Posttraumatic stress disorder, trauma, and accelerated biological aging among post-9/11 veterans.

People who experience trauma and develop posttraumatic stress disorder (PTSD) are at increased risk for poor health. One mechanism that could explain this risk is accelerated biological aging, which is associated with the accumulation of chronic diseases, disability, and premature mortality. Using data from 2309 post-9/11 United States military veterans who participated in the VISN 6 MIRECC's Post-Deployment Mental Health Study, we tested whether PTSD and trauma exposure were associated with accelerated rate of biological aging, assessed using a validated DNA methylation (DNAm) measure of epigenetic aging-DunedinPACE. Veterans with current PTSD were aging faster than those who did not have current PTSD, ß = 0.18, 95% CI [0.11, 0.27], p < .001. This effect represented an additional 0.4 months of biological aging each year. Veterans were also aging faster if they reported more PTSD symptoms, ß = 0.13, 95% CI [0.09, 0.16], p < 0.001, or higher levels of trauma exposure, ß = 0.09, 95% CI [0.05, 0.13], p < 0.001. Notably, veterans with past PTSD were aging more slowly than those with current PTSD, ß = -0.21, 95% CI [-0.35, -0.07], p = .003. All reported results accounted for age, gender, self-reported race/ethnicity, and education, and remained when controlling for smoking. Our findings suggest that an accelerated rate of biological aging could help explain how PTSD contributes to poor health and highlights the potential benefits of providing efficacious treatment to populations at increased risk of trauma and PTSD.

Social isolation, loneliness, and inflammation: A multi-cohort investigation in early and mid-adulthood.

Social isolation and loneliness have been associated with poor health and increased risk for mortality, and inflammation might explain this link. We used data from the Danish TRIAGE Study of acutely admitted medical patients (N = 6,144, mean age 60 years), and from two population-representative birth cohorts: the New Zealand Dunedin Longitudinal Study (N = 881, age 45) and the UK Environmental Risk (E-Risk) Longitudinal Twin Study (N = 1448, age 18), to investigate associations of social isolation with three markers of systemic inflammation: C-reactive protein (CRP), interleukin-6 (IL-6), and a newer inflammation marker, soluble urokinase plasminogen activator receptor (suPAR), which is thought to index systemic chronic inflammation. In the TRIAGE Study, socially isolated patients (those living alone) had significantly higher median levels of suPAR (but not CRP or IL-6) compared with patients not living by themselves. Social isolation prospectively measured in childhood was longitudinally associated with higher CRP, IL-6, and suPAR levels in adulthood (at age 45 in the Dunedin Study and age 18 in the E-Risk Study), but only suPAR remained associated after controlling for covariates. Dunedin Study participants who reported loneliness at age 38 or age 45 had elevated suPAR at age 45. In contrast, E-Risk Study participants reporting loneliness at age 18 did not show any elevated markers of inflammation. In conclusion, social isolation was robustly associated with increased inflammation in adulthood, both in medical patients and in the general population. It was associated in particular with systemic chronic inflammation, evident from the consistently stronger associations with suPAR than other inflammation biomarkers.

Accelerated Pace of Aging in Schizophrenia: Five Case-Control Studies.

BACKGROUND: Schizophrenia is associated with increased risk of developing multiple aging-related diseases, including metabolic, respiratory, and cardiovascular diseases, and Alzheimer's and related dementias, leading to the hypothesis that schizophrenia is accompanied by accelerated biological aging. This has been difficult to test because there is no widely accepted measure of biological aging. Epigenetic clocks are promising algorithms that are used to calculate biological age on the basis of information from combined cytosine-phosphate-guanine sites (CpGs) across the genome, but they have yielded inconsistent and often negative results about the association between schizophrenia and accelerated aging. Here, we tested the schizophrenia-aging hypothesis using a DNA methylation measure that is uniquely designed to predict an individual's rate of aging. METHODS: We brought together 5 case-control datasets to calculate DunedinPACE (Pace of Aging Calculated from the Epigenome), a new measure trained on longitudinal data to detect differences between people in their pace of aging over time. Data were available from 1812 psychosis cases (schizophrenia or first-episode psychosis) and 1753 controls. Mean chronological age was 38.9 (SD = 13.6) years. RESULTS: We observed consistent associations across datasets between schizophrenia and accelerated aging as measured by DunedinPACE. These associations were not attributable to tobacco smoking or clozapine medication. CONCLUSIONS: Schizophrenia is accompanied by accelerated biological aging by midlife. This may explain the wide-ranging risk among people with schizophrenia for developing multiple different age-related physical diseases, including metabolic, respiratory, and cardiovascular diseases, and dementia. Measures of biological aging could prove valuable for assessing patients' risk for physical and cognitive decline and for evaluating intervention effectiveness.

