New Directions in Geroscience: Integrating Social and Behavioral Drivers of Biological Aging.

ABSTRACT: The "geroscience hypothesis" posits that slowing the physiological processes of aging would lead to delayed disease onset and longer healthspan and lifespan. This shift from a focus on solely treating existing disease to slowing the aging process is a shift toward prevention, including a focus on risk factors found in the social environment. Although geroscience traditionally has focused on the molecular and cellular drivers of biological aging, more fundamental causes of aging may be found in the social exposome-the complex array of human social environmental exposures that shape health and disease. The social exposome may interact with physiological processes to accelerate aging biology. In this commentary, we review the potential of these insights to shape the emerging field of translational geroscience. The articles in this special issue highlight how social stress and social determinants of health are associated with biomarkers of aging such as inflammation, epigenetic clocks, and telomeres, and spotlight promising interventions to mitigate stress-related inflammation. For geroscience to incorporate the social exposome into its translational agenda, studies are needed that elucidate and quantify the effects of social exposures on aging and that consider social exposures as intervention targets. The life course perspective allows us to measure both exposures and aging biology over time including sensitive periods of development and major social transitions. In addition, given rapid changes in the measurement of aging biology, which include machine learning techniques, multisystem phenotypes of aging are being developed to better reflect whole body aging, replacing reliance on single system biomarkers. In this expanded and more integrated field of translational geroscience, strategies targeting factors in the social exposome hold promise for achieving aging health equity and extending healthy longevity.

Early life adversity predicts an accelerated cellular aging phenotype through early timing of puberty.

BACKGROUND: The current study examined if early adversity was associated with accelerated biological aging, and if effects were mediated by the timing of puberty. METHODS: In early mid-life, 187 Black and 198 White (Mage = 39.4, s.d.age = 1.2) women reported on early abuse and age at first menstruation (menarche). Women provided saliva and blood to assess epigenetic aging, telomere length, and C-reactive protein. Using structural equation modeling, we created a latent variable of biological aging using epigenetic aging, telomere length, and C-reactive protein as indicators, and a latent variable of early abuse using indicators of abuse/threat events before age 13, physical abuse, and sexual abuse. We estimated the indirect effects of early abuse and of race on accelerated aging through age at menarche. Race was used as a proxy for adversity in the form of systemic racism. RESULTS: There was an indirect effect of early adversity on accelerated aging through age at menarche (b = 0.19, 95% CI 0.03-0.44), in that women who experienced more adversity were younger at menarche, which was associated with greater accelerated aging. There was also an indirect effect of race on accelerated aging through age at menarche (b = 0.25, 95% CI 0.04-0.52), in that Black women were younger at menarche, which led to greater accelerated aging. CONCLUSIONS: Early abuse and being Black in the USA may both induce a phenotype of accelerated aging. Early adversity may begin to accelerate aging during childhood, in the form of early pubertal timing.

Intergenerational effects of maternal lifetime stressor exposure on offspring telomere length in Black and White women.

BACKGROUND: Although maternal stressor exposure has been associated with shorter telomere length (TL) in offspring, this literature is based largely on White samples. Furthermore, timing of maternal stressors has rarely been examined. Here, we examined how maternal stressors occurring during adolescence, pregnancy, and across the lifespan related to child TL in Black and White mothers. METHOD: Mothers (112 Black; 110 White; Mage = 39) and their youngest offspring (n = 222; Mage = 8) were part of a larger prospective cohort study, wherein mothers reported their stressors during adolescence (assessed twice during adolescence for the past year), pregnancy (assessed in midlife for most recent pregnancy), and across their lifespan (assessed in midlife). Mother and child provided saliva for TL measurement. Multiple linear regression models examined the interaction of maternal stressor exposure and race in relation to child TL, controlling for maternal TL and child gender and age. Race-stratified analyses were also conducted. RESULTS: Neither maternal adolescence nor lifespan stressors interacted with race in relation to child TL. In contrast, greater maternal pregnancy stressors were associated with shorter child TL, but this effect was present for children of White but not Black mothers. Moreover, this effect was significant for financial but not social pregnancy stressors. Race-stratified models revealed that greater financial pregnancy stressors predicted shorter telomeres in offspring of White, but not Black mothers. CONCLUSIONS: Race and maternal stressors interact and are related to biological aging across generations, but these effects are specific to certain races, stressors, and exposure time periods.

