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Various approaches exist to assess population differences in biological aging. Telomere length (TL) is one such measure, and is associated with disease, disability and early mortality. Yet, issues surrounding precision and reproducibility are a concern for TL measurement. An alternative method to estimate TL using DNA methylation (DNAmTL) was recently developed. Although DNAmTL has been characterized in adult and elderly cohorts, its utility in pediatric populations remains unknown. We examined the comparability of leukocyte TL measurements generated using qPCR (absolute TL; aTL) to those estimated using DNAmTL in a high-risk pediatric cohort (

Background Immune cell proportions can be used to detect pathophysiological states and are also critical covariates in genomic analyses. The complete blood count (CBC) is the most common method of immune cell proportion estimation, but immune cell proportions can also be estimated using whole-genome DNA methylation (DNAm). Although the concordance of CBC and DNAm estimations has been validated in various adult and clinical populations, less is known about the concordance of existing estimators among stress-exposed individuals. As early life adversity and acute psychosocial stress have both been associated with unique DNAm alterations, the concordance of CBC and DNAm immune cell proportion needs to be validated in various states of stress. Results We report the correlation and concordance between CBC and DNAm estimates of immune cell proportions using the Illumina EPIC DNAm array within two unique studies: Study 1, a high-risk pediatric cohort of children oversampled for exposure to maltreatment (N = 365, age 8 to 14 years), and Study 2, a sample of young adults who have participated in an acute laboratory stressor with four pre- and post-stress measurements (N = 28, number of observations = 100). Comparing CBC and DNAm proportions across both studies, estimates of neutrophils (r = 0.948, p r = 0.916, p r = 0.933, p r = 0.766, p r = 0.189, p Conclusions Although significant differences in immune cell proportion estimates between CBC and DNAm exist, as well as stress-induced changes in immune cell proportions, neither child maltreatment nor acute psychosocial stress alters the concordance of CBC and DNAm estimation methods. These results suggest that the agreement between CBC and DNAm estimators of immune cell proportions is robust to exposure to child maltreatment and acute psychosocial stress.

BackgroundNew insights into mechanisms linking obesity to poor health outcomes suggest a role for cellular aging pathways, casting obesity as a disease of accelerated biological aging. Although obesity has been linked to accelerated epigenetic aging in middle-aged adults, the impact during childhood remains unclear. We tested the association between body mass index (BMI) and accelerated epigenetic aging in a cohort of high-risk children. Participants were children (N=273, aged 8 to 14 years, 82% investigated for maltreatment) recruited to the Child Health Study, an ongoing prospective study of youth investigated for maltreatment and a comparison youth. BMI was measured as a continuous variable. Accelerated epigenetic aging of blood leukocytes was defined as the age-adjusted residuals of several established epigenetic aging clocks (Horvath, Hannum, GrimAge, PhenoAge) along with a newer algorithm, the DunedinPoAm, developed to quantify the pace-of-aging. Hypotheses were tested with generalized linear models.ResultsHigher BMI was significantly correlated with older chronological age, maltreatment status, household income, blood cell counts, and three of the accelerated epigenetic aging measures: GrimAge (r=0.29, P0001), PhenoAge (r=0.25, P0001), and DunedinPoAm (r=0.37, P0001). In fully adjusted models, GrimAge (b=.06; P=.007) and DunedinPoAm (b=.0017; P0001) remained significantly associated with higher BMI. Maltreatment-status was not independently associated with accelerated epigenetic aging after accounting for other factors.ConclusionIn a high-risk cohort of children, higher BMI predicted epigenetic aging as assessed by two epigenetic aging clocks. These results suggest the association between obesity and accelerated epigenetic aging begins in early life, with implications for future morbidity and mortality risk.

The role of short telomeres as the trigger for genomic instability and changes in cellular phenotype is well documented; however, aging and disease-related cellular changes may be driven by changes in the structure of telomeres, as influenced by their length, prior to reaching a critically short length. This is pertinent to the relationships among telomere length, psychological stress, and age-related diseases as telomere dynamics over the life span can be influenced by psychological stress. Through epigenetics, inflammation, and oxidative stress brought on by psychological stress, telomeres progressively shorten and change expression of genes. There is evidence that telomeres function as regulators of gene expression via multiple mechanisms, including changes in the telomere position effect (TPE), levels of telomeric repeat-containing RNA (TERRA), and the association of shelterin. Thus psychological stress-induced progressive telomere shortening may generate consequences for the cell that have large implications for the field of stress biology.

Background Exposure to maltreatment in childhood can lead to increased risk for poor health outcomes in adulthood. Child maltreatment and later poor health may be linked by premature biological aging. We tested whether childhood sexual abuse (CSA) was associated with telomere length (TL) in adult females. We further tested the hypothesis of intergenerational transmission of CSA-related effects by measuring TL in both CSA-exposed and non-exposed mothers and their children. Methods Participants were a subset of females and their children in a prospective-longitudinal cohort study of sexually abused females and a demographically comparable control group from the same Washington, D.C. area. TL was measured using qPCR in both leukocyte and buccal samples from females (N = 108, mean age 36.3 years) and buccal samples from their children (N = 124, mean age 10.5 years). Multilevel models were used to test associations between CSA-exposure and TL measured in leukocytes and buccal tissue in females and to test the intergenerational effect of maternal-CSA exposure on age-adjusted TL in their children. Results CSA-exposure was not associated with TL in adult females. Maternal TL and biological sex were significant predictors of child TL such that longer maternal TL predicted longer TL in children, and female children had longer TL than male children. However, maternal-CSA exposure did not predict TL in children. Discussion CSA-exposure was not associated with TL in this cohort of middle-aged females, nor was there evidence for an intergenerational effect of maternal-CSA exposure on child TL. This finding is in line with some previous results on CSA and adult TL. Previous significant results associating child maltreatment with shorter TL may be capturing a population of individuals exposed to either multiple types of maltreatment compared to controls with no childhood adversity, or maltreatment in childhood with concurrent TL measurements.