Genetic associations with parental investment from conception to wealth inheritance in six cohorts.

Genetic inheritance is not the only way parents' genes may affect children. It is also possible that parents' genes are associated with investments into children's development. We examined evidence for links between parental genetics and parental investments, from the prenatal period through to adulthood, using data from six population-based cohorts in the UK, US and New Zealand, together totalling 36,566 parents. Our findings revealed associations between parental genetics-summarized in a genome-wide polygenic score-and parental behaviour across development, from smoking in pregnancy, breastfeeding in infancy, parenting in childhood and adolescence, to leaving a wealth inheritance to adult children. Effect sizes tended to be small at any given time point, ranging from RR = 1.12 (95% confidence interval (95%CI) 1.09, 1.15) to RR = 0.76 (95%CI 0.72, 0.80) during the prenatal period and infancy; ß = 0.07 (95%CI 0.04, 0.11) to ß = 0.29 (95%CI 0.27, 0.32) in childhood and adolescence, and RR = 1.04 (95%CI 1.01, 1.06) to RR = 1.11 (95%CI 1.07, 1.15) in adulthood. There was evidence for accumulating effects across development, ranging from ß = 0.15 (95%CI 0.11, 0.18) to ß = 0.23 (95%CI 0.16, 0.29) depending on cohort. Our findings are consistent with the interpretation that parents pass on advantages to offspring not only via direct genetic transmission or purely environmental paths, but also via genetic associations with parental investment from conception to wealth inheritance.

Cross-National and Cross-Generational Evidence That Educational Attainment May Slow the Pace of Aging in European-Descent Individuals.

OBJECTIVES: Individuals with more education are at lower risk of developing multiple, different age-related diseases than their less-educated peers. A reason for this might be that individuals with more education age slower. There are 2 complications in testing this hypothesis. First, there exists no definitive measure of biological aging. Second, shared genetic factors contribute toward both lower educational attainment and the development of age-related diseases. Here, we tested whether the protective effect of educational attainment was associated with the pace of aging after accounting for genetic factors. METHODS: We examined data from 5 studies together totaling almost 17,000 individuals with European ancestry born in different countries during different historical periods, ranging in age from 16 to 98 years old. To assess the pace of aging, we used DunedinPACE, a DNA methylation algorithm that reflects an individual's rate of aging and predicts age-related decline and Alzheimer's disease and related disorders. To assess genetic factors related to education, we created a polygenic score based on the results of a genome-wide association study of educational attainment. RESULTS: Across the 5 studies, and across the life span, higher educational attainment was associated with a slower pace of aging even after accounting for genetic factors (meta-analysis effect size = -0.20; 95% confidence interval [CI]: -0.30 to -0.10; p = .006). Further, this effect persisted after taking into account tobacco smoking (meta-analysis effect size = -0.13; 95% CI: -0.21 to -0.05; p = .01). DISCUSSION: These results indicate that higher levels of education have positive effects on the pace of aging, and that the benefits can be realized irrespective of individuals' genetics.

Which Types of Stress Are Associated With Accelerated Biological Aging? Comparing Perceived Stress, Stressful Life Events, Childhood Adversity, and Posttraumatic Stress Disorder.

OBJECTIVE: Stress and stressful events are associated with poorer health; however, there are multiple ways to conceptualize and measure stress and stress responses. One physiological mechanism through which stress could result in poorer health is accelerated biological aging. This study tested which types of stress were associated with accelerated biological aging in adulthood. METHODS: Studying 955 participants from the Dunedin Longitudinal Study, we tested whether four types of stress assessed from ages 32 to 45 years-perceived stress, number of stressful life events, adverse childhood experiences, and posttraumatic stress disorder-were associated with accelerated biological aging. RESULTS: Higher levels of all four measures of stress were significantly associated with accelerated aging in separate models. In a combined model, more perceived stress and more stressful life events remained associated with faster aging, and the stress measures explained 6.9% of the variance in aging. The magnitudes of the associations between the four measures of stress and biological aging were comparable to associations for smoking and low education, two established risk factors for accelerated aging. People with high levels of perceived stress, numerous adverse childhood experiences (4+), high stressful life event counts, or posttraumatic stress disorder were aging an additional estimated 2.4 months, 1.1 additional months, 1.4 months, and 1.4 months per year, respectively. CONCLUSIONS: Assessing stress, particularly perceived stress, could help identify people at risk of accelerated aging. Intervening to treat stress or the health-relevant sequelae of stress could potentially slow the rate at which people are aging, improving their health as they age.

