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

Abstract

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.

Figure 1.

Quantitative trait loci (QTL) for mouse longevity and insulin-like growth factor 1 (IGF-1) as well as genome-wide association peaks for human longevity and mouse IGF-1, both depicted on the mouse genome, mouse chromosome 1 (mapped in Mb). Colored bars are longevity QTL; the open bar is an IGF-1 QTL. The height of the bars represents the 95% confidence interval if reported or an estimated 40 Mb if not reported; the black squares in the bars represent the QTL peaks. We determined the Mb position using a recently revised mouse map (89) and the Mouse Map Converter from the Center for Genome Dynamics (http://cgd.jax.org/mousemapconverter/). Arrows to the left of the chromosome represent human genome-wide association peaks at the homologous mouse genome locations. The arrow on the right of the chromosome is the mouse genome-wide association peak of IGF-1. (Figure is modified from Figure 1 of Yuan et al [85]). Chr = chromosome. Gelman et al (90), Harper et al (91), Leduc et al (92), Newman et al (64).