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      Hematopoietic cellular aging is not accelerated during the first 2 years of life in children born preterm

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          Abstract

          Background

          Prematurity in itself and exposure to neonatal intensive care triggers inflammatory processes and oxidative stress, leading to risk for disease later in life. The effects on cellular aging processes are incompletely understood.

          Methods

          Relative telomere length (RTL) was measured by qPCR in this longitudinal cohort study with blood samples taken at birth and at 2 years of age from 60 children (16 preterm and 44 term). Viral respiratory infections the first year were evaluated. Epigenetic biological DNA methylation (DNAm) age was predicted based on methylation array data in 23 children (11 preterm and 12 term). RTL change/year and DNAm age change/year was compared in preterm and term during the 2 first years of life.

          Results

          Preterm infants had longer telomeres than term born at birth and at 2 years of age, but no difference in telomere attrition rate could be detected. Predicted epigenetic DNAm age was younger in preterm infants, but rate of DNAm aging was similar in both groups.

          Conclusions

          Despite early exposure to risk factors for accelerated cellular aging, children born preterm exhibited preserved telomeres. Stress during the neonatal intensive care period did not reflect accelerated epigenetic DNAm aging. Early-life aging was not explained by preterm birth.

          Impact

          • Preterm birth is associated with elevated disease risk later in life.

          • Preterm children often suffer from inflammation early in life.

          • Stress-related telomere erosion during neonatal intensive care has been proposed.

          • Inflammation-accelerated biological aging in preterm is unknown.

          • We find no accelerated aging due to prematurity or infections during the first 2 years of life.

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          Most cited references30

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          Is Open Access

          Stereotypic Immune System Development in Newborn Children

          Summary Epidemiological data suggest that early life exposures are key determinants of immune-mediated disease later in life. Young children are also particularly susceptible to infections, warranting more analyses of immune system development early in life. Such analyses mostly have been performed in mouse models or human cord blood samples, but these cannot account for the complex environmental exposures influencing human newborns after birth. Here, we performed longitudinal analyses in 100 newborn children, sampled up to 4 times during their first 3 months of life. From 100 μL of blood, we analyze the development of 58 immune cell populations by mass cytometry and 267 plasma proteins by immunoassays, uncovering drastic changes not predictable from cord blood measurements but following a stereotypic pattern. Preterm and term children differ at birth but converge onto a shared trajectory, seemingly driven by microbial interactions and hampered by early gut bacterial dysbiosis.
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            The rate of telomere sequence loss in human leukocytes varies with age.

            A gradual loss of telomeric repeat sequences with aging previously has been noted in normal adult tissues, and this process has been implicated in cell senescence. No data exist that address the rate of telomere shortening in normal human cells within families or early in life. To address these questions, we measured telomere lengths in peripheral blood leukocytes (PBLs) from 75 members of 12 families and in a group of unrelated healthy children who were 5-48 months old. Here we report the surprising observation that rates of telomere attrition vary markedly at different ages. Telomeric repeats are lost rapidly (at a rate of >1 kilobase per year) from the PBLs of young children, followed by an apparent plateau between age 4 and young adulthood, and by gradual attrition later in life. These data suggest that the loss of telomeric repeats in hematopoietic cells is a dynamic process that is differentially regulated in young children and adults. Our results have implications for current models of how telomeric sequences are lost in normal somatic cells and suggest that PBLs are an excellent tissue to investigate how this process is controlled.
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              Gestational age at birth and mortality in young adulthood.

              Preterm birth is the leading cause of infant mortality in developed countries, but the association between gestational age at birth and mortality in adulthood remains unknown. To examine the association between gestational age at birth and mortality in young adulthood. National cohort study of 674,820 individuals born as singletons in Sweden in 1973 through 1979 who survived to age 1 year, including 27,979 born preterm (gestational age <37 weeks), followed up to 2008 (ages 29-36 years). All-cause and cause-specific mortality. A total of 7095 deaths occurred in 20.8 million person-years of follow-up. Among individuals still alive at the beginning of each age range, a strong inverse association was found between gestational age at birth and mortality in early childhood (ages 1-5 years: adjusted hazard ratio [aHR] for each additional week of gestation, 0.92; 95% CI, 0.89-0.94; P < .001), which disappeared in late childhood (ages 6-12 years: aHR, 0.99; 95% CI, 0.95-1.03; P = .61) and adolescence (ages 13-17 years: aHR, 0.99; 95% CI, 0.95-1.03; P = .64) and then reappeared in young adulthood (ages 18-36 years: aHR, 0.96; 95% CI, 0.94-0.97; P < .001). In young adulthood, mortality rates (per 1000 person-years) by gestational age at birth were 0.94 for 22 to 27 weeks, 0.86 for 28 to 33 weeks, 0.65 for 34 to 36 weeks, 0.46 for 37 to 42 weeks (full-term), and 0.54 for 43 or more weeks. Preterm birth was associated with increased mortality in young adulthood even among individuals born late preterm (34-36 weeks, aHR, 1.31; 95% CI, 1.13-1.50; P < .001), relative to those born full-term. In young adulthood, gestational age at birth had the strongest inverse association with mortality from congenital anomalies and respiratory, endocrine, and cardiovascular disorders and was not associated with mortality from neurological disorders, cancer, or injury. After excluding earlier deaths, low gestational age at birth was independently associated with increased mortality in early childhood and young adulthood.
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                Author and article information

                Contributors
                ewa.henckel@ki.se
                Journal
                Pediatr Res
                Pediatr. Res
                Pediatric Research
                Nature Publishing Group US (New York )
                0031-3998
                1530-0447
                13 March 2020
                : 1-7
                Affiliations
                [1 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, CLINTEC, , Karolinska Institutet, ; Stockholm, Sweden
                [2 ]ISNI 0000 0000 9241 5705, GRID grid.24381.3c, Department of Neonatology, , Karolinska University Hospital, ; Stockholm, Sweden
                [3 ]ISNI 0000 0001 1034 3451, GRID grid.12650.30, Department of Medical Biosciences, Pathology, , Umeå University, ; Umeå, Sweden
                Author information
                http://orcid.org/0000-0003-0775-1563
                Article
                833
                10.1038/s41390-020-0833-6
                7086539
                32170191
                aaa3958c-4b62-4dd1-b9fa-e22228e4f72c
                © International Pediatric Research Foundation, Inc 2020

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 23 September 2019
                : 10 February 2020
                : 19 February 2020
                Categories
                Clinical Research Article

                Pediatrics
                Pediatrics

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