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Title: Parity predicts biological age acceleration in post-menopausal, but not pre-menopausal, women

Understanding factors contributing to variation in ‘biological age’ is essential to understanding variation in susceptibility to disease and functional decline. One factor that could accelerate biological aging in women is reproduction. Pregnancy is characterized by extensive, energetically-costly changes across numerous physiological systems. These ‘costs of reproduction’ may accumulate with each pregnancy, accelerating biological aging. Despite evidence for costs of reproduction using molecular and demographic measures, it is unknown whether parity is linked to commonly-used clinical measures of biological aging. We use data collected between 1999 and 2010 from the National Health and Nutrition Examination Survey (n = 4418) to test whether parity (number of live births) predicted four previously-validated composite measures of biological age and system integrity: Levine Method, homeostatic dysregulation, Klemera–Doubal method biological age, and allostatic load. Parity exhibited a U-shaped relationship with accelerated biological aging when controlling for chronological age, lifestyle, health-related, and demographic factors in post-menopausal, but not pre-menopausal, women, with biological age acceleration being lowest among post-menopausal women reporting between three and four live births. Our findings suggest a link between reproductive function and physiological dysregulation, and allude to possible compensatory mechanisms that buffer the effects of reproductive function on physiological dysregulation during a woman’s reproductive lifespan. Future work more » should continue to investigate links between parity, menopausal status, and biological age using targeted physiological measures and longitudinal studies.

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Publication Date:
Journal Name:
Scientific Reports
Nature Publishing Group
Sponsoring Org:
National Science Foundation
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  1. Abstract Objectives

    Oxidative stress is hypothesized to contribute to age‐related somatic deterioration. Both reproductive and ecological context may necessitate tradeoffs that influence this outcome. We examined whether measures of lifetime reproductive effort were related to levels of oxidative stress biomarkers in peri‐ and post‐menopausal women and whether associations were moderated by rural or urban residence.


    We surveyed 263 healthy women (age 62.1 ± 10.0 SD) from rural (N = 161) and urban Poland (N = 102), collecting sociodemographic data and urine samples to analyze biomarkers of oxidative stress (8‐oxo‐2′‐deoxyguanosine, 8‐OHdG) and antioxidative defense (copper‐zinc superoxide dismutase, Cu‐Zn SOD). Linear regression models, adjusted for residence, were used to test for associations between reproductive effort and 8‐OHdG and Cu‐Zn SOD.


    Univariate models demonstrated significant associations between gravidity and the biomarkers of oxidative stress (8‐OHdG:R2 = 0.042,P ≤ .001; Cu‐Zn SOD:R2 = 0.123,P ≤ .001). Multivariate models incorporating potential confounding variables, as well as cross‐product interaction terms, indicated that gravidity was associated with 8‐OHdG (P < .01,R2adj = 0.067) and Cu‐Zn SOD (P = .01,R2adj = 0.159). Residence (ie, urban vs rural) did not significantly moderate the associations between the biomarkers and reproductive effort.


    Higher lifetime reproductive effort contributes to increases in oxidative stress and antioxidative defenses. Our results provide evidence of potential mechanisms underlying the physiological tradeoffs influencing senescence for women with high reproductive effort.more »We illustrate the value of applying an evolutionary perspective to elucidate variation in human health and senescence.

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  2. Abstract Introduction

    While many aspects of female ovarian function respond to environmental stressors, estradiol (E2) appears less sensitive to stressors than progesterone, except under extreme ecological conditions. However, earlier studies relied on saliva samples, considered less sensitive than blood. Here, we investigated E2 variation among 177 Bangladeshi and UK white women, aged 35–59, using single serum samples. Bangladeshi women either grew up in Sylhet, Bangladesh (exposed to poor sanitation, limited health care, and higher pathogen loads but not poor energy availability), or in the UK.