DNA methylation GrimAge version 2.

We previously described a DNA methylation (DNAm) based biomarker of human mortality risk DNAm GrimAge. Here we describe version 2 of GrimAge (trained on individuals aged between 40 and 92) which leverages two new DNAm based estimators of (log transformed) plasma proteins: high sensitivity C-reactive protein (logCRP) and hemoglobin A1C (logA1C). We evaluate GrimAge2 in 13,399 blood samples across nine study cohorts. After adjustment for age and sex, GrimAge2 outperforms GrimAge in predicting mortality across multiple racial/ethnic groups (meta P=3.6x10-167 versus P=2.6x10-144) and in terms of associations with age related conditions such as coronary heart disease, lung function measurement FEV1 (correlation= -0.31, P=1.1x10-136), computed tomography based measurements of fatty liver disease. We present evidence that GrimAge version 2 also applies to younger individuals and to saliva samples where it tracks markers of metabolic syndrome. DNAm logCRP is positively correlated with morbidity count (P=1.3x10-54). DNAm logA1C is highly associated with type 2 diabetes (P=5.8x10-155). DNAm PAI-1 outperforms the other age-adjusted DNAm biomarkers including GrimAge2 in correlating with triglyceride (cor=0.34, P=9.6x10-267) and visceral fat (cor=0.41, P=4.7x10-41). Overall, we demonstrate that GrimAge version 2 is an attractive epigenetic biomarker of human mortality and morbidity risk.

Association of subjective social status with epigenetic aging among Black and White women.

OBJECTIVE: Subjective social status (SSS), an individual's assessment of their own social status in relation to others, is associated with health and mortality independently of objective SES; however, no studies have tested whether SSS influences epigenetic aging. The current study examines if SSS is associated with epigenetic age acceleration in both Black and White women, independently of objective SES measured during both childhood and adulthood. METHOD: For 9- and 10-year-old Black and White girls, parental education and annual household income was obtained. At ages 39-42, 361 participants (175 Black, 186 White) reported their current education, household income, and SSS, and provided saliva to assess age acceleration using the GrimAge epigenetic clock. Linear regression estimated the association of SSS with epigenetic age acceleration, controlling for objective SES (current education, current income, parents' education, income during childhood), smoking, and counts of cell types. RESULTS: When all objective SES variables were included in the model, SSS remained significantly associated with epigenetic age acceleration, b = - 0.31, p = .003, ß = - 0.15. Black women had significantly greater age acceleration than White women, (t(359) = 5.20, p > .001, d = 0.55) but race did not moderate the association between SSS and epigenetic age acceleration. CONCLUSIONS: Women who rated themselves lower in SSS had greater epigenetic age acceleration, regardless of income and education. There was no difference by race for this association.

Effects of Early Life Adversity on Pubertal Timing and Tempo in Black and White Girls: The National Growth and Health Study.

OBJECTIVE: Although exposure to abuse in early life predicts earlier pubertal timing, especially for girls, it is unclear if this association generalizes to nonabuse stressors. In addition, the impact of race on the stress-maturation association remains unknown. To address these issues, we examined whether race moderates the effects of early adversity on pubertal timing and tempo using a longitudinal study design. METHODS: In a cohort of 9- and 10-year-old Black and White girls, pubertal (areolar and pubic hair) maturation was assessed annually for 7 years. In adulthood, 368 participants (186 Black, 182 White) reported on abuse and nonabuse stressors they experienced from ages 0 to 12 years. RESULTS: Early life abuse was associated with earlier pubertal timing, as indexed by younger age at menarche (b = -0.22, p = .005, 95% confidence interval [CI] = -0.39 to -0.06) and greater pubic hair development (b = 0.11, p = .003, 95% CI = 0.04 to 0.18), in addition to slower pubertal tempo, as indexed by slower rate of pubic hair (b = -0.03, p < .001, 95% CI = -0.05 to -0.01) and areolar (b = -0.02, p = .02, 95% CI = -0.03 to -0.003) development. These associations were not found for nonabuse adversity. Black girls with early life abuse had greater pubic hair development (b = 0.23, p < .001, 95% CI = 0.12 to 0.35) and were slower in pubic hair tempo (b = -0.07, p < .001, 95% CI = -0.09 to -0.04) than their White counterparts. CONCLUSIONS: Screening for early life abuse may help address health disparities related to earlier pubertal timing.

