With our previous Longevity Consortium (LC) support, we brought together four extreme longevity (EL) studies that have agreed to share their individual level genetic and phenotypic data for more powerful genetic association analyses of human EL. Working closely with the other LC projects and cores, we will utilize these and developed unique resources to achieve 3 primary goals: (1) discover additional rare/uncommon EL and compression of morbidity genetic variants; (2) analyze gene expression profiles associated with EL-genetic variants to be used to search for healthy aging therapeutics; (3) strategically enroll new participants in the New England Centenarian Study (NECS) to provide biomaterial and phenotypic and genetic data for discovery- phase and validation/replication and follow-up experiments for this and other LC projects and cores. Specifically, in Aim 1 (Discovery) we propose to conduct a genome-wide association mega-analysis of EL and selected sub-phenotypes using data from 2,070 centenarians and 6,259 controls aggregated from the 4 longevity studies. The Japanese Centenarian Study, Health and Retirement Study, the Danish Longevity Study, and new data from Aim 3 will provide independent replication. In Aim 2 (Translation) we will link genetic data to whole blood gene expression data generated from 400 Long Life Family Study (LLFS) subjects, ages ranging from 50 to 110 years. These data will be used to generate expression quantitative trait loci (eQTLs) and gene/protein sets associated with significant eQTLs that are also associated with EL. Bioinformatics analyses in conjunction with the Chemoinformatics core will be aimed at discovering biomolecules and existing drugs that mimic the effects of the EL-associated mechanisms naturally occurring in people with EL genotypes. Mediation analysis will be used to investigate the joint effects of EL-promoting variants and their associated molecular signatures on age of onset of dementia, diabetes, cardiovascular disease, stroke, and cognitive impairment. These analyses will characterize the healthy aging patterns that might be enabled by the candidate compounds. In Aim 3 (discovery, validation and follow-up) we will identify 10-15 already enrolled families with informative patterns of familial EL from the collaborating EL studies. We will enroll additional critical family members from these families (e.g. siblings, cousins, etc) and use next generation whole genome sequencing to discover novel, rare EL-variants and to perform fine mapping of variants discovered in Aim 1. Newly enrolled subjects from these families as well as non-familial 103+ year olds will also provide data and biomaterial for planned studies by the other LC projects and cores. Through these aims and in collaboration with other LC projects and cores, the Centenarians Project will build on resources and findings from the previous cycle of the LC to discover new genetic variants associated with EL, integrate genetic and molecular data to identify targets for healthy-aging therapeutics, and generate unique biomaterial and data resources for work described by the other LC projects.