Kidney-Function Trajectories From Young Adulthood to Midlife: Identifying Risk Strata and Opportunities for Intervention.

Introduction: Understanding normative patterns of change in kidney function over the life course may allow targeting of early interventions to slow or prevent the onset of kidney disease, but knowledge about kidney functional change before middle age is limited. This study used prospective longitudinal data from a representative birth cohort to examine common patterns of change from young to midadulthood and to identify risk factors and outcomes associated with poorer trajectories. Methods: We used group-based trajectory modeling in the Dunedin study birth cohort (n = 857) to identify the following: (i) common kidney function trajectories between the ages 32 and 45 years, (ii) early-life factors associated with those trajectories, (iii) modifiable physical and psychosocial factors across adulthood associated with differences in trajectory slope, and (iv) links between trajectories and kidney-related outcomes at age 45 years. Results: Three trajectory groups were identified and could be differentiated by age 32 years as follows: normal (58% of participants), low-normal (36%), and high-risk (6%) groups. Those from low socioeconomic backgrounds had higher odds of following a high-risk (vs. normal) trajectory. Modifiable factors (blood pressure, body mass index, inflammation, glycated hemoglobin, smoking, and socioeconomic status) across adulthood were associated with steeper age-related declines in kidney function, particularly among those in the low-normal and high-risk groups. Those in the low-normal and high-risk groups also had more adverse kidney-related outcomes at age 45 years. Conclusion: The current findings could be used to inform the development of early interventions and point to socioeconomic conditions across the life course and health-related risk factors and behaviors in adulthood as kidney health promotion targets.

Life-Course Persistent Antisocial Behavior and Accelerated Biological Aging in a Longitudinal Birth Cohort.

Prior research shows that individuals who have exhibited antisocial behavior are in poorer health than their same-aged peers. A major driver of poor health is aging itself, yet research has not investigated relationships between offending trajectories and biological aging. We tested the hypothesis that individuals following a life-course persistent (LCP) antisocial trajectory show accelerated aging in midlife. Trajectories of antisocial behavior from age 7 to 26 years were studied in the Dunedin Multidisciplinary Health and Development Study, a population-representative birth cohort (N = 1037). Signs of aging were assessed at age 45 years using previously validated measures including biomarkers, clinical tests, and self-reports. First, we tested whether the association between antisocial behavior trajectories and midlife signs of faster aging represented a decline from initial childhood health. We then tested whether decline was attributable to tobacco smoking, antipsychotic medication use, debilitating illnesses in adulthood, adverse exposures in childhood (maltreatment, socioeconomic disadvantage) and adulthood (incarceration), and to childhood self-control difficulties. Study members with a history of antisocial behavior had a significantly faster pace of biological aging by midlife, and this was most evident among individuals following the LCP trajectory (ß, 0.22, 95%CI, 0.14, 0.28, p ≤ 0.001). This amounted to 4.3 extra years of biological aging between ages 25-45 years for Study members following the LCP trajectory compared to low-antisocial trajectory individuals. LCP offenders also experienced more midlife difficulties with hearing (ß, -0.14, 95%CI, -0.21, -0.08, p ≤ 0.001), balance (ß, -0.13, 95%CI, -0.18, -0.06, p ≤ 0.001), gait speed (ß, -0.18, 95%CI, -0.24, -0.10, p ≤ 0.001), and cognitive functioning (ß, -0.25, 95%CI, -0.31, -0.18, p ≤ 0.001). Associations represented a decline from childhood health. Associations persisted after controlling individually for tobacco smoking, antipsychotic medication use, midlife illnesses, maltreatment, socioeconomic status, incarceration, and childhood self-control difficulties. However, the cumulative effect of these lifestyle characteristics together explained why LCP offenders have a faster Pace of Aging than their peers. While older adults typically age-out of crime, LCP offenders will likely age-into the healthcare system earlier than their chronologically same-aged peers. Preventing young people from offending is likely to have substantial benefits for health, and people engaging in a LCP trajectory of antisocial behaviors might be the most in need of health promotion programs. We offer prevention and intervention strategies to reduce the financial burden of offenders on healthcare systems and improve their wellbeing.

