Western Hunter-Gatherer genetic ancestry contributes to human longevity in the Italian population

The genetics of human longevity has been primarily studied using classical methods developed in genome-wide association studies. With the recent advances in paleogenomics, it is now possible to investigate to what extent ancient population ancestries contribute to complex traits. In this study, we explored the role of ancient genetic components in human longevity by focusing on the Italian Peninsula, whose genetic heritage includes several past genetic ancestries that have contributed to the current European genetic make-up. We analyzed genome-wide data of 333 Italian centenarians and 690 geographically matched healthy controls, and compared their genetic composition to 103 ancient genomes representative of the main past European population ancestries. Our findings indicate that Italian centenarians have a higher genetic affinity with Western Hunter-Gatherer (WHG)-related ancestry compared to controls, according to PCA and f4-statistics. Logistic regression models based on supervised admixture revealed a significant association between higher WHG ancestry and the centenarian status. Additionally, residual-based predictive analysis showed that centenarians exhibit a significantly higher WHG contribution independent of the genetic structuring of the general Italian population. By painting the chromosomes of modern Italians, we also showed a significantly higher number of WHG alleles at pro-longevity SNPs. In the present study, we demonstrate the contribution of ancient genetic components to the longevity phenotype. In particular, we showed a greater contribution from Western Hunter-Gatherer-related ancestry to Italian centenarians, thus suggesting that this pre-Neolithic genetic component, which has been linked to population shifts occurring within Europe after the Last Glacial Maximum, could be beneficial for longevity today.