In this study, we investigated the contribution of rare coding variants to human longevity by analyzing whole exome sequencing data from 1245 German long-lived individuals (LLI) and 4105 geographically matched younger controls. We identified novel exome-wide significant associations at both the single-variant and gene level, with a significant over-representation of genes involved in mechanistic target of rapamycin (mTOR) signaling. As such, three rare single variants in the mTOR-pathway genes RPS6, FLCN, and SIK3 were enriched in LLI. Additionally, RWDD1 emerged as a strong candidate gene for longevity, with LLI exhibiting a statistically significant burden of rare missense variants in this gene. Other associations involved PRAC2, SLC16 A6, FOCAD, IHH, MESD, HOXA4, and DNAJB13. Furthermore, we observed an enrichment of protein-truncating variants in the genes ASXL1 and TET2 amongst LLI, likely as a result of clonal haematopoiesis. The study emphasizes the role of rare variants in human longevity, particularly through mTOR signaling.

© 2025. The Author(s).