TY - JOUR
T1 - DRD4 genotype predicts longevity in mouse and human
AU - Grady, Deborah L.
AU - Thanos, Panayotis K.
AU - Corrada, Maria M.
AU - Barnett, Jeffrey C.
AU - Ciobanu, Valentina
AU - Shustarovich, Diana
AU - Napoli, Anthony
AU - Moyzis, Alexandra G.
AU - Grandy, David
AU - Rubinstein, Marcelo
AU - Wang, Gene Jack
AU - Kawas, Claudia H.
AU - Chen, Chuansheng
AU - Dong, Qi
AU - Wang, Eric
AU - Volkow, Nora D.
AU - Moyzis, Robert K.
PY - 2013/1/2
Y1 - 2013/1/2
N2 - 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). Wefound that the oldest-old population had a66%increase in individuals carrying theDRD47Rallele 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,whencompared 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.
AB - 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). Wefound that the oldest-old population had a66%increase in individuals carrying theDRD47Rallele 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,whencompared 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.
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U2 - 10.1523/JNEUROSCI.3515-12.2013
DO - 10.1523/JNEUROSCI.3515-12.2013
M3 - Article
C2 - 23283341
AN - SCOPUS:84871733543
SN - 0270-6474
VL - 33
SP - 286
EP - 291
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 1
ER -