This study investigates the cardioprotective and lifespan-extending effects of the natural polyamine spermidine. The researchers found that oral supplementation of spermidine in mice extended their lifespan and improved cardiac function, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine enhanced cardiac autophagy, mitophagy, and mitochondrial respiration, and improved the mechano-elastical properties of cardiomyocytes. In Dahl salt-sensitive rats, a model of hypertension-induced congestive heart failure, spermidine reduced systemic blood pressure, increased titin phosphorylation, and prevented cardiac hypertrophy and diastolic dysfunction. High dietary spermidine intake was also associated with reduced blood pressure and a lower incidence of cardiovascular disease in humans. The study suggests that spermidine may provide a new strategy for protecting against cardiovascular disease.This study investigates the cardioprotective and lifespan-extending effects of the natural polyamine spermidine. The researchers found that oral supplementation of spermidine in mice extended their lifespan and improved cardiac function, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine enhanced cardiac autophagy, mitophagy, and mitochondrial respiration, and improved the mechano-elastical properties of cardiomyocytes. In Dahl salt-sensitive rats, a model of hypertension-induced congestive heart failure, spermidine reduced systemic blood pressure, increased titin phosphorylation, and prevented cardiac hypertrophy and diastolic dysfunction. High dietary spermidine intake was also associated with reduced blood pressure and a lower incidence of cardiovascular disease in humans. The study suggests that spermidine may provide a new strategy for protecting against cardiovascular disease.