Spermidine, a natural polyamine, extends lifespan and protects the heart in mice and rats. Oral supplementation of spermidine in mice increased median lifespan by ~10% and improved cardiac function, reducing hypertrophy and enhancing diastolic function. Spermidine enhanced autophagy, mitophagy, and mitochondrial respiration, improving cardiomyocyte mechano-elastical properties and reducing subclinical inflammation. In Dahl salt-sensitive rats fed a high-salt diet, spermidine reduced blood pressure, increased titin phosphorylation, and prevented cardiac hypertrophy and diastolic dysfunction, delaying heart failure. In humans, high dietary spermidine levels correlated with lower blood pressure and reduced cardiovascular disease risk. Spermidine's cardioprotective effects were dependent on autophagy, as shown by the failure of protection in Atg5-deficient mice. Spermidine also reduced hypertension and delayed heart failure progression in Dahl rats, improving ventricular-vascular coupling and cardiac function. In humans, dietary spermidine intake inversely correlated with cardiovascular disease and blood pressure. Spermidine may improve cardiovascular health through anti-inflammatory, mitochondrial, and autophagy-related mechanisms. The study suggests that spermidine could be a viable strategy for preventing cardiovascular disease.Spermidine, a natural polyamine, extends lifespan and protects the heart in mice and rats. Oral supplementation of spermidine in mice increased median lifespan by ~10% and improved cardiac function, reducing hypertrophy and enhancing diastolic function. Spermidine enhanced autophagy, mitophagy, and mitochondrial respiration, improving cardiomyocyte mechano-elastical properties and reducing subclinical inflammation. In Dahl salt-sensitive rats fed a high-salt diet, spermidine reduced blood pressure, increased titin phosphorylation, and prevented cardiac hypertrophy and diastolic dysfunction, delaying heart failure. In humans, high dietary spermidine levels correlated with lower blood pressure and reduced cardiovascular disease risk. Spermidine's cardioprotective effects were dependent on autophagy, as shown by the failure of protection in Atg5-deficient mice. Spermidine also reduced hypertension and delayed heart failure progression in Dahl rats, improving ventricular-vascular coupling and cardiac function. In humans, dietary spermidine intake inversely correlated with cardiovascular disease and blood pressure. Spermidine may improve cardiovascular health through anti-inflammatory, mitochondrial, and autophagy-related mechanisms. The study suggests that spermidine could be a viable strategy for preventing cardiovascular disease.