Periodic Reporting for period 4 - PrenatStressAging (Prenatal Stress and Programming of Newborn and Infant Telomere Biology and Cellular Aging)
Okres sprawozdawczy: 2021-04-01 do 2022-09-30
The long-term consequences of exposure to excess stress on the initiation and progression of many age-related diseases are well established. The period of intrauterine life represents among the most sensitive developmental windows, at which time the effects of stress may be transmitted inter-generationally from a mother to her as-yet-unborn child. The elucidation of mechanisms underlying such effects is an area of intense interest and investigation. Aging, by definition, occurs with advancing age, and age-related disorders result from exposures over the life span of factors that produce and accumulate damage.
The novel concept advanced in this project is that the establishment of the integrity of key cellular aging-related processes that determine variation across individuals in the onset and progression of age-related disorders may originate very early in life (in utero) and may be plastic and influenced by developmental conditions. We proposed that telomere biology and the epigenetic DNA methylation-based aging profile (DNAmAGE) represent candidate outcomes of particular interest in this context.
The study addressed the following aims:
Aim 1: To estimate the nature and magnitude of the prospective association of maternal stress during pregnancy on markers of newborn and infant cellular aging.
Aim 2: To test the hypothesis that alterations in key biomarkers of maternal-placental-fetal (MPF) endocrine, immune and oxidative stress biology during pregnancy mediate the effect of maternal stress exposure on newborn and infant cellular aging.
Aim 3: To test the hypothesis that the effects of maternal stress exposure on newborn and infant cellular aging are modulated by potentially modifiable maternal characteristics and states.
Results of the study will help to identify new strategies for risk identification and primary and secondary interventions to augment current efforts to prevent, delay and ameliorate age-related disorders.
The novel concept advanced in this project is that the establishment of the integrity of key cellular aging-related processes that determine variation across individuals in the onset and progression of age-related disorders may originate very early in life (in utero) and may be plastic and influenced by developmental conditions. We proposed that telomere biology and the epigenetic DNA methylation-based aging profile (DNAmAGE) represent candidate outcomes of particular interest in this context.
The study addressed the following aims:
Aim 1: To estimate the nature and magnitude of the prospective association of maternal stress during pregnancy on markers of newborn and infant cellular aging.
Aim 2: To test the hypothesis that alterations in key biomarkers of maternal-placental-fetal (MPF) endocrine, immune and oxidative stress biology during pregnancy mediate the effect of maternal stress exposure on newborn and infant cellular aging.
Aim 3: To test the hypothesis that the effects of maternal stress exposure on newborn and infant cellular aging are modulated by potentially modifiable maternal characteristics and states.
Results of the study will help to identify new strategies for risk identification and primary and secondary interventions to augment current efforts to prevent, delay and ameliorate age-related disorders.
A prospective cohort study of 257 mother-child dyads was conducted from early pregnancy through birth until one year of age. Serial measures of maternal psychological, behavioral and physiological characteristics have been collected across gestation using an ecological momentary assessment (EMA) based real-time, ambulatory sampling protocol.
We found that stress-related immunological processes during pregnancy are related to shorter telomere length of the offspring at birth (Lazarides et al., 2019, DOI: 10.1016/j.bbi.2019.04.021). Maternal pro-inflammatory state across pregnancy, operationalized as the balance between tumor necrosis factor (TNF)-α, a major pro-inflammatory cytokine, and interleukin-10 (IL-10), the major anti-inflammatory cytokine, was significantly associated with shorter newborn TL. Newborn TL was, on average, 10% shorter in offspring of women in the upper compared to lower quartile of the TNF-α/IL-10 ratio during pregnancy.
The link between psychological stress and the stress hormone cortisol is of particular interest in the context of pregnancy and fetal development. Using ecological momentary assessments (EMA), we examined the association between psychological stress and cortisol at the between- and the within-person level using linear mixed models. After accounting for the effects of key determinants of variation in cortisol, momentary stress was significantly and positively associated with cortisol at the within-person level, but not at the between-person level (Lazarides et al. 2020; DOI: 10.1016/j.psyneuen.2020.104848). No association was evident for traditional retrospective measures of stress with cortisol at either the between- or the within-person level. These findings highlight the importance of characterization of the within-person variation in the stress response across time.
We then tested which pregnant women are at particular high risk to experience high levels of psychological stress during pregnancy. It is known that prenatal loss which occurs in approximately 20% of pregnancies represents a well-established risk factor for anxiety and affective disorders. In the current study, we examined whether a history of prenatal loss is associated with a subsequent pregnancy with maternal psychological state using EMA-based measures of pregnancy-specific distress and mood in everyday life. Compared to women who had not experienced a prior prenatal loss, women with a history of prenatal loss reported higher levels of pregnancy-specific distress in early as well as late pregnancy and also were more nervous and tired. Furthermore, in the comparison group pregnancy-specific distress decreased and mood improved from early to late pregnancy, whereas these changes across pregnancy were not evident in women in the prenatal loss group (Lazarides et al., 2020, DOI: 10.1017/S0033291721002221). These findings have important implications for designing EMA-based ambulatory, personalized interventions to reduce stress during pregnancy in this high-risk group.
