We have strengthened our revised proposal in several major ways. First, we have expanded our genetic sequencing of the extreme phenotype of centenarians (with appropriate controls) to include the entire human exome, in addition to regulatory/conserved regions of more genes (~1,000) selected by our Scientific Advisory Committee, based on work from model systems and previous genome-wide association studies (GWAS) for longevity. Second, instead of creating a Gene Function Core, we will analyze and characterize in silico the variants we discover in order to identify the best candidates for subsequent functional studies. Third, after careful consideration of reviewers' comments and concerns about the proposed in vitro work, we decided to defer several proposals for in vitro studies of specific pathways-insulin signaling, TOR, mitochondria and energy-sensing, micro- and regulatory RNA, and proteostasisuntil we have identified the best candidates for functional studies. In addition, we have modified the remaining projects and cores in response to the previous reviews. We are excited that the next phase of the Longevity Consortium (LC) will have a substantial impact on research on aging and chronic degenerative diseases.
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