Antagonistic pleiotropy is a term used to describe a biological mechanism that is helpful in one context, harmful in another. As most often used, this means helpful when young, harmful when old. The concept of antagonistic pleiotropy sits at the heart of any serious discussion of the evolution of aging, as well as the relationships between known mechanisms of aging and hallmarks of aging. The dominant view of aging is that it is a side-effect of natural selection operating more strongly on the characteristics of young individuals than on the characteristics of old individuals, favoring the evolution of mechanisms that enhance early survival and reproductive success at the expense of later survival and reproductive success. Optimizing for initial success no matter the later consequences is a winning strategy for near all ecological niches.
Examples of specific mechanisms and circumstances that illustrate the reality of antagonistic pleiotropy have been established in a number of species. Researchers are very interested in finding examples in humans, however. Given vast genetic and epidemiological databases, researchers have searched for longevity-associated mutations that also affect reproductive success, for example. This is challenging, as longevity-associated mutations with even modest effect sizes and replication in multiple study populations are thin on the ground. There is some debate over whether any of the human data is in fact a good demonstration of antagonistic pleiotropy. Nonetheless, researchers continue to work on the problem, as illustrated by today's open access paper.
Aging can be understood as a consequence of the declining force of natural selection with age. Consistent with this, the antagonistic pleiotropy theory of aging proposes that aging arises from trade-offs that favor early growth and reproduction. However, evidence supporting antagonistic pleiotropy in humans remains limited. In this study, Mendelian randomization (MR) was applied to investigate the associations between the ages of menarche or first childbirth and age-related outcomes and diseases. Ingenuity Pathway Analysis was employed to explore gene-related aspects associated with significant single-nucleotide polymorphisms (SNPs) detected in MR analysis. The associations between the age of menarche, childbirth, and the number of childbirths with several age-related outcomes were validated in the UK Biobank by conducting regression analysis of nearly 200,000 subjects.
Using MR, we demonstrated that later ages of menarche or first childbirth were genetically associated with longer parental lifespan, decreased frailty index, slower epigenetic aging, later menopause, and reduced facial aging. Moreover, later menarche or first childbirth was also genetically associated with a lower risk of several age-related diseases, including late-onset Alzheimer's disease, type 2 diabetes, heart disease, essential hypertension, and chronic obstructive pulmonary disease. We identified 158 significant SNPs that influenced age-related outcomes, some of which were involved in known longevity pathways, including insulin-like growth factor 1, growth hormone, AMP-activated protein kinase, and mTOR signaling. Our study also identified higher body mass index as a mediating factor in causing the increased risk of certain diseases, such as type 2 diabetes and heart failure, in women with early menarche or early pregnancy.
We validated the associations between the age of menarche, childbirth, and the number of childbirths with several age-related outcomes in the UK Biobank by conducting regression analysis of nearly 200,000 subjects. Our results demonstrated that menarche before the age of 11 and childbirth before 21 significantly accelerated the risk of several diseases and almost doubled the risk for diabetes, heart failure, and quadrupled the risk of obesity, supporting the antagonistic pleiotropy theory.
View the full article at FightAging
