Abstract In the study of longevity, increasing importance is being placed on the concept of healthy aging rather than considering the total number of years lived. Although the concept of healthy lifespan needs to be defined better, we know that cardiovascular diseases (CVDs) are the main age-related diseases. Thus, controlling risk factors will contribute to reducing their incidence, leading to healthy lifespan. CVDs are complex diseases influenced by numerous genetic and environmental factors. Numerous gene variants that are associated with a greater or lesser risk of the different types of CVD and of intermediate phenotypes (i.e., hypercholesterolemia, hypertension, diabetes) have been successfully identified. However, despite the close link between aging and CVD, studies analyzing the genes related to human longevity have not obtained consistent results and there has been little coincidence in the genes identified in both fields. The APOE gene stands out as an exception, given that it has been identified as being relevant in CVD and longevity. This review analyzes the genomic and epigenomic factors that may contribute to this, ranging from identifying longevity genes in model organisms to the importance of gene–diet interactions (outstanding among which is the case of the TCF7L2 gene).