Preparedness for healthy ageing and polysubstance use in long-term cannabis users: a population-representative longitudinal study.

BACKGROUND: Cannabis is often characterised as a young person's drug. However, people who began consuming cannabis in the 1970s and 1980s are no longer young and some have consumed it for many years. This study tested the preregistered hypothesis that long-term cannabis users show accelerated biological ageing in midlife and poorer health preparedness, financial preparedness, and social preparedness for old age. METHODS: In this longitudinal study, participants comprised a population-representative cohort of 1037 individuals born in Dunedin, New Zealand, between April, 1972, and March, 1973, and followed to age 45 years. Cannabis, tobacco, and alcohol use and dependence were assessed at ages 18 years, 21 years, 26 years, 32 years, 38 years, and 45 years. Biological ageing and health, financial, and social preparedness for old age were assessed at age 45 years. Long-term cannabis users were compared using independent samples t tests with five groups: lifelong cannabis non-users, long-term tobacco users, long-term alcohol users, midlife recreational cannabis users, and cannabis quitters. In addition, regression analyses tested dose-response associations for continuously measured persistence of cannabis dependence from age 18 years to 45 years, with associations adjusted for sex, childhood socioeconomic status, childhood IQ, low childhood self-control, family substance dependence history, and persistence of alcohol, tobacco, and other illicit drug dependence. FINDINGS: Of 997 cohort members still alive at age 45 years, 938 (94%) were assessed at age 45 years. Long-term cannabis users showed statistically significant accelerated biological ageing and were less equipped to manage a range of later-life health, financial, and social demands than non-users. Standardised mean differences between long-term cannabis users and non-users were large: 0·70 (95% CI 0·46 to 0·94; p<0·0001) for biological ageing, -0·72 (-0·96 to -0·49, p<0·0001) for health preparedness, -1·08 (-1·31 to -0·85; p<0·0001) for financial preparedness, and -0·59 (-0·84 to -0·34, p<0·0001) for social preparedness. Long-term cannabis users did not fare better than long-term tobacco or alcohol users. Tests of dose-response associations suggested that cannabis associations could not be explained by the socioeconomic origins, childhood IQ, childhood self-control, and family substance-dependence history of long-term cannabis users. Statistical adjustment for long-term tobacco, alcohol, and other illicit drug dependence suggested that long-term cannabis users' tendency toward polysubstance dependence accounted for their accelerated biological ageing and poor financial and health preparedness, although not for their poor social preparedness (ß -0·10, 95% CI -0·18 to -0·02; p=0·017). INTERPRETATION: Long-term cannabis users are underprepared for the demands of old age. Although long-term cannabis use appears detrimental, the greatest challenge to healthy ageing is not use of any specific substance, but rather the long-term polysubstance use that characterises many long-term cannabis users. Substance-use interventions should include practical strategies for improving health and building financial and social capital for healthy longevity. FUNDING: The National Institute on Aging and the UK Medical Research Council. The Dunedin Research Unit is supported by the New Zealand Health Research Council and the New Zealand Ministry of Business, Innovation and Employment.

Diminished Structural Brain Integrity in Long-term Cannabis Users Reflects a History of Polysubstance Use.

BACKGROUND: Cannabis legalization and use are outpacing our understanding of its long-term effects on brain and behavior, which is fundamental for effective policy and health practices. Existing studies are limited by small samples, cross-sectional measures, failure to separate long-term from recreational use, and inadequate control for other substance use. Here, we address these limitations by determining the structural brain integrity of long-term cannabis users in the Dunedin Study, a longitudinal investigation of a population-representative birth cohort followed to midlife. METHODS: We leveraged prospective measures of cannabis, alcohol, tobacco, and other illicit drug use in addition to structural neuroimaging in 875 study members at age 45 to test for differences in both global and regional gray and white matter integrity between long-term cannabis users and lifelong nonusers. We additionally tested for dose-response associations between continuous measures of cannabis use and brain structure, including careful adjustments for use of other substances. RESULTS: Long-term cannabis users had a thinner cortex, smaller subcortical gray matter volumes, and higher machine learning-predicted brain age than nonusers. However, these differences in structural brain integrity were explained by the propensity of long-term cannabis users to engage in polysubstance use, especially with alcohol and tobacco. CONCLUSIONS: These findings suggest that diminished midlife structural brain integrity in long-term cannabis users reflects a broader pattern of polysubstance use, underlining the importance of understanding comorbid substance use in efforts to curb the negative effects of cannabis on brain and behavior as well as establish more effective policy and health practices.

