The application of genetics approaches to the study of exceptional longevity in humans: potential and limitations

Abstract

The average life-span of the population of industrialized countries has improved enormously over the last decades. Despite evidence pointing to the role of food intake in modulating life-span, exceptional longevity is still considered primarily an inheritable trait, as pointed out by the description of families with centenarian clusters and by the elevated relative probability of siblings of centenarians to become centenarians themselves. However, rather than being two separate concepts, the genetic origin of exceptional longevity and the more recently observed environment-driven increase in the average age of the population could possibly be explained by the same genetic variants and environmentally modulated mechanisms (caloric restriction, specific nutrients). In support of this hypothesis, polymorphisms selected for in the centenarian population as a consequence of demographic pressure have been found to modulate cellular signals controlled also by caloric restriction. Here, we give an overview of the recent findings in the field of the genetics of human exceptional longevity, of how some of the identified polymorphisms modulate signals also influenced by food intake and caloric restriction, of what in our view have been the limitations of the approaches used over the past years to study genetics (sib-pair-, candidate gene association-, and genome-wide association-studies), and briefly of the limitations and the potential of the new, high-throughput, next-generation sequencing techniques applied to exceptional longevity.

Figure 1

Sample sizes required for genetic association studies. The graph shows the total number N of samples (consisting of N/2 cases and N/2 controls) required to map a genetic variant as a function of the increased risk due to the disease-causing allele (x axis) and the frequency of the disease-causing allele (various curves). The required sample size is shown in the table on the right for various different kinds of association studies [33]. Reproduced with permission from The American Association for the Advancement of Science.