Heart failure with preserved ejection fraction (HFpEF) is a common syndrome in the elderly population, especially in women. To elucidate the mechanism of HFpEF, we investigated the effects of aging and sex on cardiac function in a “two-hit” HFpEF model, which combines metabolic and mechanical stress (Nature. 568, 351-356, 2019). We induced HFpEF in 6-month-old male- and 2-year-old male- and female mice by “two-hit” model and examined the effects of aging and sex on cardiac function. Cardiac function was evaluated by echocardiography at the beginning 0, 5, and 15 weeks of the experiment. Before the treatment, aged mice showed mild cardiac hypertrophy and reduced left ventricular contractility compared to the young mice, and there was no clear sex difference in cardiac function in aged mice. At 5 weeks, young mice showed diastolic dysfunction and cardiac hypertrophy. In sharp contrast to young mice, some aged mice showed markedly reduced left ventricular contractility. Additionally, some aged mice showed symptoms of heart failure at 15 weeks, showing more varied consequences than the young mice. In particular, some mice developed heart failure with reduced ejection fraction, which was not observed in young mice. Collectively, our results demonstrate the age-related differences in the response to the “two-hit” HFpEF model.