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Antiaging therapies show promise in model organism research. Translation to humans is needed to address the challenges of an aging global population. Interventions to slow human aging will need to be applied to still-young individuals. However, most human aging research examines older adults, many with chronic disease. As a result, little is known about aging in young humans. We studied aging in 954 young humans, the Dunedin Study birth cohort, tracking multiple biomarkers across three time points spanning their third and fourth decades of life. We developed and validated two methods by which aging can be measured in young adults, one cross-sectional and one longitudinal. Our longitudinal measure allows quantification of the pace of coordinated physiological deterioration across multiple organ systems (e.g., pulmonary, periodontal, cardiovascular, renal, hepatic, and immune function). We applied these methods to assess biological aging in young humans who had not yet developed age-related diseases. Young individuals of the same chronological age varied in their \"biological aging\" (declining integrity of multiple organ systems). Already, before midlife, individuals who were aging more rapidly were less physically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biological aging in young adults can be used to identify causes of aging and evaluate rejuvenation therapies.

Educational success is associated with greater quality of life and depends, in part, on heritable cognitive and non-cognitive traits. We used polygenic scores (PGS) for smoking and educational attainment to examine different genetic influences on facets of academic adjustment in adolescence and educational attainment in adulthood. PGSs were calculated for participants of the Minnesota Twin Family Study ( N = 3225) and included as predictors of grades, academic motivation, and discipline problems at ages 11, 14, and 17 years-old, cigarettes per day from ages 14 to 24 years old, and educational attainment in adulthood (mean age 29.4 years). Smoking and educational attainment PGSs had significant incremental associations with each academic variable and cigarettes per day. About half of the adjusted effects of the smoking and education PGSs on educational attainment in adulthood were mediated by the academic variables in adolescence. Cigarettes per day from ages 14 to 24 years old did not account for the effect of the smoking PGS on educational attainment, suggesting the smoking PGS indexes genetic influences related to general behavioral disinhibition. In sum, distinct genetic influences measured by the smoking and educational attainment PGSs contribute to academic adjustment in adolescence and educational attainment in adulthood.

Childhood maltreatment is associated with increased risk for most forms of psychopathology. We examine emotion dysregulation as a transdiagnostic mechanism linking maltreatment with general psychopathology. A sample of 262 children and adolescents participated; 162 (61.8%) experienced abuse or exposure to domestic violence. We assessed four emotion regulation processes (cognitive reappraisal, attention bias to threat, expressive suppression, and rumination) and emotional reactivity. Psychopathology symptoms were assessed concurrently and at a 2-year longitudinal follow-up. A general psychopathology factor (p factor), representing co-occurrence of psychopathology symptoms across multiple internalizing and externalizing domains, was estimated using confirmatory factor analysis. Maltreatment was associated with heightened emotional reactivity and greater use of expressive suppression and rumination. The association of maltreatment with attention bias varied across development, with maltreated children exhibiting a bias toward threat and adolescents a bias away from threat. Greater emotional reactivity and engagement in rumination mediated the longitudinal association between maltreatment and increased general psychopathology over time. Emotion dysregulation following childhood maltreatment occurs at multiple stages of the emotion generation process, in some cases varies across development, and serves as a transdiagnostic mechanism linking child maltreatment with general psychopathology.

Military services provide a unique opportunity for studying resilience, a dynamic process of successful adaptation (ie, doing well in terms of functioning and symptoms) in response to significant adversity. Despite the tremendous interest in positive adaptation among military service members, little is known about the processes underlying their resilience. Understanding the neurobiological, cognitive, and social mechanisms underlying adaptive functioning following military stressor exposure is essential for enhancing the resilience of military service members. The primary objective of the Advancing Research on Mechanisms of Resilience (ARMOR) longitudinal study is to characterize the trajectories of positive adaptation among young military recruits in response to basic combat training (BCT), a well-defined, uniform, and 10-week period of intense stress (aim 1), and identify promotive and protective processes contributing to individual variations in resilience (aim 2). The secondary objective is to investigate the pathways by which neurobehavioral markers of self-regulation assessed using electroencephalography and magnetic resonance imaging contribute to adaptive trajectories (aim 3). ARMOR is an ongoing, prospective longitudinal cohort study of young military recruits who recently joined the National Guard but have not yet shipped out for BCT. Participants (N=1201) are assessed at 5 time points over the initial >2 years of military service beginning before BCT (baseline) and followed up at 2 weeks and 6, 12, and 18 months after BCT. Participants complete web-based questionnaires assessing vulnerability and protective factors, mental health, and socioemotional functioning at each time point and a battery of neurocognitive tests at time 0. A subset of participants also complete structured diagnostic interviews and additional self-report measures and perform neurobehavioral tasks before and after BCT during electroencephalography sessions and before BCT only during magnetic resonance imaging sessions. This UG3/UH3 project was initially funded in August 2017, with the UG3 pilot work completed at the end of 2018. The UH3 phase of the project was funded in March 2019. Study enrollment for the UH3 phase began on April 14, 2019, and ended on October 16, 2021. A total of 1201 participants are enrolled in the study. Follow-up data collection for the UH3 phase is ongoing and projected to continue through February 2024. We will disseminate the findings through conferences, webinars, open access publications, and communications with participants and stakeholders. The ARMOR study provides a rich data set to identify the predictors and mechanisms of resilient and nonresilient outcomes in the context of military stressors, which are intended to empirically inform the development of prevention and intervention strategies to enhance the resilience of military trainees and potentially other young people facing significant life challenges. DERR1-10.2196/51235.

