The standard way to determine whether a genetic variant is associated with longevity is to look at its prevalence in the population at various ages. If the relative proportion of the variant increases in the surviving population, then that may be because it is having an impact on survival. Only two genes have variants that robustly appear to associate with longevity in multiple study populations, however, APOE and FOXO3A, and even there the size of the effect is small. The picture that has emerged from genetic studies of longevity and aging to date is one of thousands of tiny interdependent influences, interacting with the environment and one another, such that correlations in one study population near always fail to show up in another, even when both studies are carried out in the same part of the world. Still, the studies continue, with researchers now digging deeper into areas of genetic analysis that were previously skipped for technical reasons. Here is a recent example, in which researchers do manage to replicate a finding of association with longevity for a variant of the dopamine D4 receptor:

Age at death in adulthood has a heritability of approximately 25%. According to a recent review of genome-wide association studies (GWAS) APOE and FOXO3A gene variants are associated with longevity. Although association of other genetic polymorphisms did not reach the level of genome wide significance, identified pathways and genetic signatures have been shown to be important in longevity. Inheritance of long life span seems to be rather complex, with modest individual genetic effects, along with significant gene-environment interactions. Based on a study of exceptional longevity, genetic factors seem to be even more important where familial clustering of extreme old age is robust. These individuals might lack some of the risk factors related to various diseases, and at the same time carry protective genetic variations against basic mechanisms of age-related illnesses, also referred to as ‘longevity enabling genes’.

It is important to note that due to technical reasons GWAS and SNP studies on longevity have not investigated any variable number of tandem repeat variations (VNTR) in association with longevity. It has been proposed that a specific VNTR variant, the 7 repeat allele of the dopamine D4 receptor gene (DRD4), could be an important factor in extreme longevity, because it plays a major role in the brain’s dopaminergic functioning. Surviving participants of a 30-year-old population-based health survey (N = 310, age range 90-109, mean age: 95.2 years) possessed a 66% higher rate of 7 repeat allele carriers as compared to that of an ancestry-matched young population (N = 2902, age range 7-45). In addition, this association was far more pronounced in females (there were 39.3% allele 7 carriers in the old vs 21.9% in the young population) as compared to males (29.7% in the old vs. 21.9 in the young population). There is supporting evidence from animal studies of this gene: DRD4 knock-out mice lived 7-9.7% shorter and showed reduced spontaneous locomotor activity, as compared to those with functional DRD4 genes. Also, while the wild type mice showed clear beneficial effects of an enriched environment on lifespan, the DRD4 knock-out mice did not a show lifespan increase when reared in an enriched environment.

Initial association result of the DRD4 VNTR 7 repeat allele and longevity have not yet been replicated to date, which would be reassuring given recent arguments regarding the critical importance of replication in genetic studies. The major goal of the present study was to test association of the DRD4 VNTR 7 repeat allele and longevity using continuous age groups. We analyzed association of the DRD4 VNTR with longevity. Association analyses of continuous age groups using genotype data from 1801 Caucasian participants from 18 to 97 years of age showed a significant increase of allele 7 carriers with age. Interestingly, from age 18 to 75 ratio of those carrying the 7-repeat allele increased progressively from 29.5% to 46.9% in the tested age groups, however, in the older age groups the proportion of allele 7 carriers dropped intensively (44.4% in those between 76-85 years and 31% in the 86-97 age group). This “drop” might be due to the relatively small sample size of the age groups, but might also point to the fact that relative importance of environmental, genetic and stochastic determinants of survival vary with age. Association of the DRD4 gene variants with longevity fits well with the assumption that inheritance of longevity is complex, with modest individual genetic effects interacting with each other as well as with the environment. We propose that the DRD4 allele 7 could be a “longevity enabling genetic variant,” protecting against basic mechanisms of age-related illnesses, but the precise manner in which this is accomplished is unclear at this point.


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