Childhood stress and midlife depression in women: the influence of diet quality.

OBJECTIVE: How does diet quality (DQ) moderate associations between serious childhood stress exposures and adult depression? METHODS: We analyzed a cohort of Californian women at midlife (N=382; age 36-42). Serious childhood stress was defined as high perceived stress during childhood or adverse childhood experiences (ACEs) of physical abuse, sexual abuse, and/or household substance abuse. Women were dichotomized by current depression risk (high/low). The Healthy Eating Index (HEI)-2015 and Alternate Healthy Eating Index (AHEI)-2010 measured current DQ from 3-day food records. Interactions between childhood stress exposures and DQ indices were tested one-by-one in multivariable Poisson regression models. RESULTS: Depression risks associated with endorsing all 3 ACEs differed by HEI and AHEI scores, as did risks associated with endorsing high perceived stress, physical abuse, and sexual abuse by AHEI. Where DQ moderated stress-depression associations, predicted prevalences of high depression risk did not vary with DQ among women endorsing the particular childhood stressors. However, among non-endorsing women, predicted high depression risk prevalences were significantly lower with higher DQ compared to in their stress-exposed counterparts - e.g. at the 90th AHEI percentile, depression prevalences were ∼20% among 'non-childhood-stressed' women versus 48.8% (high perceived stress, sexual abuse), 52.0% (physical abuse), and 73.0% (3 ACEs) in 'childhood-stressed' women. CONCLUSIONS: Higher current DQ, particularly as aligned with chronic disease prevention guidelines, predicts lower depression risk in women with low childhood adversity. DQ did not buffer depression risk in women with high childhood stress. Further research is warranted to examine persistent pathways of depression risk and diet's role within.

Assessing change in suicidal ideation intensity for youth in treatment for pediatric bipolar disorder.

OBJECTIVE: Suicidal ideation (SI) is significantly higher for youth with pediatric bipolar disorder (PBD), yet clinical correlates of suicidality remain poorly understood in this population. The current study investigates how change in risk factors for SI relate to change in SI intensity over a 6-month period of treatment. METHOD: Children ages 9 to 13 (N = 71; 41% female; 54% Caucasian; Mean age = 9.17) engaged in one of two psychotherapy treatment conditions and completed assessments of SI risk factors and psychopathology symptoms at baseline (pre-treatment), 4 and 8 weeks (during treatment), 12 weeks (post-treatment), and 39 weeks (follow-up assessment at 6 months post-treatment). Children also completed assessments of SI intensity at baseline, post-treatment (12 weeks), and 6 months post-treatment. RESULTS: Mixed-effects regression models indicate that increases in health-related quality of life in the family, mobilization of the family to acquire/accept help for PBD, and child self-concept were associated with decreased SI intensity over time. CONCLUSIONS: Findings highlight the importance of family and child level factors in influencing longitudinal change in SI intensity in youth with PBD. Clinical implications and future directions are discussed.

Early life adversity, pubertal timing, and epigenetic age acceleration in adulthood.

BACKGROUND: Given associations linking early life adversity, pubertal timing, and biological aging, we examined the direct and indirect effects of early life trauma on adult biological aging (via age of menarche). METHODS: Participants were premenopausal women (N = 183). Path models evaluated whether early life trauma predicted early pubertal timing and thereby, adult epigenetic age acceleration (indexed via four epigenetic clocks: Horvath DNAm Age, Hannum DNAm Age, DNAm PhenoAge, and DNAm GrimAge). Secondary analyses explored the effects of type of trauma (abuse and neglect) and adult chronic stress status (caregiver of child with autism and non-caregiver). RESULTS: Early life trauma and earlier age at menarche independently predicted accelerated aging based on one of the four epigenetic clocks, DNAm GrimAge, though early life trauma was not associated with age of menarche. Childhood abuse, but not neglect, predicted faster epigenetic aging; results did not differ by chronic stress status. CONCLUSIONS: Early trauma and early menarche appear to exert independent effects on DNAm GrimAge, which has been shown to be the strongest epigenetic predictor of mortality risk. This study identifies a potential correlate or determinant of accelerated epigenetic aging-menarcheal age. Future research should address the limitations of this study by using racially diverse samples.

