Insulin/IGF-1 Signaling Pathway Genes and Human Longevity
Mutations of genes involved in the insulin/insulin-like growth factor-1 (IGF-1) signaling pathway affect lifespan in several model organisms. Elegant genetic studies in C. elegans and Drosophila support the role of the Insulin/IGF-1 pathway in the control of aging. Studies in both the of the exceptionally long-lived Pit1 and Prop1 mouse models, also suggest that this pathway is altered in these long-lived mammalian models. More recently, transgenic mice with decreased IGF-1 receptor levels due to a single gene knockout have been demonstrated to have increased lifespan. This proposal will test the hypothesis that variations of genes in this pathway affect human lifespan. Specificallly, single nucleotide polymorphisms (SNPs) and haplotypes of genes in this pathway will be tested for associations with overall survival to late age and with protection from cause-specific mortality.
A series of candidate genes have been selected which are involved in insulin/IGF-1 signaling; these are homologous to genes which have been shown to have a longevity effect in model systems. In the initial stage of the analysis, polymorphism discovery will be performed by the genomics core laboratory. Polymorphisms and haplotypes of these candidate genes will be tested for an association with longevity in a cohort of women age 65 years and older. A 2-phase design will be employed. In the first phase, association will be tested by comparison of allele and haplotype frequencies in the 325 oldest women in the cohort and compared with the 650 women who died at the youngest ages in the cohort. In the second phase, any associations disovered in the first phase will be tested in the entire cohort to determine the association with cause-specific mortality.