The longevity-associated AKT1 rs3803304 SNP is not in LD with any other HapMap SNPs (Fig. 2A). Therefore to follow-up,

sisylana-ateM)647=n(CJA)6701=n(SHC)698=n(FOS)selamef+selam(llA PIC%59ROPIC%59ROPIC%59ROPIC%59ROeneGnosaeRPNS 04000.098.0–86.087.0140.089.0–95.077.0330.089.0–16.077.0940.099.0–26.097.01TKAytivegnoL4033083sr 78.071.1–78.010.184.002.1–76.009.071.080.1–56.048.0230.056.1–20.103.1A1OXOFytivegnoL1424331sr 41.054.1–59.071.1ANANAN35.022.1–66.019.03800.079.1–01.184.1A3OXOFytivegnoL1984401sr 4100.014.1–90.142.1610.047.1–50.163.132.014.1–29.041.1340.065.1–00.152.1A3OXOFytivegnoL9495391sr 910.023.1–20.161.118.003.1–18.030.191.014.1–39.051.1510.036.1–50.113.1A3OXOFytivegnoL0693512sr 320.054.1–30.122.191.027.1–98.042.148.092.1–37.079.07400.099.1–31.115.1A3OXOFytivegnoL8858773sr 78000.034.1–01.152.1920.027.1–30.133.111.074.1–69.091.1140.075.1–00.162.1A3OXOFytivegnoL5396494sr 370.004.1–89.081.199.005.1–66.000.139.013.1–47.099.00500.029.1–21.174.1A3OXOFytivegnoL2096849sr 350.004.1–99.081.123.066.1–48.091.106.032.1–96.039.01500.069.1–21.194.1A3OXOFytivegnoL3196849sr 330.099.0–67.078.074.061.1–17.019.055.061.1–57.049.0710.059.0–06.067.0RHGytivegnoL90035121sr 3100.073.1–90.112.1320.095.1–30.182.144.013.1–88.080.14900.016.1–60.113.1RHGytivegnoL3290492sr 1300.044.1–80.142.1640.076.1–00.103.1110.037.1–70.173.116.083.1–28.070.1RHGnoitcaretnI5390492sr 490.030.1–37.068.016.062.1–66.029.068.053.1–77.030.13900.009.0–05.086.0RHGytivegnoL1544673sr 93.032.1–29.070.1ANANAN94.031.1–67.039.0340.045.1–00.152.1RHGytivegnoL4542924sr 91.013.1–59.011.1ANANAN72.001.1–07.088.07200.087.1–21.124.1RHGytivegnoL1496684sr 25.042.1–09.050.146.023.1–36.029.084.071.1–07.019.0240.076.1–00.103.1RHGytivegnoL3253886sr 52.016.1–88.091.1ANANAN83.062.1–45.038.0210.026.2–21.127.1RHGytivegnoL8257886sr 12.027.2–18.084.1ANANAN69.012.2–64.020.1840.041.7–00.186.2RHRHGytivegnoL8708222sr 120.093.1–30.191.1ANANAN55.092.1–68.060.18400.047.1–01.193.1R1FGIytivegnoL7302722sr 57.081.1–98.020.136.091.1–47.049.063.031.1–07.098.0740.036.1–00.182.13PBFGIytivegnoL0766sr 42.022.1–59.080.153.053.1–98.001.187.082.1–28.030.134.063.1–78.090.14PBFGInoitcaretnI8279001sr 490.020.1–97.009.073.021.1–37.019.086.082.1–48.040.1210.039.0–95.057.04PBFGIytivegnoL6644127sr 63.042.1–39.070.1340.036.1–00.182.104.051.1–07.009.017.073.1–08.050.15PBFGInoitcaretnI43157511sr 06.002.1–09.040.1240.036.1–00.192.132.090.1–86.078.019.013.1–87.010.15PBFGInoitcaretnI2740773sr 31.087.1–39.082.1ANANAN99.085.1–36.000.1330.016.2–40.156.1NETPytivegnoL7242201sr seulav-PlanimoN.xesrofdetsujdaerasesylanaCJAdnaSHC,yticinhtedetroper-flesrofdetsujdaerasesylanaFOS.sisylana-atemehtrofdnaydutshcaerofledomevitiddanarofseulav-PdnaIC%59,ROwohseW rofdlohserhtehtteem5396494srdna9495391srA3OXOF;trohoceritneehtniecnacfiingislacitsitatsrofdlohserhtdesab-noitatumrepehtsteem4033083sr1TKAylno,noitacilperroF.sesylanallarofnwohsera

CJAdna,SHC,FOSnidepytonegsPNSrofytivegnolhtiwnoitaicossafosisylana-ateM3elbaT

CJAdna,SHC,FOSnidepytonegsPNSpotrofytivegnolhtiwnoitaicossafosisylana-ateM4elbaT sisylana-ateM)647=n(CJA)6701=n(SHC)698=n(FOS PIC%59ROPIC%59RONPIC%59RONPIC%59RONepytoneGPNS –––––554–––706fer––564GGC/G4033083sr1TKA 21.040.1–37.078.063.081.1–36.068.094252.031.1–26.048.054335.032.1–66.009.0903CG 61000.007.0–23.084.0320.098.0–02.034.043040.079.0–52.005.076520.019.0–72.005.007CC –––––924–––135fer––024CCT/C9495391srA3OXOF 4600.025.1–70.172.101.077.1–59.003.147251.076.1–29.042.149301.057.1–59.092.1663TC 910.010.2–70.164.1930.061.4–40.180.29365.049.1–07.061.17801.025.2–29.025.118TT –––––734–––125fer––514GGA/G5396494srA3OXOF 5300.065.1–90.113.1090.078.1–69.043.1112050.008.1–00.143.130461.096.1–29.052.1853AG 810.030.2–70.184.101.025.3–09.087.19374.040.2–27.012.148660.076.2–79.016.187AA

associations with human lifespan in a cohort of elderly sian women. Replication of nominally significant findings in independent Caucasian cohorts revealed a SNP in AKT1, was significantly associated with lifespan, and two SNPs FOXO3A, which were significantly associated with lifespan women. Overall, the longevity-associated SNPs were with the three major categories (cardiovascular, cancer, of cause of death, suggesting that their association with is due to a general effect rather than to a specific disease (Table 5).

Several previous studies have demonstrated associations between variants in other genes in the insulin/IGF1 signaling pathway and human aging phenotypes. Most of these studies investigated only a small number of SNPs or genes, and their results have not been replicated. Our study analyzed 291 SNPs in 30 genes providing the first comprehensive screen of the insu- lin/IGF1 signaling pathway in humans.

Association of genetic variation in AKT1 with human lifespan has not been previously reported; however several studies have reported associations with FOXO3A SNPs or haplotypes. A recent case–control association study in elderly Japanese men found an association with three SNPs in FOXO3A and longevity (Willcox et al., 2008); this study did not report replication of findings in independent cohorts. While the tag SNPs genotyped were different in our study, two of the three associated SNPs share strong LD (r2 > 0.8 in HapMap Caucasians) with the FOXO3A SNPs associated with longevity in our study. The effect size is larger in the Japanese cohort, but, as in our study, homo- zygosity for the minor allele is associated with longevity. The most strongly associated SNP from the Japanese cohort lies in the first intron and has lower LD in Caucasians (r2 = 0.48) than in Japanese (r2 = 0.71) with the top SNPs in our study, which are located in the last intron; this difference in LD patterns may account for the different localization of the strongest signal in our two studies.



CJAdna,SHC,FOSnidepytonegsPNSpotrofytivegnolhtiwnoitaicossafosisylana-ateM4elbaT