Why are long lived humans long lived? Why does this trait often run in families? One of the few firm advances in answering these questions is to rule out the hypothesis that long-lived lineages bear fewer detrimental gene variants. Several studies and study populations have indicated that there are just as many harmful variants present in the genomes of exceptionally long-lived people as are present in the rest of us. Beyond that, it remains to be seen as to just how much of exceptional longevity is in fact genetic. Broader genetic studies have in recent years continued to revise downward the contribution of genetics to variation in human life span. At the present time, it appears to be almost entirely a matter of lifestyle choice and environmental exposures to infectious disease, particulate air pollution, and so forth.
Centenarians (exceptionally long-lived individuals – ELLI) are a unique segment of the population, exhibiting long human lifespan and healthspan, despite generally practicing similar lifestyle habits as their peers. We tested disease-associated mutation burden in ELLI genomes by determining the burden of pathogenic variants reported in the ClinVar and HGMD databases using data from whole exome sequencing (WES) conducted in a cohort of ELLI, their offspring, and control individuals without antecedents of familial longevity (n = 1879), all descendent from the founder population of Ashkenazi Jews.
The burden of pathogenic variants did not differ between the three groups. Additional analyses of variants subtypes and variant effect predictor (VEP) biotype frequencies did not reveal a decrease of pathogenic or loss-of-function (LoF) variants in ELLI and offspring compared to the control group. Case-control pathogenic variants enrichment analyses conducted in ELLI and controls also did not identify significant differences in any of the variants between the groups and polygenic risk scores failed to provide a predictive model. Interestingly, cancer and Alzheimer’s disease-associated variants were significantly depleted in ELLI compared to controls, suggesting slower accumulation of mutation. That said, polygenic risk score analysis failed to find any predictive variants among the functional variants tested.
The high similarity in the burden of pathogenic variation between ELLI and individuals without familial longevity supports the notion that extension of lifespan and healthspan in ELLI is not a consequence of pathogenic variant depletion but rather a result of other genomic, epigenomic, or potentially nongenomic properties.