Observational studies have linked cannabis use to an array of negative outcomes, including psychiatric symptoms, cognitive impairment, and educational and occupational underachievement. These associations are particularly strong when cannabis use occurs in adolescence. Nevertheless, causality remains unclear. The purpose of the present study was thus to examine associations between prospectively assessed adolescent cannabis use and young-adult outcomes (psychiatric, cognitive, and socioeconomic) in three longitudinal studies of twins (n = 3,762). Twins reporting greater cumulative cannabis use in adolescence reported higher levels of psychopathology as well as poorer socioeconomic outcomes in young adulthood. However, cannabis use remained associated only with socioeconomic outcomes (i.e., educational attainment, occupational status, and income) in monozygotic-cotwin control analyses, which account fully for shared genetic and environmental confounding. Follow-up analyses examining associations between twin differences in adolescent cannabis use and longitudinal change in academic functioning during the middle- and high-school years provided a possible mechanism for these associations, indicating that greater cannabis use during this period was associated with decreases in grade point average and academic motivation as well as increases in academic problem behavior and school disciplinary problems. Our findings thus suggest that cannabis use in adolescence has potentially causal, deleterious effects on adolescent academic functioning and young-adult socioeconomic outcomes despite little evidence suggesting a strong, causal influence on adult mental health or cognitive ability.

Recent well-powered genome-wide association studies have enhanced prediction of substance use outcomes via polygenic scores (PGSs). Here, we test (1) whether these scores contribute to prediction over-and-above family history, (2) the extent to which PGS prediction reflects inherited genetic variation demography (population stratification and assortative mating) and indirect genetic effects of parents (genetic nurture), and (3) whether PGS prediction is mediated by behavioral disinhibition prior to substance use onset. PGSs for alcohol, cannabis, and nicotine use/use disorder were calculated for Minnesota Twin Family Study participants ( = 2483, 1565 monozygotic/918 dizygotic). Twins' parents were assessed for histories of substance use disorder. Twins were assessed for behavioral disinhibition at age 11 and substance use from ages 14 to 24. PGS prediction of substance use was examined using linear mixed-effects, within-twin pair, and structural equation models. Nearly all PGS measures were associated with multiple types of substance use independently of family history. However, most within-pair PGS prediction estimates were substantially smaller than the corresponding between-pair estimates, suggesting that prediction is driven in part by demography and indirect genetic effects of parents. Path analyses indicated the effects of both PGSs and family history on substance use were mediated via disinhibition in preadolescence. PGSs capturing risk of substance use and use disorder can be combined with family history measures to augment prediction of substance use outcomes. Results highlight indirect sources of genetic associations and preadolescent elevations in behavioral disinhibition as two routes through which these scores may relate to substance use.

Antiaging therapies show promise in model organism research. Translation to humans is needed to address the challenges of an aging global population. Interventions to slow human aging will need to be applied to still-young individuals. However, most human aging research examines older adults, many with chronic disease. As a result, little is known about aging in young humans. We studied aging in 954 young humans, the Dunedin Study birth cohort, tracking multiple biomarkers across three time points spanning their third and fourth decades of life. We developed and validated two methods by which aging can be measured in young adults, one cross-sectional and one longitudinal. Our longitudinal measure allows quantification of the pace of coordinated physiological deterioration across multiple organ systems (e.g., pulmonary, periodontal, cardiovascular, renal, hepatic, and immune function). We applied these methods to assess biological aging in young humans who had not yet developed age-related diseases. Young individuals of the same chronological age varied in their “biological aging” (declining integrity of multiple organ systems). Already, before midlife, individuals who were aging more rapidly were less physically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biological aging in young adults can be used to identify causes of aging and evaluate rejuvenation therapies. The global population is aging, driving up age-related disease morbidity. Antiaging interventions are needed to reduce the burden of disease and protect population productivity. Young people are the most attractive targets for therapies to extend healthspan (because it is still possible to prevent disease in the young). However, there is skepticism about whether aging processes can be detected in young adults who do not yet have chronic diseases. Our findings indicate that aging processes can be quantified in people still young enough for prevention of age-related disease, opening a new door for antiaging therapies. The science of healthspan extension may be focused on the wrong end of the lifespan; rather than only studying old humans, geroscience should also study the young.