    We collected samples on days 4–6 of the menstrual cycle in menstruating women and on any day for post‐menopausal women. Participants included: (i) Bangladeshi sedentees (n = 36), (ii) Bangladeshis who migrated to the UK as adults (n = 52), (iii) Bangladeshis who migrated as children (n = 40), and (iv) UK white women matched for neighborhood residence to the migrants (n = 49). Serum was obtained by venipuncture and analyzed using electrochemiluminescence. We collected anthropometrics and supplementary sociodemographic and reproductive data through questionnaires. We analyzed the data using multivariate regression.


    E2 levels did not differ between migrant groups after controlling for age, BMI, physical activity, psychosocial stress, parity, and time since last birth (parous women). Paralleling results from salivary E2, serum E2 didmore »not differ among women who experienced varying developmental conditions.


    Our results reinforce the hypothesis that E2 levels are stable under challenging environmental conditions. Interpopulation variation may only arise under chronic conditions of extreme nutritional scarcity, energy expenditure, and/or high disease burdens.

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  3. Abstract Objectives

    Pregnancy failure represents a major fitness cost for any mammal, particularly those with slow life histories such as primates. Here, we quantified the risk of fetal loss in wild hybrid baboons, including genetic, ecological, and demographic sources of variance. We were particularly interested in testing the hypothesis that hybridization increases fetal loss rates. Such an effect would help explain how baboons may maintain genetic and phenotypic integrity despite interspecific gene flow.

    Materials and Methods

    We analyzed outcomes for 1020 pregnancies observed over 46 years in a natural yellow baboon‐anubis baboon hybrid zone. Fetal losses and live births were scored based on records of female reproductive state and the appearance of live neonates. We modeled the probability of fetal loss as a function of a female's genetic ancestry (the proportion of her genome estimated to be descended from anubis [vs. yellow] ancestors), age, number of previous fetal losses, dominance rank, group size, climate, and habitat quality using binomial mixed effects models.


    Female genetic ancestry did not predict fetal loss. Instead, the risk of fetal loss is elevated for very young and very old females. Fetal loss is most robustly predicted by ecological factors, including poor habitat quality prior to a home rangemore »shift and extreme heat during pregnancy.


    Our results suggest that gene flow between yellow and anubis baboons is not impeded by an increased risk of fetal loss for hybrid females. Instead, ecological conditions and female age are key determinants of this component of female reproductive success.

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  4. Abstract Background

    Consistent with evolutionarily theorized costs of reproduction (CoR), reproductive history in women is associated with life expectancy and susceptibility to certain cancers, autoimmune disorders and metabolic disease. Immunological changes originating during reproduction may help explain some of these relationships.


    To explore the potential role of the immune system in female CoR, we characterized leukocyte composition and regulatory processes using DNA methylation (DNAm) in a cross-sectional cohort of young (20–22 years old) women differing in reproductive status.


    Compared to nulliparity, pregnancy was characterized by differential methylation at 828 sites, 96% of which were hypomethylated and enriched for genes associated with T-cell activation, innate immunity, pre-eclampsia and neoplasia. Breastfeeding was associated with differential methylation at 1107 sites (71% hypermethylated), enriched for genes involved in metabolism, immune self-recognition and neurogenesis. There were no significant differences in DNAm between nulliparous and parous women. However, compared to nullipara, pregnant women had lower proportions of B, CD4T, CD8T and natural killer (NK) cells, and higher proportions of granulocytes and monocytes. Monocyte counts were lower and NK counts higher among breastfeeding women, and remained so among parous women.


    Our findings point to widespread differences in DNAm during pregnancy and lactation. These effects appear largely transient, butmore »may accumulate with gravidity become detectable as women age. Nulliparous and parous women differed in leukocyte composition, consistent with more persistent effects of reproduction on cell type. These findings support transient (leukocyte DNAm) and persistent (cell composition) changes associated with reproduction in women, illuminating potential pathways contributing to CoR.

    Lay Summary: Evolutionary theory and epidemiology support costs of reproduction (CoR) to women’s health that may involve changes in immune function. We report differences in immune cell composition and gene regulation during pregnancy and breastfeeding. While many of these differences appear transient, immune cell composition may remain, suggesting mechanisms for female CoR.

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