Extreme longevity, which manifests as an exceptionally prolonged physical and cognitive performance into very old age, can be considered a model of successful aging. Studies of this phenomenon have delineated a complex interaction of genetic, lifestyle, and environmental factors contributing to increased longevity and healthspan. Centenarians and supercentenarians (those living to 100 and 110 years of age, respectively) display distinct genetic profiles when compared to younger cohorts, and such profiles include favorable mutations that are protective of cardiovascular health, support DNA damage repair, and promote inflammatory regulation. Lifestyle-related nongenetic factors (diet, physical activity, socialization) also play a role in healthy aging, often through the filter of epigenetic mechanisms, to which DNA methylation belongs. It is clear that complex interactions between genetic background, lifestyle, and environmental exposures during the lifespan impact the aging process by altering methylation patterns that activate or silence genes relevant to crucial metabolic functions, sometimes not even directly related to aging. In this framework, an omnigenic and multiomic view of aging and longevity encompassing functional genomics, epigenetic markers, and environmental/lifestyle influences could allow for a holistic interpretation of this complex phenotype and instigate targeted, personalized solutions to maximize healthy aging and healthspan.