Long-Term Cannabis Use and Cognitive Reserves and Hippocampal Volume in Midlife.

OBJECTIVE: Cannabis use is increasing among midlife and older adults. This study tested the hypotheses that long-term cannabis use is associated with cognitive deficits and smaller hippocampal volume in midlife, which is important because midlife cognitive deficits and smaller hippocampal volume are risk factors for dementia. METHODS: Participants are members of a representative cohort of 1,037 individuals born in Dunedin, New Zealand, in 1972-1973 and followed to age 45, with 94% retention. Cannabis use and dependence were assessed at ages 18, 21, 26, 32, 38, and 45. IQ was assessed at ages 7, 9, 11, and 45. Specific neuropsychological functions and hippocampal volume were assessed at age 45. RESULTS: Long-term cannabis users showed IQ decline from childhood to midlife (mean=-5.5 IQ points), poorer learning and processing speed relative to their childhood IQ, and informant-reported memory and attention problems. These deficits were specific to long-term cannabis users because they were either not present or were smaller among long-term tobacco users, long-term alcohol users, midlife recreational cannabis users, and cannabis quitters. Cognitive deficits among long-term cannabis users could not be explained by persistent tobacco, alcohol, or other illicit drug use, childhood socioeconomic status, low childhood self-control, or family history of substance dependence. Long-term cannabis users showed smaller hippocampal volume, but smaller hippocampal volume did not statistically mediate cannabis-related cognitive deficits. CONCLUSIONS: Long-term cannabis users showed cognitive deficits and smaller hippocampal volume in midlife. Research is needed to ascertain whether long-term cannabis users show elevated rates of dementia in later life.

Association of Treatable Health Conditions During Adolescence With Accelerated Aging at Midlife.

IMPORTANCE: Biological aging is a distinct construct from health; however, people who age quickly are more likely to experience poor health. Identifying pediatric health conditions associated with accelerated aging could help develop treatment approaches to slow midlife aging and prevent poor health in later life. OBJECTIVE: To examine the association between 4 treatable health conditions in adolescence and accelerated aging at midlife. DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed data from participants in the Dunedin Study, a longitudinal investigation of health and behavior among a birth cohort born between April 1, 1972, and March 31, 1973, in Dunedin, New Zealand, and followed up until age 45 years. Participants underwent an assessment at age 45 years and had data for at least 1 adolescent health condition (asthma, smoking, obesity, and psychological disorders) and outcome measure (pace of aging, gait speed, brain age, and facial age). Data analysis was performed from February 11 to September 27, 2021. EXPOSURES: Asthma, cigarette smoking, obesity, and psychological disorders were assessed at age 11, 13, and 15 years. MAIN OUTCOMES AND MEASURES: The outcome was a midlife aging factor composite score comprising 4 measures of biological aging: pace of aging, gait speed, brain age (specifically, BrainAGE score), and facial age. RESULTS: A total of 910 participants (459 men [50.4%]) met the inclusion criteria, including an assessment at age 45 years. Participants who had smoked daily (0.61 [95% CI, 0.43-0.79] SD units), had obesity (0.82 [95% CI, 0.59-1.06] SD units), or had a psychological disorder diagnosis (0.43 [95% CI, 0.29-0.56] SD units) during adolescence were biologically older at midlife compared with participants without these conditions. Participants with asthma were not biologically older at midlife (0.02 [95% CI, -0.14 to 0.19] SD units) compared with those without asthma. These results remained unchanged after adjusting for childhood risk factors such as poor health, socioeconomic disadvantage, and adverse experiences. CONCLUSIONS AND RELEVANCE: This study found that adolescent smoking, obesity, and psychological disorder diagnoses were associated with older biological age at midlife. These health conditions could be treated during adolescence to reduce the risk of accelerated biological aging later in life.

Differential Effects of Cannabis and Tobacco on Lung Function in Mid-Adult Life.

