Early menarche and childbirth accelerate aging-related outcomes and age-related diseases: Evidence for antagonistic pleiotropy in humans
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eLife Assessment
This important study uses Mendelian Randomisation to show that early life phenotypes (i.e. onset of age at menarche and age at first birth) have an influence on a multitude of health outcomes later in life. The provided empirical evidence supporting the antagonistic pleiotropy theory is solid. However, some additional analyses and a more comprehensive discussion of the findings are needed to make the study stronger.
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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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eLife Assessment
This important study uses Mendelian Randomisation to show that early life phenotypes (i.e. onset of age at menarche and age at first birth) have an influence on a multitude of health outcomes later in life. The provided empirical evidence supporting the antagonistic pleiotropy theory is solid. However, some additional analyses and a more comprehensive discussion of the findings are needed to make the study stronger.
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Reviewer #1 (Public review):
Summary:
The present study aims to associate reproduction with age-related disease as support of the antagonistic pleiotorpy hypothesis of ageing, predominantly using Mendelian Randomization. The authors found evidence that early-life reproductive success is associated with advanced ageing.
Strengths:
Large sample size. Many analyses.
Weaknesses:
There are some errors in the methodology, that require revisions.
In particular, the main conclusions drawn by the authors refer to the Mendelian Randomization analyses. However, the authors made a few errors here that need to be reconsidered:
(1) Many of the outcomes investigated by the authors are continuous outcomes, while the authors report odds ratios. This is not correct and should be revised.
(2) Some of the odds ratios (for example the one for osteoporosis) …
Reviewer #1 (Public review):
Summary:
The present study aims to associate reproduction with age-related disease as support of the antagonistic pleiotorpy hypothesis of ageing, predominantly using Mendelian Randomization. The authors found evidence that early-life reproductive success is associated with advanced ageing.
Strengths:
Large sample size. Many analyses.
Weaknesses:
There are some errors in the methodology, that require revisions.
In particular, the main conclusions drawn by the authors refer to the Mendelian Randomization analyses. However, the authors made a few errors here that need to be reconsidered:
(1) Many of the outcomes investigated by the authors are continuous outcomes, while the authors report odds ratios. This is not correct and should be revised.
(2) Some of the odds ratios (for example the one for osteoporosis) are really small, while still reaching the level of statistical significance. After some checking, I found the GWAS data used to generate these MR estimates were processed by the program BOLT-LLM. This program is a linear mixed model program, which requires the transformation of the beta estimates to be useful for dichotomous outcomes. The authors should check the manual of BOLT-LLM and recalculate the beta estimates of the SNP-outcome associations prior to the Mendelian Randomization analyses. This should be checked for all outcomes as it doesn't apply to all.
(3) The authors should follow the MR-Strobe guidelines for presentation.
(4) The authors should report data in the text with a 95% confidence interval.
(5) The authors should consider correction for multiple testing.
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Reviewer #2 (Public review):
Summary:
The authors present an interesting paper where they test the antagonistic pleiotropy theory. Based on this theory they hypothesize that genetic variants associated with later onset of age at menarche and age at first birth have a positive causal effect on a multitude of health outcomes later in life, such as epigenetic aging and prevalence of chronic diseases. Using a mendelian randomization and colocalization approach, the authors show that SNPs associated with later age at menarche are associated with delayed aging measurements, such as slower epigenetic aging and reduced facial aging, and a lower risk of chronic diseases, such as type 2 diabetes and hypertension. Moreover, they identified 128 fertility-related SNPs that are associated with age-related outcomes and they identified BMI as a …
Reviewer #2 (Public review):
Summary:
The authors present an interesting paper where they test the antagonistic pleiotropy theory. Based on this theory they hypothesize that genetic variants associated with later onset of age at menarche and age at first birth have a positive causal effect on a multitude of health outcomes later in life, such as epigenetic aging and prevalence of chronic diseases. Using a mendelian randomization and colocalization approach, the authors show that SNPs associated with later age at menarche are associated with delayed aging measurements, such as slower epigenetic aging and reduced facial aging, and a lower risk of chronic diseases, such as type 2 diabetes and hypertension. Moreover, they identified 128 fertility-related SNPs that are associated with age-related outcomes and they identified BMI as a mediating factor for disease risk, discussing this finding in the context of evolutionary theory.
Strengths:
The major strength of this manuscript is that it addresses the antagonistic pleiotropy theory in aging. Aging theories are not frequently empirically tested although this is highly necessary. The work is therefore relevant for the aging field as well as beyond this field, as the antagonistic pleiotropy theory addresses the link between fitness (early life health and reproduction) and aging.
Points that have to be clarified/addressed:
(1) The antagonistic pleiotropy is an evolutionary theory pointing to the possibility that mutations that are beneficial for fitness (early life health and reproduction) may be detrimental later in life. As it concerns an evolutionary process and the authors focus on contemporary data from a single generation, more context is necessary on how this theory is accurately testable. For example, why and how much natural variation is there for fitness outcomes in humans? How do genetic risk score distributions of the exposure data look like? Also, how can the authors distinguish in their data between the antagonistic pleiotropy theory and the disposable soma theory, which considers a trade-off between investment in reproduction and somatic maintenance and can be used to derive similar hypotheses? There is just a very brief mention of the disposable soma theory in lines 196-198.
(2) The antagonistic pleiotropy theory, used to derive the hypothesis, does not necessarily distinguish between male and female fitness. Would the authors expect that their results extrapolate to males as well? And can they test that?
(3) There is no statistical analyses section providing the exact equations that are tested. Hence it's not clear how many tests were performed and if correction for multiple testing is necessary. It is also not clear what type of analyses have been done and why they have been done. For example in the section starting at line 47, Odds Ratios are presented, indicating that logistic regression analyses have been performed. As it's not clear how the outcomes are defined (genotype or phenotype, cross-sectional or longitudinal, etc.) it's also not clear why logistic regression analysis was used for the analyses.
(4) Mendelian Randomization is an important part of the analyses done in the manuscript. It is not clear to what extent the MR assumptions are met, how the assumptions were tested, and if/what sensitivity analyses are performed; e.g. reverse MR, biological knowledge of the studied traits, etc. Can the authors explain to what extent the genetic instruments represent their targets (applicable expression/protein levels) well?
(5) It is not clear what reference genome is used and if or what imputation panel is used. It is also not clear what QC steps are applied to the genotype data in order to construct the genetic instruments of MR.
(6) A code availability statement is missing. It is understandable that data cannot always be shared, but code should be openly accessible.
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