Gene and variant selection: Variants were selected for genotyping in 30 genes encoding the key proteins (Figure 1) in the human insulin/IGF1 signaling pathway, including ligands (IGF1, insulin, GH1, GHRH), binding proteins (IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6), receptors (IGF1R, INSR, INSRR, GHR, GHRHR), signal transduction proteins (AKT1, AKT2, AKT3, IRS1, IRS2, IRS4, PDPK1, PIK3CA, PIK3CB, PIK3R1, PIK3R2, PTEN, SHC1), and transcription factors (AFX, FOXO1A, FOXO3A). GH1 was included initially, but all three SNPs available in dbSNP failed genotyping attempts. Initially, variants in FOXO1A and FOXO3A were identified by sequencing exons, intron-exon boundaries and the promoter in 80 Caucasians and selecting haplotype-tagging variants. Subsequently, we utilized the International HapMap Consortium data from CEU Caucasians (The International HapMap Consortium 2005; Frazer et al., 2007) (http://www.hapmap.org) to select haplotypeAkt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell, Clancy DJ, Gems D, Harshman LG, Oldham S, Stocker H, Hafen E, Leevers SJ, Partridge L () Extension of lifespan by loss of CHICO, a Drosophila insulin receptor substrate protein. Science, Cummings SR, Black DM, Nevitt MC, Browner WS, Cauley JA, Genant HK, Mascioli SR, Scott JC, Seeley DG, Steiger P, Vogt TM () Appendicular bone density and age predict hip fracture in women. The Study of Osteoporotic Fractures Research Group. JAMA, Dorman JB, Albinder B, Shroyer T, Kenyon C () The age- and daf-genes function in a common pathway to control the lifespan of Caenorhabditis elegans. Genetics, Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D et al. () Genome-wide association study identifies novel breast cancer susceptibility loci. Nature, Frayling TM () Genome-wide association studies provide new insights into type 2 diabetes aetiology. Nat. Rev. Genet., Frazer KA et al. () A second-generation human haplotype map of over million SNPs. Nature, Fried LP et al. () The Cardiovascular Health Study: design and rationale. Ann. Epidemiol., Harley JB et al. () Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA and other loci. Nat. Genet., van Heemst D et al. () Reduced insulin/IGF-signalling and human longevity. Aging Cell.

Acknowledgments: We acknowledge D. Lind for coordination of pilot studies; J. Atilano; S.-W. Chan; E. Lovins; and T.J. Nguyen for technical assistance; and the staff of SOF and CHS Coordinating Centers for study support. This work was supported by the Longevity Consortium (National Institute on Aging (NIA) 5U19AG023122 to S.R.C. and W.S.B.). The SOF is supported by the NIA (AG05407, AR35582, AG05394, AR35584, AR35583, R01 AG005407, R01 AG027576-22, 2 R01 AG005394-22A1, and 2 R01 AG027574-22A1). The CHS is supported by the National Heart, Lung, and Blood Institute (N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295) with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm.

Author contributions: Ludmila Pawlikowska: Study design, acquisition of data, interpretation of data, preparation of manuscript. Donglei Hu: Analysis and interpretation of data, preparation of manuscript. Scott Huntsman: Analysis and interpretation of data. Andrew Sung: Acquisition of data, preparation of manuscript. Catherine Chu: Acquisition of data, preparation of manuscript. Justin Chen: Acquisition of data, preparation of manuscript. Alexander H. Joyner: Interpretation of data, preparation of manuscript. Nicholas J. Schork: Interpretation of data, preparation of manuscript. Wen-Chi Hsueh: Interpretation of data, preparation of manuscript. Alexander P. Reiner: Interpretation of data, preparation of manuscript. Bruce M. Psaty: Interpretation of data, preparation of manuscript. Gil Atzmon: Interpretation of data, preparation of manuscript. Nir Barzilai: Interpretation of data, preparation of manuscript. Steven R. Cummings: Study design, interpretation of data, preparation of manuscript. Warren S. Browner: Study design, interpretation of data, preparation of manuscript. Pui-Yan Kwok: Interpretation of data, preparation of manuscript. Elad Ziv: Study design, analysis and interpretation of data, preparation of manuscript.

References: 
- Clancy DJ, Gems D, Harshman LG, Oldham S, Stocker H, Hafen E, Leevers SJ, Partridge L. Extension of lifespan by loss of CHICO, a Drosophila insulin receptor substrate protein. Science.
- Cummings SR, Black DM, Nevitt MC, Browner WS, Cauley JA, Genant HK, Mascioli SR, Scott JC, Seeley DG, Steiger P, Vogt TM. Appendicular0.05. The two longevity-associated SNPs are marked by white triangles, and other SNPs in LD with them are boxed.