Association of the FOXO3A Locus with Extreme Longevity in a Southern Italian Centenarian Study

Chiara Viviani Anselmi,1* Alberto Malovini,1,2* Roberta Roncarati,1 Valeria Novelli,1 Francesco Villa,1 Gianluigi Condorelli,1 Riccardo Bellazzi,2 and Annibale Alessandro Puca,1

Abstract:

Several potential candidate genes in various biological pathways have been associated with longevity in model organisms. Many of these genes have human homologs and thus have the potential to provide insights into human longevity. Recently, several studies have suggested that FOXO3A functions as a key bridge for various signaling pathways that influence aging and longevity. Interestingly, Willcox and colleagues identified several variants that displayed significant genotype-gender interaction in male human longevity. In particular, a nested case-control study was performed in an ethnic Japanese population in Hawaii, and five candidate longevity genes were chosen based on links to the insulin-insulin-like growth factor-1 (IGF-1) signaling pathway. In the Willcox study, the investigated genetic variations (rs2802292, rs2764264, and rs13217795) within the FOXO3A gene were significantly associated with longevity in male centenarians. We validated the association of FOXO3A polymorphisms with extreme longevity in males from the Southern Italian Centenarian Study. Particularly, rs2802288, a proxy of rs2802292, showed the best allelic association minor allele frequency (MAF) 0.49; p 0.003; odds ratio (OR) 1.51; 95% confidence interval (CI), 1.15-1.98). Furthermore, we undertook a meta-analysis to explore the significance of rs2802292 association with longevity by combining the association results of the current study and the findings coming from the Willcox et al. investigation. Our data point to a key role of FOXO3A in human longevity and confirm the feasibility of identifying such genes with centenarian-controls studies. Moreover, we hypothesize that susceptibility to the longevity phenotype may well be the result of complex interactions involving genes and environmental factors but also gender.

Introduction:

Aging is a multifactorial and complex process caused by stochastic interactions (random damage to vital molecules), extrinsic interventions (such as diet and caloric restriction), and intrinsic/genetic alterations. Several centenarian (people aged 100 years old or older) studies exploit the strong selection of favorable genotypes in exceptionally aged individuals to study candidate genes and to perform genome-wide analyses. Replications of observed associations of genotypes with longevity, coupled with functional studies to define mechanisms whereby specific genotypes influence lifespan-associated phenotypes, are essential to delineate true positive genetic findings. Such findings could potentially lead to preventive and therapeutic interventions. Numerous genes have been identified that are either positively or negatively selected in the centenarian population as a consequence of demographic selection, but no consistent replications have been observed in independent populations, with the exception of Apolipoprotein E (APOE). In addition, animal studies have provided insights into the types of genes that can be involved in the regulation of lifespan. The first longevity mutant to be identified was the Caenorhabditis elegans gene PAX2 age-1. This mutant encodes phosphatidylinositol-3-kinase (PI3K), which has a key role in a signaling pathway that is homologous to the mammalian insulin-insulin-like growth factor-1 (IGF-1) pathway. Genetic studies in C. elegans have demonstrated that activation of the PIK3/Akt pathway by IGF-1 suppresses activity of the DAF-16 forkhead transcription factor, the nematode ortholog of mammalian FOXO proteins. FOXO transcription factors belong to the Forkhead family of proteins, a family characterized by a conserved DNA-binding domain (Forkhead box) for phosphorylation by the survival kinase Akt. Particularly, in mammals, the FOXO subgroup (FOXO1, FOXO3, FOXO4, and FOXO6) promotes the expression of numerous downstream genes that mediate stress resistance, innate immunity, metabolic processes, and toxin degradation.