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Early menarche and childbirth accelerate aging-related outcomes and age-related diseases: Evidence for antagonistic pleiotropy in humans. | LitMetric

AI Article Synopsis

  • Aging reflects a decline in the effectiveness of natural selection with age; the antagonistic pleiotropic theory suggests that aging arises from trade-offs that enhance early growth and reproduction, although human evidence is limited.
  • Using Mendelian Randomization, the research found that later ages of menarche and childbirth are linked to longer parental lifespan, reduced frailty, slower epigenetic aging, later menopause, and a lower risk of age-related diseases.
  • The study identified 128 genetic variants related to age-related outcomes, connecting early reproductive years with significantly higher risks of diseases like type 2 diabetes, heart disease, and obesity, thus supporting the antagonistic pleiotropy theory.

Article Abstract

Aging can be understood as a consequence of the declining force of natural selection with age. Consistent with this the antagonistic pleiotropic theory of aging suggests that aging results from the trade-offs that promote early growth and reproduction. However, evidence for antagonistic pleiotropy in humans is largely lacking. Using Mendelian Randomization (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 were also genetically associated with a lower risk of several age-related diseases, including late-onset Alzheimer's disease (LOAD), type 2 diabetes, heart disease, essential hypertension, and chronic obstructive pulmonary disease (COPD). 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 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. We identified 128 significant single nucleotide polymorphisms (SNPs) that influenced age-related outcomes, some of which were involved in known longevity pathways, including IGF1, growth hormone, AMPK, and mTOR signaling. Our study also identified higher BMI 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, emphasizing the importance of the thrifty gene hypothesis in explaining in part the mechanisms behind antagonistic pleiotropy. Our study highlights the complex relationship between genetic legacies and modern diseases, emphasizing the need for gender-sensitive healthcare strategies that consider the unique connections between female reproductive health and aging.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11469407PMC
http://dx.doi.org/10.1101/2024.09.23.24314197DOI Listing

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