Discovery of functional gene variants associated with human longevity: opportunities and challenges

Age is a major risk factor for many human diseases. Extremely long-lived individuals, such as centenarians, have managed to ward off age-related diseases and serve as human models to search for the genetic factors that influence longevity. The discovery of evolutionarily conserved pathways with major impact on life span in animal models has provided tantalizing opportunities to test the relevance of these pathways for human longevity. Here we specifically focus on the insulin/insulin-like growth factor-1 signaling as a prime candidate pathway. Coupled with the rapid advances in ultra high-throughput sequencing technologies, it is now feasible to comprehensively analyze all possible sequence variants in candidate genes segregating with a longevity phenotype and to investigate the functional consequences of the associated variants. A better understanding of the functional genes that affect healthy longevity in humans may lead to a rational basis for intervention strategies that can delay or prevent age-related diseases.