FOXO3A genotype is strongly associated with human longevity

Abstract

Human longevity is a complex phenotype with a significant familial component, yet little is known about its genetic antecedents. Increasing evidence from animal models suggests that the insulin/ IGF-1 signaling (IIS) pathway is an important, evolutionarily conserved biological pathway that influences aging and longevity. However, to date human data have been scarce. Studies have been hampered by small sample sizes, lack of precise phenotyping, and population stratification, among other challenges. Therefore, to more precisely assess potential genetic contributions to human longevity from genes linked to IIS signaling, we chose a large, homogeneous, long-lived population of men well-characterized for aging phenotypes, and we performed a nested-case control study of 5 candidate longevity genes. Genetic variation within the FOXO3A gene was strongly associated with human longevity. The OR for homozygous minor vs. homozygous major alleles between the cases and controls was 2.75 (P ‫؍‬ 0.00009; adjusted P ‫؍‬ 0.00135). Long-lived men also presented several additional phenotypes linked to healthy aging, including lower prevalence of cancer and cardiovascular disease, better self-reported health, and high physical and cognitive function, despite significantly older ages than controls. Several of these aging phenotypes were associated with FOXO3A genotype. Long-lived men also exhibited several biological markers indicative of greater insulin sensitivity and this was associated with homozygosity for the FOXO3A GG genotype. Further exploration of the FOXO3A gene, human longevity and other aging phenotypes is warranted in other populations.gene ͉ insulin ͉ healthy aging ͉ disease ͉ disability

Genomewide meta‐analysis identifies loci associated with IGF ‐I and IGFBP ‐3 levels with impact on age‐related traits

“…ASXL2 is a polycomb group protein with known functions in development that has also been associated with pediatric cancer, but to our knowledge has not before been suggested as a longevity gene (Huether et al ., 2014). The SNP in the known longevity gene FOXO3 has not only been previously associated with reduced fasting insulin and HOMA‐IR (Willcox et al ., 2008), but here it was found to produce lower circulating IGF‐I levels. Multiple genetic determinants for circulating IGF‐I in normal and IGF1R resistance states might partially explain the U‐shaped association of circulating IGF‐I concentration with mortality (Suh et al ., 2008; Burgers et al ., 2011).…”

“…In animal models, diminished IGF‐I/insulin signaling has been associated with extended lifespans (Ziv & Hu, 2011), although the role of the IGF axis in human longevity remains inconclusive. Human genetic studies have suggested an association between polymorphisms in IGF‐I signaling pathway genes and longevity (Willcox et al ., 2008; Ziv & Hu, 2011; Di Bona et al ., 2014). Heritability studies have provided evidence for a substantial genetic contribution to circulating concentrations of IGF‐I (with heritability estimates ~40–60%) and IGFBP‐3 (80%) (Harrela et al ., 1996; Hong et al ., 1996; Souren et al ., 2007).…”

“…Some of these genes are involved in well‐described IGF regulatory or signaling pathways (such as IGFBP3 and IGFALS ) (Deal et al ., 2001; Gu et al ., 2010; Schumacher et al ., 2010) and are believed to influence traits that are also associated with concentrations or bioactivity of IGFs (e.g., FOXO3 locus associated with longevity (Willcox et al ., 2008) and IGFBP3 locus associated with hip osteoarthritis (Evans et al ., 2015)). To identify additional genetic variants with smaller effect sizes and enable sex specific analyses, we expanded our GWAS meta‐analysis to include up to a total of 30 884 individuals of European ancestry from 21 studies with measured circulating concentrations of IGF‐I and IGFBP‐3.…”

Predicting all‐cause mortality from basic physiology in the Framingham Heart Study

“…Aging is a complex biological process with multiple contributing genetic pathways (Kenyon et al ., 1993; Lakowski & Hekimi, 1996; Hansen et al ., 2007; Lunetta et al ., 2007; Pan et al ., 2007; Willcox et al ., 2008; Li et al ., 2009; Imai & Guarente, 2014; Satoh & Imai, 2014), significant variation among even closely related organisms (Jones et al ., 2014), and an ongoing debate about its root causes and origin (Kirkwood, 2005). At its core, however, aging is simply the statistical phenomenon of an increased probability of death over time.…”

Immunochip analysis identifies association of the RAD 50/ IL 13 region with human longevity

“…Despite more than 20 years of research into the genetic basis of human longevity, only alleles in the APOE and FOXO3 genes have repeatedly been shown to be associated with survival to very advanced ages (Schächter et al ., 1994; Willcox et al ., 2008; Flachsbart et al ., 2009; Soerensen et al ., 2010; Deelen et al ., 2013). APOE and FOXO3 were initially detected in candidate‐driven case–control investigations, but APOE has since then been confirmed in a number of genome‐wide association studies (GWAS).…”