The Centenarian project will discover new rare 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 and cores.
Working closely with other LC projects and cores, we propose three aims in order to: (1) discover additional rare/uncommon extreme longevity (EL) variants and variants associated with compression of morbidity, (2) use gene expression profiles associated with EL variants that may be used to find healthy-aging therapeutics, (3) strategically enroll new NECS participants to validate, extend and follow-up discoveries from this and other LC projects, and, importantly, (4) provide phenotypic data and biomaterial to other LC projects and cores.
The project has 3 specific aims:
Aim 1. Discovery. We propose a genome-wide association mega-analysis of EL using data from 2,070 centenarians and 6,259 controls aggregated from the 4 longevity studies. Genetic data will be imputed using newly available reference panels of thousands of genomes that produce much improved imputation of rare variants. We will complement this analysis with a series of survival analyses to distinguish variants associated with EL because of mortality selection at younger ages vs. those that promote EL and aging free of specific diseases, cognitive impairment and/or physical disability. The Japanese Centenarian Study, Health and Retirement Study, the Danish Longevity Study, and new data from Aim 3 will provide replication for analysis of variants in-common or not with Japanese ethnicity.
Aim 2: Translation. We will use gene expression data from 450 LLFS blood samples, ages ranging from 50 to 110 years, obtained from long-lived individuals, siblings, offspring and spouses to generate expression quantitative trait loci (eQTLs) and select gene sets associated with significant eQTLs that are also associated with EL. The Girke chemoinformatics core will query bioinformatics repositories such as the Connectivity Map/LINCS to discover biomolecules and existing drugs that mimic the effects of the longevity-associated mechanisms naturally occurring in people with EL genotypes. We will use mediation analysis to investigate the joint effects of EL promoting variants (discovered by us, Price systems and Schork disease context projects) and their associated molecular signatures on age of onset of dementia, diabetes, cardiovascular disease, stroke, and cognitive impairment and characterize the healthy aging patterns that might be enabled by the candidate compounds.
Aim 3: Discovery, Validation and Follow-Up. Aim 3a: Given our preliminary findings suggesting rare variants positively associated with EL, we will select 10-15 families demonstrating potent patterns of EL with members already enrolled in one of the participating centenarian studies, enroll additional first and second-degree family members and use whole genome sequencing to discover novel, rare EL-variants and to perform fine mapping of variants discovered in Aim 1. Aim 3b: Newly enrolled subjects from these families as well as sporadic 103+ year olds will also provide data and biomaterial (DNA and plasma for analyses by the Orwoll-proteomics and Fiehn -metabolomics projects, and genetic data for the Schork disease context project).
Figure 1: Overview