The search for longevity and healthy aging genes: insights from epidemiological studies and samples of long-lived individuals.

Genetic factors clearly contribute to exceptional longevity and healthy aging in humans, yet the identification of the underlying genes remains a challenge. Longevity is a complex phenotype with modest heritability. Age-related phenotypes with higher heritability may have greater success in gene discovery. Candidate gene and genome-wide association studies (GWAS) for longevity have had only limited success to date. The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium conducted a meta-analysis of GWAS data for longevity, defined as survival to age 90 years or older, that identified several interesting associations but none achieved genome-wide significance. A recent GWAS of longevity conducted in the Leiden Longevity Study identified the ApoE E4 isoform as deleterious to longevity that was confirmed in an independent GWAS of long-lived individuals of German descent. Notably, no other genetic loci for longevity have been identified in these GWAS. To examine the conserved genetic mechanisms between the mouse and humans for life span, we mapped the top Cohorts for Heart and Aging Research in Genomic Epidemiology GWAS associations for longevity to the mouse chromosomal map and noted that eight of the ten top human associations were located within a previously reported mouse life-span quantitative trait loci. This work suggests that the mouse and human may share mechanisms leading to aging and that the mouse model may help speed the understanding of how genes identified in humans affect the biology of aging. We expect these ongoing collaborations and the translational work with basic scientists to accelerate the identification of genes that delay aging and promote a healthy life span.