Genotype Predicts Longevity in Mouse and Human

Deborah L. Grady,1 Panayotis K. Thanos,2–4 Maria M. Corrada,5 Jeffrey C. Barnett Jr.,3 Valentina Ciobanu,1 Diana Shustarovich,3 Anthony Napoli,3 Alexandra G. Moyzis,1 David Grandy,6 Marcelo Rubinstein,7 Gene-Jack Claudia H. Kawas,5 Chuansheng Chen,8 Qi Dong,9 Eric Wang,1,10,11 Nora D. Volkow,2,3,12 and Robert K. Moyzis1,9,11

1Department of Biological Chemistry, College of Medicine, University of California, Irvine, California 92697, 2Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland 20892, 3Behavioral Neuropharmocology and Neuroimaging Laboratory, Medical Department, Brookhaven National Laboratory, Upton, New York 11973, 4Department of Psychology, Stony Brook University, Stony Brook, New York 11794, 5Department of Neurology, University of California, Orange, California 92868, 6Physiology and Pharmacology, Oregon Health Sciences University, Portland, Oregon, 97239, 7Institute for Research on Genetic Engineering and Molecular Biology, National Council for Science and Technology (CONICET), C1428ADN Buenos Aires, Argentina, 8Department of Psychology and Social Behavior, University of California, Irvine, California 92697, 9National Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing 100875, Peoples Republic of China, 10Aria Diagnostics, Inc., San Jose, California 95138, 11Institute of Genomics and Bioinformatics, University of California, Irvine, California 92697, and 12National Institute on Drug Abuse, NIH, Bethesda, Maryland 20892

Longevity is influenced by genetic and environmental factors. The brain’s dopamine system may be particularly relevant, since it modulatestraits(e.g.,sensitivitytoreward,incentivemotivation,sustainedeffort)thatimpactbehavioralresponsestotheenvironment. In particular, the dopamine D4 receptor (DRD4) has been shown to moderate the impact of environments on behavior and health. We tested the hypothesis that the DRD4 gene influences longevity and that its impact is mediated through environmental effects. Surviving  0+. participants of a 30-year-old population-based health survey (N 310; age range, 90–109 years; the 90 Study) were genotyped/ y= 2 resequenced at the DRD4 gene and compared with a European ancestry-matched younger population (N 2902; age range, 7–45 years).  Wefoundthattheoldest-oldpopulationhada66%increaseinindividualscarryingtheDRD47Rallelerelativetotheyoungersample(p 3.5(cid:3) 10(cid:4)9),andthatthisgenotypewasstronglycorrelatedwithincreasedlevelsofphysicalactivity.Consistentwiththeseresults,DRD4 knock-outmice,whencomparedwithwild-typeandheterozygousmice,displayeda7–9.7%decreaseinlifespan,reducedspontaneouslocomo- tor activity, and no lifespan increase when reared in an enriched environment. These results support the hypothesis that DRD4 gene variants contributetolongevityinhumansandinmice,andsuggestthatthiseffectismediatedbyshapingbehavioralresponsestotheenvironment.

Introduction

Undoubtedly, genetic factors contribute to both longevity (Sebastiani et al., 2012) and health among the oldest-old (Martin et al., 2007). Surprisingly, little attention has been directed to- ward genes that influence personality as “longevity genes” (Eaton et al., 2012). This is puzzling not only because the impact of life-style choices on longevity is self-evident (e.g., smoking and early death from pulmonary disease or cancer), but also because of the strong genetic contributions to human personality

 Individuals 90 years of age constitute the fastest growing segment of our population (Fig. 1) (Day, 1996), yet little is known about the factors that contribute to their extreme lon- gevity. Addressing this gap would help develop smarter strat- egies to increase the number of people who reach old age in good health.

A good example is the human dopamine receptor D4 (DRD4) gene, whose associations with the personality trait of novelty seeking (MIM 601696) (Kluger et al., 2002; Gillespie et al., 2003) and with attention deficit hyperactivity disorder (ADHD) (MIM 126452) (Faraone et al., 2001; Grady et al., 2003, 2005; Li et al., 2006) havebeenreplicatednumeroustimes.TheDRD4geneexhib- its an unusually high amount of expressed polymorphism (Fig. 1, inset). Most of this variation is the result of a 48 bp variable number tandem repeat (VNTR), located in exon 3 that encodes the third intracellular loop of the receptor. Alleles containing from 2 to 11 repeats (2R to 11R) have been identified, with the three most com- mon variants (2R, 4R, and 7R) accounting for Mis 51 >9 90% of the allelic diversity (Ding et al., 2002; Wang et al., 2004).

Authorcontributions:D.G.,P.K.T.,A.N.,D.L.G.,M.R.,G.-J.W.,C.C.,Q.D.,N.D.V.,andR.K.M.designedresearch; D.G.,M.M.C.,J.C.B.,V.C.,D.S.,A.N.,D.L.G.,A.G.M.,G.-J.W.,C.H.K.,C.C.,E.W.,N.D.V.,andR.K.M.performedresearch; E.W.contributedunpublishedreagents/analytictools;M.M.C.,V.C.,D.L.G.,M.R.,C.H.K.,Q.D.,andR.K.M.analyzed data;N.D.V.andR.K.M.wrotethepaper.

This work was supported by grants from the U.S. Department of Energy and National Institute of Aging C.H.K.),the111Gene/Brain/BehaviorProjectfromtheMinistryofEducationofChina(toQ.D.),andtheNational VanTol,whosepioneeringworkontheDRD4proteinwillnotbeforgotten.Wethanktheparticipants,especially those of the 90(cid:2) Study, for their generous involvement in this project; Hao-Yuan Cheng and Simin Hakim for technicalassistance;andRubenBalerforeditorialassistance.

Correspondenceshouldbeaddressedtoeitherofthefollowing:Dr.RobertK.Moyzis,DepartmentofBiological Chemistry,CollegeofMedicine,UniversityofCalifornia,IrvineCA92697,E-mail:rmoyzis@uci.edu;orDr.NoraD. Volkow,NationalInstituteonDrugAbuse,NIH,6001ExecutiveBoulevard,Room5274,Bethesda,MD20892,E-mail: nvolkow@nida.nih.gov.

The functional significance of these length/sequence changes in the DRD4 protein, in a region that couples to G-proteins, has

DOI:10.1523/JNEUROSCI.3515-12.2013