Evidence indicates the pathogenic role of cellular senescence in age-related cardiovascular-metabolic disorders including heart failure, atherosclerotic diseases, obesity, and diabetes. Protein p53 is described as a “guardian of the genome”, but is also known to mediate cellular senescence. Activation of p53 was observed in aged vessels, and failing hearts, and this is recognized to promote pathogenesis in atherosclerosis or heart failure. Suppression of cellular senescence takes the risk of tumorigenesis, and more safe approach needs to be explored to suppress the accumulation of senescent cells. Recently, the senolytic approach opened a new avenue for aging research. Senolysis, the specific depletion of senescent cells, mediated through the genetic/ pharmacologic/ vaccination approach reversed aging and pathologies in age-related diseases. Specific depletion of senescent cells would become next-generation therapies for cardiovascular diseases.