leukocytes into the mouse atria induces the up-regulation of matrix metalloproteinases (MMPs), leading to the reduction of collagen. LAA thrombus might start from the breakdown of endocardial fibril collagen by MMPs, which then triggers platelet adhesion and aggregation along the slit. An enlarged left atrium chamber may trigger blood clotting and the formation of an unstable mural thrombus in the early phase. After 19 months, reduced expression of MMPs causes collagen accumulation and atrial fibrosis. The remaining or recurrent thrombi are infiltrated by leukocytes and myofibroblasts at the late phase, and then covered by fibrotic tissue to form a stable, organized thrombus (A). Temporal changes of leukocytes, MMPs, and total collagen in the atria of aging mice (B). [Display omitted] • Cardioembolic strokes that occurred in aged mice are independent of atrial fibrillation. • Stroke mice had more dilated left atrium and heightened atrial inflammatory responses compared with mice of similar age but without stroke. • Elevated levels of MMPs and reductions in collagen content within the atria of mice at 18 months are associated with LAA thrombus formation and cardioembolic stroke. • Treatment with the MMP inhibitor XL-784 between 18 and 19 months of age repressed atrial dilatation as well as the incidence of stroke in aged mice. [ABSTRACT FROM AUTHOR]