Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity has been replicated in two additional Caucasian cohorts, including both males and females: the Cardiovascular Health Study and Ashkenazi Jewish Centenarians. An intronic single nucleotide polymorphism in AKT1, rs3803304, was significantly associated with lifespan in a meta-analysis across the three cohorts (OR = 0.78, 95% CI = 0.68-0.89, adjusted P = 0.043). Two intronic single nucleotide polymorphisms in FOXO3A demonstrated a significant lifespan association among women only (rs1935949, OR = 1.35, 95% CI = 1.15-1.57, adjusted P = 0.0093). These results demonstrate that common variants in several genes in the insulin/IGF1 pathway are associated with human lifespan. Key words: AKT1; FOXO3A; gene; IGF1; longevity; SNP.

Ludmila Pawlikowska,1,2,* Donglei Hu,3,* Scott Huntsman,3 Andrew Sung,4 Catherine Chu,4 Justin Chen,4 Alexander H. Joyner,5 Nicholas J. Schork,5 Wen-Chi Hsueh,2,3 Alexander P. Reiner,6 Bruce M. Psaty,6,7 Gil Atzmon,8 Nir Barzilai,8 Steven R. Cummings,9 Warren S. Browner,9 Pui-Yan Kwok2,4 and Elad Ziv2,3 for the Study of Osteoporotic of Anesthesia and Perioperative Care, University San Francisco, CA, USA for Human Genetics, University of California, San CA, USA of Medicine, University of California, San USA Research Institute, University of California, San CA, USA Genomic Medicine, The Scripps Translational Science and Department of Molecular and Experimental The Scripps Research Institute, La Jolla, CA, USA Health Research Unit, Departments of and Health Services, University of Washington, WA, USA for Health Studies, Group Health, Seattle, WA, USA for Aging Research and Department of Medicine, College of Medicine, Bronx, NY, USA Pacific Medical Center Research Institute, San CA, USA

Introduction 

Genes in the insulin/IGF1 signaling pathway affect lifespan in yeast, nematodes, fruit flies and mice (Kuningas et al., 2008). Mutation of genes in this signaling pathway confers greater resistance to oxidative stress and phenotypic characteristics. The insulin/IGF1 pathway was first implicated in aging in Caenorhabditis elegans (Kenyon et al., 1993; Larsen et al., 1995; Morris et al., 1996). Mutation of daf-2, the nematode ortholog of the IGF1 and insulin receptors, results in extended lifespan and increased stress resistance (Kenyon et al., 1993; Kimura et al., 1997); these effects are mediated by the nuclear transcription factor DAF-16, which is a homolog of the mammalian forkhead (FKHRL or FOXO) transcription factors (Ogg et al., 1997). Mutations in age-1, the homolog of mammalian PI3Kinase which is involved in signal transduction from the insulin and IGF1 receptors (Dorman et al., 1995), also increase lifespan in C. elegans. Similarly, in Drosophila mutations of the insulin receptor homolog, its substrate chico (Clancy et al., 2001), and of the daf-16/foxo homolog (Hwangbo et al., 2004).

Summary