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Accelerated epigenetic aging in newborns with Down syndrome.

ABSTRACT: Accelerated aging is a hallmark of Down syndrome (DS), with adults experiencing early-onset Alzheimer's disease and premature aging of the skin, hair, and immune and endocrine systems. Accelerated epigenetic aging has been found in the blood and brain tissue of adults with DS but when premature aging in DS begins remains unknown. We investigated whether accelerated aging in DS is already detectable in blood at birth. We assessed the association between age acceleration and DS using five epigenetic clocks in 346 newborns with DS and 567 newborns without DS using Illumina MethylationEPIC DNA methylation array data. We compared two epigenetic aging clocks (DNAmSkinBloodClock and pan-tissue DNAmAge) and three epigenetic gestational age clocks (Haftorn, Knight, and Bohlin) between DS and non-DS newborns using linear regression adjusting for observed age, sex, batch, deconvoluted blood cell proportions, and genetic ancestry. Targeted sequencing of GATA1 was performed in a subset of 184 newborns with DS to identify somatic mutations associated with transient abnormal myelopoiesis. DS was significantly associated with increased DNAmSkinBloodClock (effect estimate = 0.2442, p < 0.0001), with an epigenetic age acceleration of 244 days in newborns with DS after adjusting for potential confounding factors (95% confidence interval: 196-292 days). We also found evidence of epigenetic age acceleration associated with somatic GATA1 mutations among newborns with DS (p = 0.015). DS was not associated with epigenetic gestational age acceleration. We demonstrate that accelerated epigenetic aging in the blood of DS patients begins prenatally, with implications for the pathophysiology of immunosenescence and other aging-related traits in DS.

SUBMITTER: Xu K

PROVIDER: S-EPMC9282838 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Importance:Telomere length is a marker of biological aging that may provide a cellular memory of exposures to oxidative stress and inflammation. Telomere length at birth has been related to life expectancy. An association between prenatal air pollution exposure and telomere length at birth could provide new insights in the environmental influence on molecular longevity. Objective:To assess the association of prenatal exposure to particulate matter (PM) with newborn telomere length as reflected by cord blood and placental telomere length. Design, Setting, and Participants:In a prospective birth cohort (ENVIRONAGE [Environmental Influence on Ageing in Early Life]), a total of 730 mother-newborn pairs were recruited in Flanders, Belgium between February 2010 and December 2014, all with a singleton full-term birth (?37 weeks of gestation). For statistical analysis, participants with full data on both cord blood and placental telomere lengths were included, resulting in a final study sample size of 641. Exposures:Maternal residential PM2.5 (particles with an aerodynamic diameter ?2.5 ?m) exposure during pregnancy. Main Outcomes and Measures:In the newborns, cord blood and placental tissue relative telomere length were measured. Maternal residential PM2.5 exposure during pregnancy was estimated using a high-resolution spatial-temporal interpolation method. In distributed lag models, both cord blood and placental telomere length were associated with average weekly exposures to PM2.5 during pregnancy, allowing the identification of critical sensitive exposure windows. Results:In 641 newborns, cord blood and placental telomere length were significantly and inversely associated with PM2.5 exposure during midgestation (weeks 12-25 for cord blood and weeks 15-27 for placenta). A 5-µg/m3 increment in PM2.5 exposure during the entire pregnancy was associated with 8.8% (95% CI, -14.1% to -3.1%) shorter cord blood leukocyte telomeres and 13.2% (95% CI, -19.3% to -6.7%) shorter placental telomere length. These associations were controlled for date of delivery, gestational age, maternal body mass index, maternal age, paternal age, newborn sex, newborn ethnicity, season of delivery, parity, maternal smoking status, maternal educational level, pregnancy complications, and ambient temperature. Conclusions and Relevance:Mothers who were exposed to higher levels of PM2.5 gave birth to newborns with shorter telomere length. The observed telomere loss in newborns by prenatal air pollution exposure indicates less buffer for postnatal influences of factors decreasing telomere length during life. Therefore, improvements in air quality may promote molecular longevity from birth onward.

Project description:In utero air pollution exposure has been associated with adverse birth outcomes, yet effects of air pollutants on regulatory mechanisms in fetal growth and critical windows of vulnerability during pregnancy are not well understood. There is evidence that epigenetic alterations may contribute to these effects. DNA methylation (DNAm) based age estimators have been developed and studied extensively with health outcomes in recent years. Growing literature suggests environmental factors, such as air pollution and smoking, can influence epigenetic aging. However, little is known about the effect of prenatal air pollution exposure on epigenetic aging. In this study, we leveraged existing data on prenatal air pollution exposure and cord blood DNAm from 332 mother-child pairs in the Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), two pregnancy cohorts enrolling women who had a previous child diagnosed with autism spectrum disorder, to assess the relationship of prenatal exposure to air pollution and epigenetic aging at birth. DNAm age was computed using existing epigenetic clock algorithms for cord blood tissue-Knight and Bohlin. Epigenetic age acceleration was defined as the residual of regressing chronological gestational age on DNAm age, accounting for cell type proportions. Multivariable linear regression models and distributed lag models (DLMs), adjusting for child sex, maternal race/ethnicity, study sites, year of birth, maternal education, were completed. In the single-pollutant analysis, we observed exposure to PM2.5, PM10, and O3 during preconception period and pregnancy period were associated with decelerated epigenetic aging at birth. For example, pregnancy average PM10 exposure (per 10 unit increase) was associated with epigenetic age deceleration at birth (weeks) for both Knight and Bohlin clocks (β = -0.62, 95% CI: -1.17, -0.06; β = -0.32, 95% CI: -0.63, -0.01, respectively). Weekly DLMs revealed that increasing PM2.5 during the first trimester and second trimester were associated with decelerated epigenetic aging and that increasing PM10 during the preconception period was associated with decelerated epigenetic aging, using the Bohlin clock estimate. Prenatal ambient air pollution exposure, particularly in early and mid-pregnancy, was associated with decelerated epigenetic aging at birth.

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Accelerated epigenetic aging in newborns with Down syndrome.

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