Metformin improves cardiac stress tolerance and mitochondrial function during early aging

Cardiac aging reduces stress resistance and increases the susceptibility to myocardial injury. Although cardiac dysfunction typically manifests in late-stage aging, the underlying process begins in middle age. Elevated endoplasmic reticulum (ER) stress is a key contributor to cardiac aging. We have shown that ER stress increases in middle-aged hearts and peaks in advanced age, while chronic metformin treatment reduces ER stress and improves mitochondrial function in late-aged hearts. This study examined whether metformin could protect early aged hearts exposed to a superimposed stress, given that ER stress is already elevated at this stage. Eighteen-month-old mice were used as a model of early cardiac aging, and isoproterenol (ISO; 100 mg/kg, subcutaneous injection for five consecutive days) was applied to induce cardiac stress. Metformin was administered in drinking water for two weeks prior to ISO treatment and continued throughout the exposure and recovery period. ISO treatment impaired cardiac function and mitochondrial respiration in 18-month-old mice compared to saline vehicle controls. Metformin reduced baseline ER stress and significantly improved both cardiac performance and mitochondrial function following ISO-induced stress. These findings demonstrate that chronic metformin treatment confers cardioprotection in early aging by attenuating ER stress and preserving mitochondrial function.