title: DRD4 genotype predicts longevity in mouse and human.
abstract: Longevity is influenced by genetic and environmental factors. The brain's dopamine system may be particularly relevant, since it modulates traits (e.g., sensitivity to reward, incentive motivation, sustained effort) that impact behavioral responses to the environment. 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 participants of a 30-year-old population-based health survey (N = 310; age range, 90-109 years; the 90+ Study) were genotyped/resequenced at the DRD4 gene and compared with a European ancestry-matched younger population (N = 2902; age range, 7-45 years). We found that the oldest-old population had a 66% increase in individuals carrying the DRD4 7R allele relative to the younger sample (p = 3.5 × 10(-9)), and that this genotype was strongly correlated with increased levels of physical activity. Consistent with these results, DRD4 knock-out mice, when compared with wild-type and heterozygous mice, displayed a 7-9.7% decrease in lifespan, reduced spontaneous locomotor activity, and no lifespan increase when reared in an enriched environment. These results support the hypothesis that DRD4 gene variants contribute to longevity in humans and in mice, and suggest that this effect is mediated by shaping behavioral responses to the environment.
authors.affiliation: Department of Biological Chemistry, College of Medicine, University of California, Irvine, California 92697, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Grady
authors.forename: Panayotis K
authors.initials: PK
authors.lastname: Thanos
authors.forename: Maria M
authors.initials: MM
authors.lastname: Corrada
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Barnett
authors.forename: Valentina
authors.initials: V
authors.lastname: Ciobanu
authors.forename: Diana
authors.initials: D
authors.lastname: Shustarovich
authors.forename: Anthony
authors.initials: A
authors.lastname: Napoli
authors.forename: Alexandra G
authors.initials: AG
authors.lastname: Moyzis
authors.forename: David
authors.initials: D
authors.lastname: Grandy
authors.forename: Marcelo
authors.initials: M
authors.lastname: Rubinstein
authors.forename: Gene-Jack
authors.initials: GJ
authors.lastname: Wang
authors.forename: Claudia H
authors.initials: CH
authors.lastname: Kawas
authors.forename: Chuansheng
authors.initials: C
authors.lastname: Chen
authors.forename: Qi
authors.initials: Q
authors.lastname: Dong
authors.forename: Eric
authors.initials: E
authors.lastname: Wang
authors.forename: Nora D
authors.initials: ND
authors.lastname: Volkow
authors.forename: Robert K
authors.initials: RK
authors.lastname: Moyzis
mesh_terms: D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D000483:Alleles; D000818:Animals; D002648:Child; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009043:Motor Activity / Q000235:genetics; D050638:Receptors, Dopamine D4 / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D050638:Receptors, Dopamine D4