Rationale: Evidence suggests that the effects of smoking cannabis on lung function are different from tobacco. However, long-term follow-up data are scarce and mostly based on young adults. Objectives: To assess the effects of cannabis and tobacco on lung function in mid-adult life. Methods: Cannabis and tobacco use were reported at ages 18, 21, 26, 32, 38, and 45 years in a population-based cohort study of 1,037 participants. Spirometry, plethysmography, and carbon monoxide transfer factor were measured at age 45. Associations between lung function and cannabis use were adjusted for tobacco use. Measurements and Main Results: Data were available from 881 (88%) of 997 surviving participants. Cumulative cannabis use was associated with lower FEV1/FVC ratios, owing to a tendency toward higher FVCs. Cannabis use was also associated with higher TLC, FRC, residual volume, and Va along with lower midexpiratory flows, airway conductance, and transfer factor. Quitting regular cannabis use between assessments was not associated with changes in spirometry. Conclusions: Cannabis use is associated with higher lung volumes, suggesting hyperinflation. There is evidence of increased large-airway resistance and lower midexpiratory airflow, but impairment of FEV1/FVC ratio is because of higher FVC. This pattern of effects is different to those of tobacco. We provide the first evidence that lifetime cannabis use may be associated with impairment of gas transfer.

Longitudinal associations between adolescents' individualised risk for depression and inflammation in a UK cohort study.

Inflammation is associated with poor physical and mental health including major depressive disorder (MDD). Moreover, there is evidence that childhood adversity - a risk factor for MDD - becomes biologically embedded via elevated inflammation. However, the risk of developing MDD arises from multiple sources and yet there has been little investigation of the links between individuals' constellation of MDD risk and subsequent inflammation. We therefore examined associations between individual risk for MDD calculated in early adolescence and levels of inflammation six years later. We use data from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative UK birth cohort of 2,232 children followed to age 18 with 93% retention. Participants' individual risk for developing future MDD was calculated at age 12 using a recently developed prediction model comprising multiple psychosocial factors. Plasma levels of three inflammation biomarkers were measured at age 18: C-reactive protein (CRP), interleukin-6 (IL-6), and a newer biomarker, soluble urokinase plasminogen activator receptor (suPAR), which is thought to reflect the level of systemic chronic inflammation. MDD risk scores calculated at age 12 were positively associated with levels of suPAR (but not CRP or IL-6) at age 18 after adjusting for key covariates (b = 1.70, 95% CI = 0.46 - 2.95, p = 0.007). Adolescents at high risk of MDD (risk scores ≥ 90th centile) had significantly higher mean levels of suPAR six years later than adolescents who had been identified as low risk (risk scores ≤ 10th centile) (b = 0.41, 95% CI = 0.18 - 0.64, p < 0.001). Findings support the notion that childhood psychosocial risk for MDD leads to increased levels of low-grade inflammation. If replicated in studies with repeated assessments of inflammation biomarkers throughout childhood and adolescence, these findings would support targeted interventions to reduce inflammation, as measured by suPAR, for adolescents at high risk of MDD to potentially prevent development of depression and physical health problems related to chronic inflammation.

Eleven genomic loci affect plasma levels of chronic inflammation marker soluble urokinase-type plasminogen activator receptor.

Soluble urokinase-type plasminogen activator receptor (suPAR) is a chronic inflammation marker associated with the development of a range of diseases, including cancer and cardiovascular disease. The genetics of suPAR remain unexplored but may shed light on the biology of the marker and its connection to outcomes. We report a heritability estimate of 60% for the variation in suPAR and performed a genome-wide association meta-analysis on suPAR levels measured in Iceland (N = 35,559) and in Denmark (N = 12,177). We identified 13 independently genome-wide significant sequence variants associated with suPAR across 11 distinct loci. Associated variants were found in and around genes encoding uPAR (PLAUR), its ligand uPA (PLAU), the kidney-disease-associated gene PLA2R1 as well as genes with relations to glycosylation, glycoprotein biosynthesis, and the immune response. These findings provide new insight into the causes of variation in suPAR plasma levels, which may clarify suPAR's potential role in associated diseases, as well as the underlying mechanisms that give suPAR its prognostic value as a unique marker of chronic inflammation.

Assessing the co-variability of DNA methylation across peripheral cells and tissues: Implications for the interpretation of findings in epigenetic epidemiology.

