Analysis of Human Inheritance of Longevity is not as Straightforward as One Might Think
Here, researchers note some of the challenges inherent in trying to analyze data on human inheritance of longevity; it isn't as easy as it sounds. Considerable effort has gone into analysis of long-lived families to try to identify genetic variants that might explain why some lineages exhibit greater longevity than others. Nonetheless, so far only a small number of gene variants have been robustly demonstrated to influence human longevity. This poor yield is not for lack of searching, but because it seems likely that individual genetic contributions to longevity are both very small and very specific to environmental circumstances. Every study finds novel variants that correlate within that study population, but no other study is able to replicate that finding. This ultimately leads to a growing consensus that familial longevity is more a matter of transmission of culture and environment than transmission of genes: exercise, diet, exposure to persistent pathogens, and so forth.
The study of such exceptionally old individuals (longevity) is important as they likely harbor gene-environment interactions which beneficially regulate molecular pathways involved in longevity, resistance to disease, resilience to negative side-effects of treatment and therefore healthy aging. It has been estimated that age at death (lifespan) attributes for ~25% to genetic variation and this number rises for long-lived individuals as shown by its strong familial clustering. Nevertheless, two decades of genetic research to understand the mechanisms of longevity and healthy aging had limited robust results. Amongst a number of potential determinants, only the APOE and FOXO3A genes have been consistently identified.
One of the main reasons for the difficulty of identifying genes promoting longevity and healthy aging is the lack of a consistent definition for heritable longevity, which resulted in a mix of sporadically long-lived cases with those descending from a long-lived family and a large variation of longevity definitions used in longevity research. The presence of sporadically long-lived cases is illustrated by the increase of centenarians in the United States between 1994 and 2012 from 1 in 10,000 to 2 in 10,000. Secondly, Genome Wide Association (GWA) analysis, the leading method in complex disease mapping, relies on comparing living long-lived individuals (cases) with averagely living individuals (controls). These averagely lived individuals can in fact become long-lived over time, thus potentially confusing cases and controls.
In addition, recent research revealed the importance of rare and structural variants in addition to the common single nucleotide polymorphisms (SNPs) studied in GWAS. Thirdly, socio-behavioral and environmental factors, such as lifestyle, socioeconomic status, social network, and the living environment shaped the aging process of long-lived persons in interaction with their genes. However, these factors are rarely included in genetic longevity studies and surprisingly little is known about how they cluster in long-lived families.
The issue of unintentionally including sporadically long-lived cases has recently been addressed in two studies, using multiple large scale family tree databases; the Utah Population Database (UPDB), the LINKing System for historical family reconstruction (LINKS), and the Historical Sample of the Netherlands Long Lives (HSN-LL) which contain thousands of families. The studies showed that longevity is only transmitted across generations if at least 30% of the ancestors of a person belonged to the top 10% survivors of their birth cohort and the persons themselves also belong to the 10% longest lived. Importantly, 27% of the HSN-LL research persons showed a survival pattern similar to the general population even though they had at least one long-lived parent. Based on these results, the Longevity Relatives Count (LRC) score was developed as an instrument to identify genetically enriched long-lived persons for case inclusion in genetic studies and thus avoid the inclusion of sporadically long-lived persons.