Abstract
The antagonistic pleiotropy hypothesis posits that natural selection for pleiotropic mutations that confer earlier or more reproduction but impair the post-reproductive life causes aging. This hypothesis of the evolutionary origin of aging is supported by case studies but lacks unambiguous genomic evidence. Here, we genomically test this hypothesis using the genotypes, reproductive phenotypes, and death registry of 276,406 U.K. Biobank participants. We observe a strong, negative genetic correlation between reproductive traits and life span. Individuals with higher polygenetic scores for reproduction (PGS(R)) have lower survivorships to age 76 (SV(76)), and PGS(R) increased over birth cohorts from 1940 to 1969. Similar trends are seen from individual genetic variants examined. The antagonistically pleiotropic variants are often associated with cis-regulatory effects across multiple tissues or on multiple target genes. These and other findings support the antagonistic pleiotropy hypothesis of aging in humans and point to potential molecular mechanisms of the reproduction-life-span antagonistic pleiotropy.