Psychological resilience may function as a buffer of the effects of maternal stress. We therefore examined the relationship between maternal psychological resilience during pregnancy and newborn telomere length. We quantified maternal stress, negative and positive emotional responses to pregnancy events, positive affect, and perceived social support. Principal component analysis identified two latent factors: stress and positivity. A measure of resilience was computed by regressing the positivity factor on the stress factor, in order to quantify positivity after accounting for stress. Maternal resilience was significantly and positively associated with newborn TL (Verner et al., 2021, doi: 10.1176/appi.ajp.2020.19101003 see Figure 1). The results indicate that maternal psychological resilience may exert a salubrious effect on offspring telomere biology and highlight the importance of enhancing maternal mental health and well-being during pregnancy.
Findings of this project have been presented at national and international scientific conferences and have been published in scientific journals. Furthermore, presentations have been given to disseminate the findings to stakeholders, i.e. audiences that including midwifes, obstetricians and social workers medical and psychology students. The paper on maternal resilience and newborn telomere length received substantial media coverage on the national and international level.
We found that stress-related immunological processes during pregnancy are related to shorter telomere length of the offspring at birth (Lazarides et al., 2019, DOI: 10.1016/j.bbi.2019.04.021). Maternal pro-inflammatory state across pregnancy, operationalized as the balance between tumor necrosis factor (TNF)-α, a major pro-inflammatory cytokine, and interleukin-10 (IL-10), the major anti-inflammatory cytokine, was significantly associated with shorter newborn TL. Newborn TL was, on average, 10% shorter in offspring of women in the upper compared to lower quartile of the TNF-α/IL-10 ratio during pregnancy.
The link between psychological stress and the stress hormone cortisol is of particular interest in the context of pregnancy and fetal development. Using ecological momentary assessments (EMA), we examined the association between psychological stress and cortisol at the between- and the within-person level using linear mixed models. After accounting for the effects of key determinants of variation in cortisol, momentary stress was significantly and positively associated with cortisol at the within-person level, but not at the between-person level (Lazarides et al. 2020; DOI: 10.1016/j.psyneuen.2020.104848). No association was evident for traditional retrospective measures of stress with cortisol at either the between- or the within-person level. These findings highlight the importance of characterization of the within-person variation in the stress response across time.
We then tested which pregnant women are at particular high risk to experience high levels of psychological stress during pregnancy. It is known that prenatal loss which occurs in approximately 20% of pregnancies represents a well-established risk factor for anxiety and affective disorders. In the current study, we examined whether a history of prenatal loss is associated with a subsequent pregnancy with maternal psychological state using EMA-based measures of pregnancy-specific distress and mood in everyday life. Compared to women who had not experienced a prior prenatal loss, women with a history of prenatal loss reported higher levels of pregnancy-specific distress in early as well as late pregnancy and also were more nervous and tired. Furthermore, in the comparison group pregnancy-specific distress decreased and mood improved from early to late pregnancy, whereas these changes across pregnancy were not evident in women in the prenatal loss group (Lazarides et al., 2020, DOI: 10.1017/S0033291721002221). These findings have important implications for designing EMA-based ambulatory, personalized interventions to reduce stress during pregnancy in this high-risk group.
Psychological resilience may function as a buffer of the effects of maternal stress. We therefore examined the relationship between maternal psychological resilience during pregnancy and newborn telomere length. We quantified maternal stress, negative and positive emotional responses to pregnancy events, positive affect, and perceived social support. Principal component analysis identified two latent factors: stress and positivity. A measure of resilience was computed by regressing the positivity factor on the stress factor, in order to quantify positivity after accounting for stress. Maternal resilience was significantly and positively associated with newborn TL (Verner et al., 2021, doi: 10.1176/appi.ajp.2020.19101003 see Figure 1). The results indicate that maternal psychological resilience may exert a salubrious effect on offspring telomere biology and highlight the importance of enhancing maternal mental health and well-being during pregnancy.
Findings of this project have been presented at national and international scientific conferences and have been published in scientific journals. Furthermore, presentations have been given to disseminate the findings to stakeholders, i.e. audiences that including midwifes, obstetricians and social workers medical and psychology students. The paper on maternal resilience and newborn telomere length received substantial media coverage on the national and international level.
The results of the study will help to identify maternal conditions and intrauterine processes associated with her offspring’s long-term disease susceptibility for aging-related disorders. In the context of mother-child transmission of the effects of maternal stress we addressed specific knowledge gaps related to: a) ascertainment of the earliest period(s) of time during the offspring’s development when such inter-generational transmission may occur; b) elucidation of the primary biological pathways that may mediate this effect; and c) elucidation of stress-related and potential stress-buffering states and conditions that may be amenable to interventions. For these reasons, this study moved the field forward in an informed manner, and it will help to guide future translational research and identify targets for early identification of risk and for the subsequent development of intervention strategies.
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