The quest for genetic determinants of human longevity: challenges and insights

Abstract

Twin studies indicate that approximately 25% of the variation in adult lifespan is caused by genetic differences between individuals, and that genetic influences on lifespan are minimal before the age of 60 but increase after this age. Animal models have made fundamental contributions to lifespan research. In addition, genetic insights into disease (in particular for cardiovascular diseases and premature ageing syndromes), the DNA repair and maintenance system and the immune system have suggested a large number of genes as candidates for involvement in the control of human lifespan. Only for one gene, APOE, have findings of common polymorphisms that have a modest effect on lifespan been replicated in several association studies. No rare genetic variants with substantial beneficial effects on lifespan have been identified. Linkage analyses of longevity are hampered by a lack of multi-generational DNA and the aetiological heterogeneity of longevity, but large international collaborations that aim to ascertain exceptionally long-lived families are underway. The lack of replication in genetic association studies of variants that are candidates for influencing lifespan is probably the result of a combination of factors. These include the predicted small effects of the genetic variants, the small sample sizes that are used, a lack of appropriate control groups and publication bias. Large longitudinal studies are less prone to these problems. Large longitudinal association studies and large linkage studies of long-lived families are useful in the difficult task of finding longevity genes. The resulting data should be combined with demographical data and survival analyses. This combined approach should be used to simultaneously analyse all genetic and non-genetic covariates for which data are available, and to control for the effect of unobserved risk factors. Understanding the genetic basis of longevity is a difficult task, but has the potential to provide insights into central ageing and disease mechanisms that could be targets for the prevention and treatment of late-life disabilities and diseases.