Genetic Associations with Longevity in a Calabrian Cohort: A Genome-Wide Study

Abstract

Human longevity is a complex trait shaped by genetic background and population-specific factors. Calabria, a region in Southern Italy with a high prevalence of centenarians and relative genetic isolation, is a valuable model for investigating the genetic architecture of extreme survival. Here, we performed a genome-wide association study of longevity in 705 Calabrian individuals, comparing long-lived subjects to younger controls using a mixed-model approach that accounts for relatedness and population structure. We identified 267 candidate longevity-associated variants, including 23 suggestive genomic risk loci, of which one reached genome-wide significance. Although most loci did not replicate in external datasets, one intronic variant regulating proteasome-related gene expression was confirmed by meta-analysis. Gene- and pathway-based analyses highlighted biological processes central to aging, including proteostasis, DNA repair, telomere maintenance, apoptosis, insulin signaling, inflammation, and cancer-related pathways. Notably, established longevity loci such as APOE and FOXO3 were not associated, underscoring population-specific genetic effects. Overall, our findings suggest that longevity in the Calabrian population arises from a combination of unique genetic influences and conserved aging-related mechanisms, providing new insights into the molecular basis of human lifespan extension.