Evidence for the role of selection for reproductively advantageous alleles in human aging

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 UK Biobank participants. We observe a strong, negative genetic correlation between reproductive traits and lifespan. Individuals with higher polygenetic scores for reproduction (PGSR) have lower survivorships to age 76 (SV76), and PGSR increased over birth cohorts from 1940 to 1969. Similar trends are found from individual genetic variants examined. PGSR and SV76 remain negatively correlated upon the control of the offspring number, revealing horizontal pleiotropy between reproduction and lifespan. Intriguingly, regardless of PGSR, having two children maximizes SV76. These and other findings strongly support the antagonistic pleiotropy hypothesis of aging in humans.