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The development of biological markers of aging has primarily focused on adult samples. Epigenetic clocks are a promising tool for measuring biological age that show impressive accuracy across most tissues and age ranges. In adults, deviations from the DNA methylation (DNAm) age prediction are correlated with several age-related phenotypes, such as mortality and frailty. In children, however, fewer such associations have been made, possibly because DNAm changes are more dynamic in pediatric populations as compared to adults. To address this gap, we aimed to develop a highly accurate, noninvasive, biological measure of age specific to pediatric samples using buccal epithelial cell DNAm. We gathered 1,721 genome-wide DNAm profiles from 11 different cohorts of typically developing individuals aged 0 to 20 y old. Elastic net penalized regression was used to select 94 CpG sites from a training dataset (n = 1,032), with performance assessed in a separate test dataset (n = 689). DNAm at these 94 CpG sites was highly predictive of age in the test cohort (median absolute error = 0.35 y). The Pediatric-Buccal-Epigenetic (PedBE) clock was characterized in additional cohorts, showcasing the accuracy in longitudinal data, the performance in nonbuccal tissues and adult age ranges, and the association with obstetric outcomes. The PedBE tool for measuring biological age in children might help in understanding the environmental and contextual factors that shape the DNA methylome during child development, and how it, in turn, might relate to child health and disease.

Evolutionary-minded developmentalists studying predictive-adaptive-response processes linking childhood adversity with accelerated female reproductive development and health scientists investigating the developmental origins of health and disease (DOoHaD) may be tapping the same process, whereby longer-term health costs are traded off for increased probability of reproducing before dying via a process of accelerated reproductive maturation. Using data from 73 females, we test the following propositions using path analysis: (a) greater exposure to prenatal stress predicts greater maternal depression and negative parenting in infancy, (b) which predicts elevated basal cortisol at 4.5 years, (c) which predicts accelerated adrenarcheal development, (d) which predicts more physical and mental health problems at age 18. Results prove generally consistent with these propositions, including a direct link from cortisol to mental health problems. DOoHaD investigators should consider including early sexual maturation as a core component linking early adversity and stress physiology with poor health later in life in females.

Despite widespread recognition that the physiological systems underlying stress reactivity are well coordinated at a neurobiological level, surprisingly little empirical attention has been given to delineating precisely how the systems actually interact with one another when confronted with stress. We examined cross-system response proclivities in anticipation of and following standardized laboratory challenges in 664 4- to 14-year-olds from four independent studies. In each study, measures of stress reactivity within both the locus coeruleus-norepinephrine system (i.e., the sympathetic and parasympathetic branches of the autonomic nervous system) and the corticotrophin releasing hormone system (i.e., the hypothalamic-pituitary-adrenal axis) were collected. Latent profile analyses revealed six distinctive patterns that recurred across the samples: moderate reactivity (average cross-system activation; 52%-80% of children across samples), parasympathetic-specific reactivity (2%-36%), anticipatory arousal (4%-9%), multisystem reactivity (7%-14%), hypothalamic-pituitary-adrenal axis specific reactivity (6%-7%), and underarousal (0%-2%). Groups meaningfully differed in socioeconomic status, family adversity, and age. Results highlight the sample-level reliability of children's neuroendocrine responses to stress and suggest important cross-system regularities that are linked to development and prior experiences and may have implications for subsequent physical and mental morbidity.

Study objectivesTo examine the patterns of insomnia and sleep-related movement from ages 4.5 to 9 years, their concurrent associations with mental health symptoms in childhood, and the longitudinal associations of sleep-problem persistence with mental health symptoms at ages 9 and 18 years.DesignA 14-year prospective follow-up study. Assessments included maternal report on the Children's Sleep Habits Questionnaire at ages 4.5 and 9, and child mental health symptoms via maternal report at age 4.5, multi-informant (child, teacher, mother) report at age 9, and adolescent report at age 18.SettingCommunity.ParticipantsA total of 396 children (51% female).InterventionsN/A.Measurements and resultsSleep problems were more common at age 4.5 than 9; symptoms of insomnia and abnormal sleep movement both had persistence rates of 9-10%. At age 4.5, insomnia was associated with hostile-aggressive and hyperactive-distractible behavior, but there were no significant associations for sleep movement. At age 9, both insomnia and sleep movement were associated with symptoms of depression, externalizing, and attention deficit hyperactivity disorder (ADHD). Insomnia persistence was associated with symptoms of depression, externalizing, and ADHD at age 9 and anxiety and externalizing at age 18; sleep- movement persistence was associated with externalizing and ADHD at age 9, and ADHD at age 18. The age 18 persistence effects for insomnia and anxiety and for sleep movement and ADHD were significant when controlling for earlier mental health.ConclusionsChildhood insomnia and sleep movement are common and associated with mental health symptoms. Their persistence from middle to late childhood predicts associations with specific types of mental health symptoms at age 18.

Fifteen-year-old adolescents (N = 109) in a longitudinal study of child development were recruited to examine differences in DNA methylation in relation to parent reports of adversity during the adolescents' infancy and preschool periods. Microarray technology applied to 28,000 cytosine-guanine dinucleotide sites within DNA derived from buccal epithelial cells showed differential methylation among adolescents whose parents reported high levels of stress during their children's early lives. Maternal stressors in infancy and paternal stressors in the preschool years were most strongly predictive of differential methylation, and the patterning of such epigenetic marks varied by children's gender. To the authors' knowledge, this is the first report of prospective associations between adversities in early childhood and the epigenetic conformation of adolescents' genomic DNA. (Contains 5 figures and 1 table.)

