Evidence for the Role of Selection for Reproductively Advantageous Alleles in Human Aging

The antagonistic pleiotropy hypothesis is one of the leading theories in the evolutionary origin of aging. It states that mutations contributing to aging could be positively selected for if they are advantageous early in life and promote earlier reproduction or more offspring. The evidence supporting the antagonistic pleiotropy hypothesis in humans is mixed and lacks unambiguous genome-wide support. The UK Biobank contains the genotypes and various phenotypes of 500,000 participants, offering an opportunity to test the antagonistic pleiotropy hypothesis in humans. This analysis aimed to use the UK Biobank to determine whether genetic variants influencing reproduction are likely to affect lifespan, whether pleiotropy between reproduction and lifespan are largely antagonistic, and whether pleiotropic mutations promoting reproduction but causing aging are favored by natural selection. In addition, potential molecular mechanisms linking reproduction to aging were investigated. Genetic correlation between 2 phenotypic traits was defined as the proportion of variance that the 2 traits share due to genetic causes and is a measure of the contribution of pleiotropy to the covariation of the traits. Four reproductive traits were focused on negative age at first birth, negative age at first sex, number of children fathers, and age at menopause, with larger values of these traits corresponding to higher reproduction. Two life span traits were examined: father's age at death and mother's age at death. Data were available for a total of 276,406 UK Biobank participants, and 583 genetic variants were reported to be associated with at least 1 reproductive trait. A strong, negative genetic correlation was observed between the 3 reproductive traits and 2 life span traits, supporting the antagonistic pleiotropy hypothesis. Individuals ranked in the top third in polygenic score (PGS) for the 3 reproductive traits had a significantly lower probability of survival to age 76 (SV76) than that of individuals ranked in the bottom third. Compared with randomly selected polymorphisms, those impacting reproduction were 5 times more likely to affect life span and 7.5 times more likely to affect life span antagonistically. Among individuals with the same number of children ever born, SV76 was negatively correlated with the PGS for each of the 4 reproductive traits. In this study, the evidence shows a strong negative genetic correlation between reproduction and parental life span, as well as between parental reproduction and parental life span. This supports the antagonistic pleiotropy hypothesis of aging in humans.