The Contextualized Genetics of Human Longevity: JACC Focus Seminar

The genetics of human longevity has long been studied, and in this regard, centenarians represent a very informative model. Centenarians are characterized by 2 main features: 1) the capability to avoid or postpone the major age-related diseases; and 2) a high level of heterogeneity of their phenotype. The first suggests that longevity and resistance to diseases are mediated by shared mechanisms, the latter that many strategies can be used to become long lived, likely as a result of variable genome-environment interactions. The authors suggest that the complexity of genome-environment interactions must be considered within an evolutionary and ecological perspective and that the concept of “risk allele” is highly context dependent, changing with age, time, and geography. Genes involved in both longevity and cardiovascular diseases, taken as a paradigmatic example of age-related diseases, as well as other emerging topics in genetics of longevity, such as micro–ribonucleic acid (miRNA) genetics, polygenic risk scores, environmental pollutants, and somatic mutations are discussed.