Most epigenome-wide association studies (EWAS) quantify DNA methylation (DNAm) in peripheral tissues such as whole blood to identify positions in the genome where variation is statistically associated with a trait or exposure. As whole blood comprises a mix of cell types, it is unclear whether trait-associated DNAm variation is specific to an individual cellular population. We collected three peripheral tissues (whole blood, buccal epithelial and nasal epithelial cells) from thirty individuals. Whole blood samples were subsequently processed using fluorescence-activated cell sorting (FACS) to purify five constituent cell-types (monocytes, granulocytes, CD4+ T cells, CD8+ T cells, and B cells). DNAm was profiled in all eight sample-types from each individual using the Illumina EPIC array. We identified significant differences in both the level and variability of DNAm between different sample types, and DNAm data-derived estimates of age and smoking were found to differ dramatically across sample types from the same individual. We found that for the majority of loci variation in DNAm in individual blood cell types was only weakly predictive of variance in DNAm measured in whole blood, although the proportion of variance explained was greater than that explained by either buccal or nasal epithelial samples. Covariation across sample types was much higher for DNAm sites influenced by genetic factors. Overall, we observe that DNAm variation in whole blood is additively influenced by a combination of the major blood cell types. For a subset of sites, however, variable DNAm detected in whole blood can be attributed to variation in a single blood cell type providing potential mechanistic insight about EWAS findings. Our results suggest that associations between whole blood DNAm and traits or exposures reflect differences in multiple cell types and our data will facilitate the interpretation of findings in epigenetic epidemiology.

Association of History of Psychopathology With Accelerated Aging at Midlife.

Importance: Individuals with mental disorders are at an elevated risk of developing chronic age-related physical diseases. However, it is not clear whether psychopathology is also associated with processes of accelerated aging that precede the onset of age-related disease. Objective: To test the hypothesis that a history of psychopathology is associated with indicators of accelerated aging at midlife. Design, Setting, and Participants: This prospective cohort study was based on the Dunedin Multidisciplinary Health and Development Study, a population-representative birth cohort of 1037 individuals born between April 1, 1972, and March 31, 1973, in Dunedin, New Zealand. Members were followed up to age 45 years (until April 2019). Data were analyzed from January 6 to December 7, 2020. Exposures: Mental disorders were assessed in 6 diagnostic assessments from ages 18 to 45 years and transformed through confirmatory factor analysis into continuous measures of general psychopathology (p-factor) and dimensions of internalizing, externalizing, and thought disorders (all standardized to a mean [SD] of 100 [15]). Main Outcomes and Measures: Signs of aging (biological pace of aging; declines in sensory, motor, and cognitive functioning; and facial age) were assessed up to age 45 years using previously validated measures including biomarkers, clinical tests, and self-reports. Results: Of the original 1037 cohort participants, 997 were still alive at age 45 years, of whom 938 (94%) were assessed (474 men [50.5%]). Participants who had experienced more psychopathology exhibited a faster pace of biological aging (ß, 0.27; 95% CI, 0.21-0.33; P < .01); experienced more difficulties with hearing (ß, 0.18; 95% CI, 0.12-0.24; P < .01), vision (ß, 0.08; 95% CI, 0.01-0.14; P < .05), balance (ß, 0.20; 95% CI, 0.14-0.26; P < .01), and motor functioning (ß, 0.19; 95% CI, 0.12-0.25; P < .01); experienced more cognitive difficulties (ß, 0.24; 95% CI, 0.18-0.31; P < .01); and were rated as looking older (ß, 0.20; 95% CI, 0.14-0.26; P < .01). Associations persisted after controlling for sex, childhood health indicators, maltreatment, and socioeconomic status and after taking into account being overweight, smoking, use of antipsychotic medication, and the presence of physical disease. Tests of diagnostic specificity revealed that associations were generalizable across externalizing, internalizing, and thought disorders. Conclusions and Relevance: In this cohort study, a history of psychopathology was associated with accelerated aging at midlife, years before the typical onset of age-related diseases. This link is not specific to any particular disorder family but generalizes across disorders. Prevention of psychopathology and monitoring of individuals with mental disorders for signs of accelerated aging may have the potential to reduce health inequalities and extend healthy lives.

Population vs Individual Prediction of Poor Health From Results of Adverse Childhood Experiences Screening.