Air pollution exposure damages the brain, but its associations with the development of psychopathology are not fully characterized. To assess whether air pollution exposure in childhood and adolescence is associated with greater psychopathology at 18 years of age. The Environmental-Risk Longitudinal Twin Study is a population-based cohort study of 2232 children born from January 1, 1994, to December 4, 1995, across England and Wales and followed up to 18 years of age. Pollution data generation was completed on April 22, 2020; data were analyzed from April 27 to July 31, 2020. High-resolution annualized estimates of outdoor nitrogen oxides (NOx) and particulate matter with aerodynamic diameter less than 2.5 μm (PM2.5) linked to home addresses at the ages of 10 and 18 years and then averaged. Mental health disorder symptoms assessed through structured interview at 18 years of age and transformed through confirmatory factor analysis into continuous measures of general psychopathology (primary outcome) and internalizing, externalizing, and thought disorder symptoms (secondary outcomes) standardized to a mean (SD) of 100 (15). Hypotheses were formulated after data collection, and analyses were preregistered. A total of 2039 participants (1070 [52.5%] female) had full data available. After adjustment for family and individual factors, each interquartile range increment increase in NOx exposure was associated with a 1.40-point increase (95% CI, 0.41-2.38; P = .005) in general psychopathology. There was no association between continuously measured PM2.5 and general psychopathology (b = 0.45; 95% CI, -0.26 to 1.11; P = .22); however, those in the highest quartile of PM2.5 exposure scored 2.04 points higher (95% CI, 0.36-3.72; P = .02) than those in the bottom 3 quartiles. Copollutant models, including both NOx and PM2.5, implicated NOx alone in these significant findings. NOx exposure was associated with all secondary outcomes, although associations were weakest for internalizing (adjusted b = 1.07; 95% CI, 0.10-2.04; P = .03), medium for externalizing (adjusted b = 1.42; 95% CI, 0.53-2.31; P = .002), and strongest for thought disorder symptoms (adjusted b = 1.54; 95% CI, 0.50-2.57; P = .004). Despite NOx concentrations being highest in neighborhoods with worse physical, social, and economic conditions, adjusting estimates for neighborhood characteristics did not change the results. Youths exposed to higher levels of outdoor NOx experienced greater psychopathology at the transition to adulthood. Air pollution may be a nonspecific risk factor for the development of psychopathology.

What’s known? Reports of youth mental health from different informants (youth, caregivers, teachers) often show discrepancies. However, less is known about their systematic relationship with symptom types, reporter characteristics, and social contexts. What’s new? Youth self‐reports were typically higher than adults, a discrepancy that widens as they age, especially for inattention. These gaps are systematically associated with youth characteristics (e.g., being female), caregiver factors (e.g., depression), and social environments (e.g., family conflict). What’s relevant? Whom you ask about a youth's mental health profoundly matters. Reporter perspectives are not interchangeable. This choice can significantly impact research findings and is critical for the accurate and early detection of emerging mental health problems.

Exposure to psychosocial stress is a robust predictor of subsequent psychopathology. However, only a portion of individuals with these experiences will develop psychiatric symptoms. The concept of gene-environment interaction (GxE) has provided one theoretical framework for reconciling these observations, but the empirical findings from this literature are mixed and often fail to replicate across studies. This dissertation explores the use of a relatively new approach to measuring the mental-health effects of environmental stress (the “p-factor”), and examines whether this approach has the potential to advance and consolidate studies of gene-environment interaction and psychopathology. First, I present lifetime prevalence data from The Dunedin Multidisciplinary Health and Development Study indicating that mental disorder is near-ubiquitous, consistent with the notion that liability to these conditions is distributed quantitatively throughout the population. Second, I present analyses from the Environmental Risk Longitudinal Twin Study showing that the mental-health effects of victimization exposure (one of the most common and severe types of psychosocial stress) are both non-specific and likely causal. These data suggest that stressful life experiences increase risk of psychopathology largely through effects on general liability. Third, I examine whether victimization’s effects on general psychopathology vary as a function of multiple measures of genetic propensity. Results consistently indicate that they do not, suggesting minimal gene-environment interaction. Implications for future research that seeks to identify the genetic and non-genetic factors that determine vulnerability and resilience to the mental-health effects of environmental stress are discussed.