Sirtuins are an evolutionarily conserved family of nicotinamide adenine dinucleotide (NAD+)-dependent enzymes that regulate aging, cellular stress responses, and metabolic homeostasis. In mammals, seven isoforms (SIRT1-SIRT7) differ in subcellular localization, substrate specificity, and enzymatic activity, allowing them to control genomic stability, mitochondrial function, redox balance, inflammation, apoptosis, autophagy, and cell proliferation. Increasing evidence links sirtuin dysregulation to age-related chronic diseases, particularly cardiovascular disease (CVD). This review provides an integrated overview of the structure, enzymatic functions, localization, and biological specialization of mammalian sirtuins, with an emphasis on their roles in physiological aging and cardiovascular homeostasis. We discuss the involvement of individual sirtuins in major cardiovascular pathologies, including metabolic cardiomyopathy, myocardial ischemia-reperfusion injury (IRI), cardiac hypertrophy, fibrosis, heart failure, atherosclerosis, coronary artery disease, and hypertension. Particular focus is placed on SIRT1, SIRT3, and SIRT6, which emerge as key regulators of endothelial integrity, mitochondrial quality control, oxidative stress, inflammatory signaling, and myocardial remodeling. We also highlight the context-dependent and sometimes dual effects of other sirtuin isoforms in CVD. Finally, we summarize current therapeutic strategies targeting sirtuins, including activators, NAD+-boosting approaches, and selective inhibitors, and discuss the main challenges for future clinical translation in cardiovascular medicine, including precision, isoform-specific intervention design strategies, and long-term clinical implementation.
