Yi Zeng,1,2,* Lingguo Cheng,2 Huashuai Chen,3 Huiqing Cao,4 Elizabeth R. Hauser,5 Yuzhi Liu,2 Zhenyu Xiao,2 Qihua Tan,6 Xiao-Li Tian,4,* and James W. Vaupel7,8. 2 China Center for Economic Research, National School of Development, Peking University, Beijing, China. 3 Department of International Trade, Business School of Xiangtan University, Xiangtan, China. 4 Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China. 5 Center for Human Genetics, Medical School of Duke University, Durham, North Carolina. 6 Institute of Public Health, University of Southern Denmark, Odense, Denmark. 7 Max Planck Institute for Demographic Research, Rostock, Germany. * Yi Zeng and Xiao-Li Tian should be regarded as the co-corresponding authors. Address correspondence to Yi Zeng PhD at the Center for the Study of Aging and Human Development at Medical School of Duke University and China Center for Economic Research at National School of Development of Peking University. Box 3003 Duke University Durham NC 27710 Email: 

Based on data from 760 centenarians and 1060 middle-age controls (all Han Chinese), this article contributes to biodemographic independent and joint effects of the genotypes of FOXO1A and FOXO3A genes on long-term survival while considering gender differences in the independent effects. Positive effects of FOXO3A and negative effects of FOXO1A largely come into effect when considering the carrying effect on FOXO3A-310 or FOXO3A-292 decrease survival likelihood by 32% to 36% (p < .05), whereas carrying FOXO1A-209 and regular exercise increase survival likelihood by 31% to 32% (p < .05).

Key Words: Biodemographic analysis, FOXO genes, GG and GE interactions, Longevity, Mortality.

Received April 7, 2010; Accepted August 11, 2010

Decision Editor: Rafael de Cabo, PhD

The genotypes of FOXO1A (rs2755209 and rs2755213) were found to be negatively associated with longevity in women (OR = 0.70 and 0.71, p = .007 and .015; dominant model), whereas in the dominant model for men, FOXO1A-rs2755213 is marginally and negatively associated with longevity (OR = 0.65, p = .025) and the association of FOXO1A-rs2755209 is not significant (OR = 0.73, p = .093). One SNP (rs17630266) from FOXO1A was found not to be associated with longevity. The negative association of FOXO1A with female longevity was replicated in 350 centenarians and 350 younger individuals who were sampled in a geographically distinct region.

FOXO1A and FOXO3A gene variants have also been linked to longevity in the Framingham cohort in the United States (7) and in the Leiden85-plus study (8). In her most recent Nature review article, Kenyon stated that the reason why FOXO variants are so consistently associated with longevity is perhaps because FOXO proteins act on many pathways to affect lifespan (9). In vivo, FOXO1A and FOXO3A regulate a group of genes expression, such as TRAIL, ApoC3, angiopoietin-2, ENOS, Agrp, pomc, FasL.

AKT1-FOXO-mediated signaling pathways significantly affect the maximum life process of FOXO in Caenorhabditis elegans and Drosophila melanogaster. Does carrying FOXO genotypes influence longevity in opposite directions, and if yes, what are the direction and size of the effects?

Materials and Methods

Data Sources

578 female centenarians and 182 male centenarians survived to age 100+ when they participated in the inter-examinations involving ordinary people. These 760 centenarians and the 1060 middle-age controls were all from Southern China (China is traditionally and culturally referred to as a single region, but there is no legitimate or official administrative meaning to this division). Among the 22 provinces where CLHLS was previously estimated, the frequencies of genetic variants between long-lived individuals and younger adults were found to be more frequent in centenarians than in 90+ and colleagues (6) on which our current study was produced by and described in the genetic analysis.

FOXO1A gene and the three SNPs rs2253310, rs2755209, rs2755213, and 3A-936, respectively.

The Extended10 still survived in the 2008 wave. The cohort follow-up data on survival and death, socioeconomics, lifestyle, psychological characteristics, and health status, etc. of the participants used in the multivariate statistical survival analysis in this article are from the CLHLS conducted in 1998, 2000, 2002, 2005, and 2008 using questionnaires that followed the international standards adapted to the Chinese cultural context (19). The careful evaluations (such as reliability coefficients and factor analysis) have shown that the data quality of the CLHLS surveys was reasonably good (19).

We use the centenarians' age at death (or age in 2008 for the 10 centenarians who survived in the 2008 follow-up survey) in our case-control analysis. The mean age of the male and female centenarian samples were 101.9 and 103.2, respectively. The mean ages of the male and female controls were 46.0 and 45.4, respectively. Similar to the previously published studies on association between the FOXO genotypes and longevity (28), the centenarians and middle-age controls of this study are ethnically (all Han Chinese) and geographically (Southern China) compatible, and thus the where p(x) is the proportion of individuals who are x years old and have the fixed attribute.

Zeng and Vaupel (22) derived Formula (1) and empirically justified it. Note that Formula (1) provides estimates of the general impacts of one genetic variant on survival from age x to x+n, regardless of carrying or not-carrying another relevant genetic variant. We extend the FAD method here to provide formulas to estimate the independent effect of a genetic variant in the absence of another relevant genetic variant, the joint effects when both are present, and the effects of interactions between them.