ObjectiveExposure to early-life adversity (ELA) can result in long-term changes to physiological systems, which predispose individuals to negative health outcomes. This biological embedding of stress-responsive systems may operate via dysregulation of physiological resources in response to common stressors. The present pilot study outlines a novel experimental design to test how young adults' exposure to ELA influences neuroendocrine and inflammatory responses to acute stress.Materials and methodsParticipants were 12 males (mean age = 21.25), half of whom endorsed at least three significant adverse events up to age 18 years ('ELA group'), and half who confirmed zero ('controls'). Using a randomized within-subjects, between-groups experimental design, we induced acute psychosocial stress (Trier Social Stress Test, TSST), and included a no-stress control condition one week apart. During these sessions, we obtained repeated measurements of physiological reactivity, gene expression of the glucocorticoid receptor (NR3C1), and plasma levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-8 and TNFα) over a 4-hour window post-test.ResultsIn this pilot study, the ELA group evinced higher cortisol response and blunted NR3C1 gene expression in response to the TSST compared with controls, while no differences were observed in the no-stress condition. For pro-inflammatory cytokines, only IL-6 increased significantly in response to the TSST, with no differences between the two groups.ConclusionOverall, this pilot feasibility study provides a framework to investigate the biological embedding of early-adversity via dysregulation across physiological and genomic systems in response to acute psychosocial stress. ELA may program such systems in a maladaptive manner more likely to manifest during times of duress, predisposing individuals to the negative health consequences of everyday stressors. Future studies with larger sample size including both males and females are needed to replicate and expand upon these preliminary findings.

ObjectiveExposure to early-life adversity (ELA) can result in long-term changes to physiological systems, which predispose individuals to negative health outcomes. This biological embedding of stress-responsive systems may operate via dysregulation of physiological resources in response to common stressors. The present study used a novel experimental design to test how young adults’ exposure to ELA influence neuroendocrine and inflammatory responses to acute stress.Materials and methodsParticipants were 12 males (mean age= 21.25), half of whom endorsed at least three significant adverse events up to age 18 years (‘ELA group’), and half who confirmed zero (‘controls’). Using a randomized within-subjects, between-groups experimental design, we induced acute psychosocial stress (Trier Social Stress Test, TSST), and included a no-stress control condition one week apart. During these sessions, we obtained repeated measurements of physiological reactivity, gene expression of NR3C1, FKBP5 and NFKB1, and plasma levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-8 and TNFα) over a 4-hour window post-test.ResultsThe ELA group evinced significantly higher cortisol response and lower NR3C1 gene expression in response to the TSST compared with controls, while no differences were observed in the no-stress condition. Cortisol and group status interacted such that increase in cortisol predicted increase in both NR3C1 and NFKB1 expression among controls, but decrease in the ELA group. For pro-inflammatory cytokines, only IL-6 increased significantly in response to the TSST, with no differences between the two groups.ConclusionOverall, we provide preliminary findings for the biological embedding of stress via a dynamic and dysregulated pattern evidenced in response to acute psychosocial stress. ELA may program physiological systems in a maladaptive manner more likely to manifest during times of duress, predisposing individuals to the negative health consequences of everyday stressors. Future studies with larger sample size including both males and females are needed to replicate these findings.

Exposure to maltreatment during childhood can lead to increased risk for poor health outcomes in adulthood. Child maltreatment and later poor health may be linked by premature biological aging. We tested whether childhood sexual abuse (CSA) is associated with telomere length (TL) in adult females. We further tested the hypothesis of intergenerational transmission of trauma by measuring TL in both CSA-exposed and non-exposed mothers and their children. TL was measured in a subset of participants and their children from a prospective-longitudinal cohort study of sexually abused females and a demographically matched comparison group. Linear regression models were used to test for associations between CSA-exposure and age-adjusted TL in females (N=108, mean age 36.3 years). Multilevel linear models were used to test the intergenerational effect of maternal-CSA exposure on age-adjusted TL in their children (N=124 children mean age 10.5 years across 61 mothers). CSA-exposure was not associated with TL in females. Replicating previous work in this area, maternal TL and sex were significant predictors of child TL in all models tested. Longer maternal TL predicted longer TL in children, and female children had longer TL than male children. Maternal-CSA exposure did not predict TL in children. This finding is in line with some previous results on CSA and TL measured in adulthood. Previous significant results associating child maltreatment with shorter TL in adulthood may be capturing a population of individuals exposed to either multiple types of maltreatment or maltreatment in childhood with concurrent TL measurements.