Aggressive victims--children who are both perpetrators and victims of peer aggression--experience greater concurrent mental health problems and impairments than children who are only aggressive or only victimized. The stability of early identified aggressive victim status has not been evaluated due to the fact that most studies of aggressor/victim subgroups have focused on preadolescents and/or adolescents. Further, whether children who exhibit early and persistent patterns of aggression and victimization continue to experience greater mental health problems and functional impairments through the transition to adolescence is not known. This study followed 344 children (180 girls) previously identified as socially adjusted, victims, aggressors, or aggressive victims at Grade 1 (Burk et al. "2008") to investigate their involvement in peer bullying through Grade 5. The children, their mothers, and teachers reported on children's involvement in peer aggression and victimization at Grades 1, 3, and 5; and reported on internalizing symptoms, externalizing symptoms, inattention and impulsivity, as well as academic functioning, physical health, and service use at Grades 5, 7, and 9. Most children categorized as aggressive victims in Grade 1 continued to be significantly involved in peer bullying across elementary school. Children with recurrent aggressive victim status exhibited higher levels of some mental health problems and greater school impairments across the adolescent transition when compared to other longitudinal peer status groups. This study suggests screening for aggressive victim status at Grade 1 is potentially beneficial. Further early interventions may need to be carefully tailored to prevent and/or attenuate later psychological, academic, and physical health problems.

This study utilized growth mixture modeling to examine the impact of parents, child care providers, teachers, and peers on the prediction of distinct developmental patterns of classroom externalizing behavior in elementary school. Among 241 children, three groups were identified. 84.6% of children exhibited consistently low externalizing behavior. The externalizing behavior of the Chronic High group (5.8%) remained elevated throughout elementary school; it increased over time in the Low Increasing group (9.5%). Negative relationships with teachers and peers in the kindergarten classroom increased the odds of having chronically high externalizing behavior. Teacher-child conflict increased the likelihood of a developmental pattern of escalating externalizing behavior. Boys were overrepresented in the behaviorally risky groups, and no sex differences in trajectory types were found. (Contains 6 tables and 1 figure.)

We investigated whether differences in positive and negative emotional reactivity could be found in depressed preschoolers and preschoolers at risk for later internalizing symptoms relative to nondepressed/low risk comparison groups. Observational measures of emotional reactivity, used to derive a score of the balance between anger and sadness, were obtained and analyzed in independent samples. One study utilized cross-sectional data from preschoolers (M age = 4.6 years) with a current depressive syndrome and two nondepressed comparison groups. The other study utilized longitudinal data that assessed emotional reactivity at preschool age (M age = 4.5 years) and later mental health symptoms during the transition to primary school, allowing a retrospective determination of risk. Depressed and at-risk boys displayed more anger than sadness in contrast to girls in the same groups and in contrast to no disorder/low-risk controls. This finding was detected in depressed and "at risk for internalizing" boys who were not comorbid for externalizing problems. (Contains 2 tables and 2 figures.)

This prospective investigation sought to discriminate children who were both aggressive towards and victimized by peers in the first grade, from those who were only aggressive, only victimized, or neither (i.e., socially adjusted), using early child and family risk factors. Two hundred thirty-eight children, their mothers, and teachers participated in a longitudinal study since birth. All three aggressor/victim subgroups showed greater temperamental dysregulation than the socially adjusted children, but only aggressive victims had significantly poorer social perception skills. Aggressive victims were distinguished from aggressors by greater exposure to maternal depression and from victims by lower levels of early inhibition, but they shared the experiences of negative family emotional expressiveness with aggressors and greater mother-child negativity with victims. The identification of early risk factors is crucial to prevention and early intervention efforts that have the potential to attenuate the long term emotional, social, and academic problems associated with aggressive victim status.

Molecular mechanisms are explored that regulate the permeabilization of the outer and the inner membrane of mitochondria for understanding the role of mitochondria in cell death in diseases like cancer and neurodegenerative diseases. Each membrane is treated as an individual system and a set of biochemical signals considered to cause a specific mode of cell death are required for permeabilization of each membrane, which is very crucial in designing and developing therauptic agents for treating diseases caused by cell death.

A hypothesis to explain the preferential synthesis of the superoxide sensitive form of aconitase in mitochondria and the phenotype observed in manganese superoxide dismutase mutant mice, which show a gross over accumulation of stored fat in liver is discussed. The intermediary metabolism is redox regulated by mitochondrial superoxide generated during mitochondrial respiration, is proposed.

Increased superoxide anion ([O.sup.-.sub.2]*) may contribute to vascular dysfunction in aging. In aged cavernosal tissue, lucigenin-enhanced chemiluminescence demonstrated a threefold increase in superoxide formation, and the oxidative fluorescent probe hydroethidine indicated higher superoxide levels throughout the aged penis. This increase in superoxide was associated with impaired cavernosal nerve-mediated and agonist-induced erectile responses, increased nitrotyrosine staining, and lower cGMP levels, but no compensatory change in cavernosal extracellular (EC)-superoxide dismutase (EC-SOD) mRNA or protein. In vivo adenoviral (Ad) gene transfer of EC-SOD to the penis resulted in higher expression of EC-SOD mRNA, protein, SOD activity, cGMP levels, and lower nitrotyrosine staining. Transfection with AdCMVEC-SOD resulted in a significant increase in erectile response to cavernosal nerve stimulation, ACh, and zaprinast to a magnitude similar to young rats. These data provide evidence in support of the hypothesis that erectile dysfunction associated with aging is related in part to an increase in cavernosal [O.sup.-.sub.2]* formation. Gene-transfer of EC-SOD reduces superoxide formation and restores age-associated erectile function and may represent a novel therapeutic target for the treatment of erectile dysfunction. gene therapy; aging; nitric oxide; erectile dysfunction