In conclusion, we observed a striking increase in DRD4 7R allele frequency in the oldest-old population and a strong associ- ationofthisallelewithincreasedactivitylevels.Thesefindingsare consistent with our animal model results showing that the DRD4 gene moderates the beneficial effects of an enriched environment in increasing the rodent’s lifespan. We propose that DRD4 gene vari- antsmoderatelongevitybyalteringbehavioralresponsestoenviron- mentalfactors.Itislikelythatsuchgene–environmentalinteractions underlie much human variability and many common disorders af- flicting humankind (Wang et al., 2006; Manolio et al., 2009).

A strength and a weakness of the current study is that the oldest- old population studied is of predominantly European ancestry. We specifically chose this population to reduce the genetic diversity and allow for better case-control matching, essential for genetic studies. Itshouldbecautioned,therefore,thatitisunclearhowbroadlysuch results can be inferred beyond the ancestry group examined. The ubiquitous presence of DRD4 7R (and its derived 2R allele) in most human populations (Ding et al., 2002; Wang et al., 2004), however, make it likely that this study can be generalized (and potentially replicated) in individuals whose ancestry is from different geo- graphic origins. While a prospective design would allow for much stronger inferences, the logistics and cost of a prospective study to assess the effects of genotype on longevity are enormous, and data would not be available for analysis until the cohorts died.

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