Germline burden of rare damaging variants negatively affects human healthspan and lifespan

Genome-wide association studies often explore links between particular genes and phenotypes of interest. Known genetic variants, however, are responsible for only a small fraction of human lifespan variation evident from genetic twin studies. To account for the missing longevity variance, we hypothesized that the cumulative effect of deleterious variants may affect human longevity. Here, we report that the burden of rarest protein-truncating variants (PTVs) negatively impacts both human healthspan and lifespan in two large independent cohorts. Longer-living subjects have both fewer rarest PTVs and less damaging PTVs. In contrast, we show that the burden of frequent PTVs and rare non-PTVs is less deleterious, lacking association with longevity. The combined effect of rare PTVs is similar to that of known variants associated with longer lifespan and accounts for 1-2 years of lifespan variability. We further find that somatic accumulation of PTVs accounts for a minute fraction of mortality and morbidity acceleration and hence provides little support for its causal role in aging. Thus, damaging mutations, germline and somatic, can only contribute to aging as a result of higher-order effects including interactions of multiple forms of damage.