Genotype predicts longevity in mice and humans. Deborah L. Grady, Panayotis K. Thanos, Maria M. Corrada, Jeffrey C. Barnett Jr., Valentina Ciobanu, Diana Shustarovich, Anthony Napoli, Alexandra G. Moyzis, David Grandy, Marcelo Rubinstein, Gene-Jack Claudia H. Kawas, Chuansheng Chen, Qi Dong, Eric Wang, Nora D. Volkow and Robert K. Moyzis conducted research to investigate the impact of genetic factors on longevity. The dopamine system in the brain is a crucial factor that affects traits like sensitivity to reward, incentive motivation and sustained effort which influence behavioral responses to the environment. The dopamine D4 receptor (DRD4) moderates the effects of the environment on behavior and health and may be involved in longevity. The hypothesis that DRD4 gene variants contribute to longevity was tested by comparing surviving participants of a 30-year-old population-based health survey (N 310; age range 90-109 years; the 90 Study) with a younger population of European ancestry (N 2902; age range 7-45 years). The oldest-old population had a 66% increase in individuals carrying the DRD4 7R allele compared to the younger sample (p <3.5x10^-9), and this genotype was strongly associated with increased levels of physical activity. DRD4 knock-out mice exhibited a 79.7% decrease in lifespan, reduced spontaneous locomotor activity and no lifespan increase when reared in an enriched environment compared with wild-type and heterozygous mice. These results suggest that DRD4 gene variants contribute to longevity in humans and mice and that this effect is mediated by shaping behavioral responses to the environment.

The study also revealed that genetic factors contribute to both longevity and health among the oldest-old population. Although lifestyle choices like smoking and early death from pulmonary disease or cancer have a significant impact on longevity, little attention has been directed towards genes that influence personality as longevity genes. Individuals aged 90 years and above represent the fastest-growing segment of the population, yet little is known about the factors that contribute to their extreme longevity. Investigating these factors would help develop strategies to increase the number of people who reach old age in good health.

The human dopamine receptor D4 (DRD4) gene is an excellent example of a gene that influences personality traits like novelty-seeking and attention deficit hyperactivity disorder (ADHD). The DRD4 gene exhibits an unusually high amount of expressed polymorphism due to 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 common variants (2R, 4R, and 7R) accounting for more than 90% of the allelic diversity. The functional significance of these length/sequence changes in the DRD4 protein, in a region that couples to G-proteins, has been studied extensively. The 7R variant shows a blunted response to dopamine when compared with the 4R variant and does not form heteromers with the short isoform of the presynaptic dopamine D2 receptor. The DRD4 protein is expressed in several brain regions, with high levels in the prefrontal cortex. DRD4 knock-out mice display better performance on complex motor tasks and reduced exploration of novel stimuli. ADHD individuals with a 7R allele have faster reaction times than non-7R individuals.

In conclusion, the study by Grady et al. supports the hypothesis that DRD4 gene variants contribute to longevity in humans and mice mediated by shaping behavioral responses to the environment. Investigating genetic factors that influence personality traits like novelty-seeking and ADHD could help develop smarter strategies to increase the number of people who reach old age in good health.Cell lines, DNA, genotyping, and resequencing were used to obtain genotypes from a subset of 310 subjects. The subjects consisted of 91 males and 219 females, representative of the entire cohort with respect to gender, education, BMI, exercise, drinking, or medical histories. Two hundred seventy participants had complete information available from the Leisure World Cohort Study. Lymphoblastoid cell lines were established for all 310 participants using a modified protocol involving up to five months of cell culture. Detailed ancestry information was collected from the 90 study participants to confirm self-declared ancestry for matching to the European ancestry population-based control sample DRD4 genotypes. Controls ranged in age from 7 to 45 years (mostly adolescents and college students). Previously established methods were used to genotype and resequence the DRD4VNTR variant. Single-nucleotide polymorphisms in other genes used as controls were genotyped by DNA sequencing. The Institutional Review Board of the University of California, Irvine approved all procedures.

Given that the DRD4 7R allele is associated with increased activity/novelty-seeking in children and young adults, we hypothesized that this allele would be associated with increased physical activity in the elderly. In addition, since physical activity is associated with increased lifespan and health, we hypothesized that the DRD4 7R allele would be over-represented in the oldest old.