Cardiovascular aging is a major contributor to the development of cardiovascular diseases (CVDs), yet the mechanisms linking metabolic imbalance to age-related cardiovascular dysfunction remain unclear. Protein palmitoylation, a reversible lipid post-translational modification, regulates protein localization, stability, and signaling, but its role in cardiovascular aging has not been systematically defined. Importantly, protein palmitoylation appears to act as a double-edged sword: whereas its physiological regulation is indispensable for cardiovascular homeostasis, aberrant palmitoylation under metabolic stress may drive aging and disease progression. In this review, we summarize current evidence indicating that dysregulated palmitoylation contributes to key features of cardiovascular aging, including mitochondrial dysfunction, impaired autophagy, oxidative stress, and cellular senescence. We further integrate findings across cardiomyocytes, endothelial cells, fibroblasts, and immune cells to highlight the role of palmitoylation in coordinating cellular dysfunction and intercellular communication during cardiovascular aging and disease. We propose a "palmitoylation-driven metabolic vicious cycle" that links metabolic disorders to enhanced palmitoylation and progressive cardiovascular injury. In addition, we discuss emerging detection approaches and therapeutic strategies targeting palmitoylation. Overall, this review provides a mechanistic framework linking palmitoylation to cardiovascular aging and disease and identifies potential targets for intervention in aging-related CVDs.
