Sirtuins in Cellular Senescence and Cardiovascular Diseases: From Mechanistic Basis to Activator Development and Translational Perspectives.

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, and cellular senescence serves as a core driving factor in the pathogenesis and progression of cardiovascular degeneration and related diseases. Sirtuins act as a crucial molecular hub linking cellular senescence to CVDs, and their upregulated activity is closely associated with delayed cellular senescence and preserved normal cardiovascular function; therefore, the research and development of small-molecule Sirtuin-activating compounds (STACs) hold important research value and promising translational potential for CVD intervention. This review systematically elucidates the molecular mechanisms by which various Sirtuin subtypes influence senescence-related processes in CVDs through the regulation of biological events such as DNA damage repair, mitochondrial homeostasis, oxidative stress, and inflammatory responses. Furthermore, it comprehensively outlines their roles in major cardiovascular conditions, including hypertension, angiogenesis, atherosclerosis, aortic aneurysm and dissection, and heart failure. Finally, this paper summarizes recent advances in the development of Sirtuin activators and, in light of current challenges such as insufficient specificity and hurdles in clinical translation, provides perspectives on the future development of Sirtuin-targeted therapies for the prevention and treatment of CVDs.