Importance: Adverse childhood experiences (ACEs) are well-established risk factors for health problems in a population. However, it is not known whether screening for ACEs can accurately identify individuals who develop later health problems. Objective: To test the predictive accuracy of ACE screening for later health problems. Design, Setting, and Participants: This study comprised 2 birth cohorts: the Environmental Risk (E-Risk) Longitudinal Twin Study observed 2232 participants born during the period from 1994 to 1995 until they were aged 18 years (2012-2014); the Dunedin Multidisciplinary Health and Development Study observed 1037 participants born during the period from 1972 to 1973 until they were aged 45 years (2017-2019). Statistical analysis was performed from May 28, 2018, to July 29, 2020. Exposures: ACEs were measured prospectively in childhood through repeated interviews and observations in both cohorts. ACEs were also measured retrospectively in the Dunedin cohort through interviews at 38 years. Main Outcomes and Measures: Health outcomes were assessed at 18 years in E-Risk and at 45 years in the Dunedin cohort. Mental health problems were assessed through clinical interviews using the Diagnostic Interview Schedule. Physical health problems were assessed through interviews, anthropometric measurements, and blood collection. Results: Of 2232 E-Risk participants, 2009 (1051 girls [52%]) were included in the analysis. Of 1037 Dunedin cohort participants, 918 (460 boys [50%]) were included in the analysis. In E-Risk, children with higher ACE scores had greater risk of later health problems (any mental health problem: relative risk, 1.14 [95% CI, 1.10-1.18] per each additional ACE; any physical health problem: relative risk, 1.09 [95% CI, 1.07-1.12] per each additional ACE). ACE scores were associated with health problems independent of other information typically available to clinicians (ie, sex, socioeconomic disadvantage, and history of health problems). However, ACE scores had poor accuracy in predicting an individual's risk of later health problems (any mental health problem: area under the receiver operating characteristic curve, 0.58 [95% CI, 0.56-0.61]; any physical health problem: area under the receiver operating characteristic curve, 0.60 [95% CI, 0.58-0.63]; chance prediction: area under the receiver operating characteristic curve, 0.50). Findings were consistent in the Dunedin cohort using both prospective and retrospective ACE measures. Conclusions and Relevance: This study suggests that, although ACE scores can forecast mean group differences in health, they have poor accuracy in predicting an individual's risk of later health problems. Therefore, targeting interventions based on ACE screening is likely to be ineffective in preventing poor health outcomes.

Association Between Elevated suPAR, a New Biomarker of Inflammation, and Accelerated Aging.

BACKGROUND: To understand and measure the association between chronic inflammation, aging, and age-related diseases, broadly applicable standard biomarkers of systemic chronic inflammation are needed. We tested whether elevated blood levels of the emerging chronic inflammation marker soluble urokinase plasminogen activator receptor (suPAR) were associated with accelerated aging, lower functional capacity, and cognitive decline. METHODS: We used data from the Dunedin Study, a population-representative 1972-1973 New Zealand birth cohort (n = 1037) that has observed participants to age 45 years. Plasma suPAR levels were analyzed at ages 38 and 45 years. We performed regression analyses adjusted for sex, smoking, C-reactive protein, and current health conditions. RESULTS: Of 997 still-living participants, 875 (88%) had plasma suPAR measured at age 45. Elevated suPAR was associated with accelerated pace of biological aging across multiple organ systems, older facial appearance, and with structural signs of older brain age. Moreover, participants with higher suPAR levels had greater decline in physical function and cognitive function from childhood to adulthood compared to those with lower suPAR levels. Finally, improvements in health habits between ages 38 and 45 (smoking cessation or increased physical activity) were associated with less steep increases in suPAR levels over those years. CONCLUSIONS: Our findings provide initial support for the utility of suPAR in studying the role of chronic inflammation in accelerated aging and functional decline.

Social Distancing as a Health Behavior: County-Level Movement in the United States During the COVID-19 Pandemic Is Associated with Conventional Health Behaviors.

BACKGROUND: Social distancing-when people limit close contact with others outside their household-is a primary intervention available to combat the COVID-19 pandemic. The importance of social distancing is unlikely to change until effective treatments or vaccines become widely available. However, relatively little is known about how best to promote social distancing. Applying knowledge from social and behavioral research on conventional health behaviors (e.g., smoking, physical activity) to support public health efforts and research on social distancing is promising, but empirical evidence supporting this approach is needed. PURPOSE: We examined whether one type of social distancing behavior-reduced movement outside the home-was associated with conventional health behaviors. METHOD: We examined the association between GPS-derived movement behavior in 2,858 counties in USA from March 1 to April 7, 2020 and the prevalence of county-level indicators influenced by residents' conventional health behaviors. RESULTS: Changes in movement were associated with conventional health behaviors, and the magnitude of these associations were similar to the associations among the conventional health behaviors. Counties with healthier behaviors-particularly less obesity and greater physical activity-evidenced greater reduction in movement outside the home during the initial phases of the pandemic in the USA. CONCLUSIONS: Social distancing, in the form of reduced movement outside the home, is associated with conventional health behaviors. Existing scientific literature on health behavior and health behavior change can be more confidently used to promote social distancing behaviors during the COVID-19 pandemic.