Conflict of Interest statement. None declared.

FUNDING

This study was supported by grants from the National Basic Research Program of the Chinese Ministry of Science and Technology (973 grant no.: 2007CB512100) and a key program from the National Sciences Foundation of China (grant no.: 30730047). The collection of blood samples from oldest old was jointly supported by Max Planck Institute for Demographic Research, the U.S. National Institute of Aging and the Chinese Resources.

REFERENCES

Yashin, A.I., De Benedictis, G., Vaupel, J.W., Tan, Q., Andreev, K.F., Iachine, I.A., Bonafe, M., D

uca, M., Valensin, S., Carotenuto, L. et (

) Genes, demography, and life span: the contribution of demographic data in genetic studies on aging and longevity. Am. J. Genet.,

,

–

Vijg, J. and Suh, Y. (

) Genetics of longevity and aging. Annu. Med.,

,

–

Herskind, A.M., M

ue, M., Iachine, I.A., Holm, N., Sorensen, T.I., Harvald, B. and Vaupel, J.W. (

) Untangling genetic influences on smoking, body mass index and longevity: a multivariate study of

Danish twins followed for

years. Hum. Genet.,

,

–

Hjelmborg, J.B., Iachine, I., Skytthe, A., Vaupel, J.W., M

ue, M., Koskenvuo, M., Kaprio, J., Pedersen, N.L. and Christensen, K. (

) Genetic influence on human lifespan and longevity. Hum. Genet.,

,

–

Terry, D.F., Nolan, V.G., Andersen, S.L., Perls, T.T. and Cawthon, R. (

) Association of longer telomeres with better health in J. Gerontol. A Biol. Sci. Med. Sci.,

,

–

Adams, E.R., Nolan, V.G., Andersen, S.L., Perls, T.T. and Terry, D.F. (

) Centenarian offspring: start healthier and stay healthier. J. Am. Geriatr. Soc.,

,

–

Puca, A.A., Daly, M.J., Brewster, S.J., Matise, T.C., Barrett, J., Shea-Drinkwater, M., Kang, S., Joyce, E., Nicoli, J., Benson, E. et al. (

) A genome-wide scan for linkage to human exceptional identifies a locus on chromosome

Proc. Natl Acad. Sci. USA,

,

–

Reed, T., Dick, D.M., Uniacke, S.K., Foroud, T. and Nichols, W.C. Genome-wide scan for a healthy aging phenotype provides support for locus near D

S

promoting healthy aging. J. Gerontol. A Biol. Sci. Med. Sci.,

,

–

Statistical methods

Allele and genotype frequencies for single SNPs were calcu- lated and tested for departure from Hardy–Weinberg equili- brium using the x2 test. Differences in allele and genotype distribution between cases (centenarians) and controls (younger population) were analyzed using logistic regression adjusted for non-genetic covariates under various genetic models that were defined as 1 (aa þ Aa) versus 0 (AA) for dominant, 1 (aa) versus 0 (AA þ Aa) for recessive, and 0 (AA) versus 1 (Aa) versus 2 (aa) for additive (A: major allele; a: minor allele). A Bonferroni step-down method was used for multiple comparison correction in allele association tests (63).

Linkage disequilibrium and haplotype blocks (D0 / 0.90) were defined and visualized by the solid spine of LD method using Haploview 4.0 (http://www.broad.mit.edu/ haploview/haploview). The haplotypes with frequency (cid:4)5%

Westendorp, R.G. and Slagboom, P.E. (

) Chromosome

q

, microsomal transfer protein gene, and human longevity: novel data and a meta-analysis of association studies. J. Gerontol. A Biol. Sci. Med. Sci.,

,

–

Novelli, V., Viviani Anselmi, C., Roncarati, R., Guffanti, G., Malovini, A., Piluso, G. and Puca, A.A. (

) Lack of replication of genetic associations with human longevity. Biogerontology,

,

–

Lunetta, K.L., D’Agostino, R.B. Sr, Karasik, D., Benjamin, E.J., Guo, C.Y., Govindaraju, R., Kiel, D.P., Kelly-Hayes, M., Massaro, J.M., Pencina, M.J. et al. (

) Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study. BMC Med. Genet.,

, S

Willcox, B.J., Donlon, T.A., He, Q., Chen, R., Grove, J.S., Yano, K., Masaki, K.H., Willcox, D.C., Rodriguez, B. and Curb, J.D. (

) FOXO

A genotype is strongly associated with human longevity. Proc. Natl Acad. Sci. USA,

,

–

Flachsbart, F., Caliebe, A., Kleindorp, R., Blanche, H., von Eller-Eberstein, H., Nikolaus, S., Schreiber, S. and Nebel, A. (

) Association of FOXO

A variation with human longevity confirmed in German centenarians. Proc. Natl Acad. Sci. USA,

,

–

Anselmi, C.V., Malovini, A., Roncarati, R., Novelli, V., Villa, F., Condorelli, G., Bellazzi, R. and Puca, A.A. (

) Association of the FOXO

A locus with extreme longevity in a southern italian centenarian study. Rejuvenation Res.,

,

–

Cao, Y., Kamioka, Y., Yokoi, N., Kobayashi, T., Hino, O., Onodera, M., Mochizuki, N. and Nakae, J. (

) Interaction of Fo

and TSC

induces insulin resistance through activation of the mammalian target of rapamycin/p

S

K pathway. J. Biol. Chem.,

,

–

Burgering, B.M. and Kops, G.J. (

) Cell cycle and death control: long live Forkheads. Trends Biochem. Sci.,

,

–

de Candia, P., Blekhman, R., Chabot, A.E., Oshlack, A. and Gilad, Y. (

) A combination of genomic approaches reveals the role of FOXO

a in regulating an oxidative stress response pathway. PL

ONE,

, e

Bonafe, M. and Olivieri, F. (

) Genetic polymorphism in long-lived people: cues for the presence of an insulin/IGF-pathway-dependent network affecting human longevity. Mol. Cell. Endocrinol.,

,

–

Lin, K., Dorman, J.B., Rodan, A. and Kenyon, C. (

) daf-

: an HNF-

/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science,

,

–

Ogg, S., Paradis, S., Gottlieb, S., Patterson, G.I., Lee, L., Tissenbaum, H.A. and Ruvkun, G. (

) The Fork head transcription factor DAF-

transduces insulin-like metabolic and longevity signals in C. elegans. Nature,

,

–

Giannakou, M.E., Goss, M., Junger, M.A., Hafen, E., Leevers, S.J. and Partridge, L. (

) Long-lived Drosophila with overexpressed

OXO in adult fat body. Science,

,

Cameron, A.R., Anton, S., Melville, L., Houston, N.P., Dayal, S., M

ougall, G.J., Stewart, D. and Rena, G. (