YiZeng,1,2,*LingguoCheng,2HuashuaiChen,3HuiqingCao,4ElizabethR.Hauser,5YuzhiLiu,2 ZhenyuXiao,2QihuaTan,6Xiao-LiTian,4,*andJamesW.Vaupel7,8

2ChinaCenterforEconomicResearch,NationalSchoolofDevelopment,PekingUniversity,Beijing,China. 3DepartmentofInternationalTrade,BusinessSchoolofXiangtanUniversity,Xiangtan,China. 4DepartmentofHumanPopulationGenetics,InstituteofMolecularMedicine,PekingUniversity,Beijing,China. 5CenterforHumanGenetics,MedicalSchoolofDukeUniversity,Durham,NorthCarolina. 6InstituteofPublicHealth,UniversityofSouthernDenmark,Odense,Denmark. 7MaxPlanckInstituteforDemographicResearch,Rostock,Germany.

*YiZengandXiaoLiTianshouldberegardedastheco-correspondingauthors.

AddresscorrespondencetoYiZeng,PhD,CenterfortheStudyofAgingandHumanDevelopmentatMedicalSchoolofDukeUniversityandChina CenterforEconomicResearchatNationalSchoolofDevelopmentofPekingUniversity.Box3003,DukeUniversity,Durham,NC27710.Email:

Basedondatafrom760centenariansand1060middle-agecontrols(allHanChinese),thisarticlecontributesbiodemo- independentandjointeffectsofthegenotypesofFOXO1AandFOXO3Agenesonlong-termsurvival,consideringcarry- genderdifferencesintheindependenteffects;positiveeffectsofFOXO3AandnegativeeffectsofFOXO1Alargelycom- FOXO3A-310orFOXO3A-292decreasesurvivallikelihoodby32%–36%(p FOXO1A-209andregularexerciseincreasesurvivallikelihoodby31%–32%(p <.05).

Key Words: Biodemographicanalysis—FOXOgenes—G×GandG×Einteractions—Longevity—Mortality.

Received April 7, 2010; Accepted August 11, 2010

Decision Editor: Rafael de Cabo, PhD

ofFOXO1A(rs2755209andrs2755213)werefoundtobe negativelyassociatedwithlongevityinwomen(OR=0.70 and0.71,p=.007and.015;dominantmodel),whereasin thedominantmodelformen,FOXO1A-rs2755213ismar- ginally and negatively associated with longevity (OR = 0.65,p =.025)andtheassociationofFOXO1A-rs2755209 is not significant (OR = 0.73, p = .093). One SNP (rs17630266)fromFOXO1Awasfoundnottobeassociated withlongevity.ThenegativeassociationofFOXO1Awith femalelongevitywasreplicatedin350centenariansand350 youngerindividualswhoweresampledinageographically distinctregion.FOXO1AandFOXO3Agenevariantshave alsobeenlinkedtolongevityintheFraminghamcohortinthe UnitedStates(7)andintheLeiden85-plusstudy(8).

class O) subfamily of forkhead transcription factors associated with human longevity in fromHawaii(2),Italians(3),AshkenaziJews(4),Califor- nians(4),NewEnglanders(4),Germans(5),andHanChi- variantsweremorefrequentincentenariansthanin90- andcolleagues(6)onwhichourcurrent Chinesepopulation.Sixtaggingsingle-nucleotidepolymor-

InhermostrecentNaturereviewarticle,Kenyonstated thatthereasonwhyFOXOvariantsaresoconsistentlyasso- ciatedwithlongevityisperhapsbecauseFOXOproteinsact inmanypathwaystoaffectlifespan(9).Invivo,FOXO1A andFOXO3Aregulateagroupofgene’sexpression,suchas TRAIL,ApoC3,angiopoietin-2,ENOS,Agrp,pomc,FasL,

cytoplasm(10,11).AKT1-FOXO–mediatedsignalingpath- resistance, and metabolism (12,13). Early studies FOXOinCaenorhabditiselegansandDrosophila mela- nogaster significantly affects their maximum life process.

ages?Ifyes,whatarethedirectionandsizeoftheeffects?

Materials and Methods

Data Sources

578 female centenarians and 182 male centenarians survivedtoage100+whentheyparticipatedintheinter- examinationsinvolvingordinarypeople.These760cente- narians and the 1060 middle-age controls were all SouthernChina(Chinaistraditionallyandculturallycon- isnolegitimateorofficialadministrativemeaningtothisdivi- Among the 22 provinces where CLHLS was thisstudywereproducedbyanddescribedinthegeneticanal- FOXO1A gene and the three SNPs rs2253310, producingthegenotypicdatawerepresented our present more in-depth biodemographic analysis. withrecessiveandadditivemodels,andthelinkagedisequilib- and3A-936,respectively.

previously)estimate thefrequenciesofgeneticvariantsbetweenlong-livedindi- vidualsandyoungeradults,usuallyfollowingtheconven- tional approach of logistic regression. If the ORs associatedwithlongevity.The ORsestimatedinthecon- probability of survival from younger ages to older otherwords,theydonotspecifythemagnitudeofthege- neticeffectsonthesurvivalprobability.Furthermore,previ- influencelongevityinoppositedirections,butnoinvestiga- joint(presenceofboth),andinteractiveeffectshasbeenre- interactionsbetweenthesegenotypes(G×G)andinterac- (G×E)onsurvivalatadvancedages.Buildinguponprevi- ousrelevantresearch(2–18),especiallybasedonthegeno- HanChinese,weaddressthefollowingpreviouslyunan- sweredquestions,byabiodemographicanalysisapproach:

ofsurvivalfrommiddleagetoages

+?

carrierofboth?Arethereanystatisticallysignificantef- onsurvivalfrommiddleagetoage

+?

Does the carrying or not-carrying the genotypes them,andthei

×Einteractionswithsocialandbehav-

Todefinethegenotypestobeanalyzedinthisarticle,car- rying or not-carrying the minor allele of one of the

Table1. FrequencyDistributionoftheGenotypesDefinedbyCarryingtheMinorAllelesofOneoftheTwoSNPsofFOXO1AorOneofthe Age100+MeasuringtheGeneralEffectsoftheGenotypes

Women Men Genotypes Cent.%car. Contr%car. RS(95%CI) p Cent.%car. Contr%car. RS(95%CI) Carryingminoralleleof1A-209 42.3 51.3 0.70(0.53–0.91) 0.0073 41.8 49.5 0.73(0.51–1.05) Carryingminoralleleof1A-213 57.8 65.8 0.71(0.54–0.91) 0.0152 58.8 68.6 0.65(0.45–0.95) Carryingminoralleleof3A-310 51.9 39.3 1.67(1.27–2.18) 0.0002 55.5 43.0 1.65(1.19–2.30) Carryingminoralleleof3A-292 51.7 39.8 1.62(1.24–2.12) 0.0004 56.3 42.7 1.73(1.24–2.41) Carryingminoralleleof3A-936 49.5 37.1 1.66(1.26–2.18) 0.0003 51.9 40.2 1.61(1.16–2.24)

Note:Samplesize—centenarians:578womenand182men;middle-agecontrols:378womenand682men,allHanChinesefromSouthernChina.CI= confidenceinterval.Cent.%car.=Percentageofcentenarianswhocarrytheminorallele;Contr%car.=Percentageofmiddle-agecontrolswhocarrytheminorallele; SNP=single-nucleotidepolymorphisms.

from http://biomedgerontology.oxfordjournals.org/ at Northern Arizona University on May 23, 2015