Early pubertal timing predicts onset and recurrence of depressive episodes in boys and girls.

BACKGROUND: Recurrent depressive episodes during adolescence result in significant impairment and increased risk for subsequent adverse outcomes throughout the life span. Evidence suggests that early pubertal timing predicts the onset of depressive episodes (particularly for girls); however, it is not known if pubertal timing prospectively predicts recurrent depressive episodes in youth. METHODS: At baseline, 603 youth (56% female, at baseline: Mage  = 12.09, SD = 2.35) reported on their pubertal development. Youth and their parents completed a semistructured diagnostic interview to assess depressive episodes at baseline and then evaluated for onset repeatedly every 6 months for a period of 36 months. RESULTS: Controlling for past history of depression, Cox proportional hazards models examined whether earlier pubertal timing predicted (a) days to first depressive episode from baseline and (b) days to a second (recurrent) depressive episode from the end of the first episode. Early pubertal timing predicted the onset of the first depressive episode after baseline (b = .19, Wald = 5.36, p = .02, HR = 1.21), as well as a recurrent episode during course of study follow-up episode (b = .32, Wald = 6.16, p = .01, HR = 1.38). CONCLUSIONS: Findings reinforce the importance of considering the impact of early pubertal timing on depression risk. Investigation on how pubertal timing interacts with other risk factors to predict depression recurrence is needed.

Developmental Course of Personality Disorder Traits in Childhood and Adolescence.

Developmental patterns of personality pathology traits are not well delineated from childhood through late adolescence. In the present study, participants (N = 675, 56% female) were recruited to create three cohorts of third (n = 205), sixth (n = 248), and ninth (n = 222) graders to form an accelerated longitudinal cohort design. We assessed six PD (avoidant, dependent, histrionic, narcissistic, borderline, schizotypal) traits based on DSM-IV trait diagnostic conceptualizations via parent report at baseline, 18 months, and 36 months. According to parent report, mean levels of avoidant, dependent, histrionic, narcissistic, borderline, and schizotypal traits all declined for both boys and girls. The changes in dependent and histrionic traits were of medium effect size, and the changes in avoidant, narcissistic, borderline, and schizotypal traits were of small effect size. Over the 3 years of the study, the traits of each PD also demonstrated moderate to high rank-order stability.

A Latent Structure Analysis of Cognitive Vulnerability to Depression in Adolescence.

Whether cognitive vulnerability to depression exists along a continuum of severity or as a qualitatively discrete phenomenological entity has direct bearing on theoretical formulations of risk for depression and clinical risk assessment. This question is of particular relevance to adolescence, given that cognitive vulnerability appears to coalesce and rates of depression begin to rise markedly during this period of development. Although a dimensional view is often assumed, it is necessary to submit this assumption to direct empirical evaluation. Taxometric analysis is a family of statistical techniques developed directly to test such assumptions. The present study applied taxometric methods to address this question in a community sample of early adolescents (n = 485), drawing on three indices of cognitive vulnerability to depression (i.e., negative inferential style, ruminative response style, self-referent information processing). The results of three taxometric analyses (i.e., mean above minus below a cut [MAMBAC], maximum eigenvalue [MAXEIG], and latent mode [L-Mode]) were consistent in unambiguously supporting a dimensional conceptualization of this construct. The latent structure of the tested indices of cognitive vulnerability to depression in adolescence appears to exist along a continuum of severity rather than as a discrete clinical entity.

Pubertal Timing as a Transdiagnostic Risk for Psychopathology in Youth.

Evidence suggests that early pubertal timing may operate as a transdiagnostic risk factor (i.e., shared across syndromes of psychopathology) for both genders. The current study examined associations between pubertal timing and dimensional psychopathology, structured across different levels of three organizational models: 1) DSM-based syndrome model, 2) traditional model of internalizing and externalizing factors, and 3) bifactor (p-factor) model, which includes a general psychopathology factor as well as internalizing- and externalizing- specific factors. For study analyses, 567 youth-parent pairs completed psychopathology measures when youth (55.5% female) were 13.58 (SD = 2.37, range = 9-17). Findings across all models revealed that early pubertal timing served as a transdiagnostic risk factor and also displayed some syndrome specific associations. Gender did not moderate any relationships between pubertal timing and psychopathology. Study findings reinforce the importance of examining risk across different levels of psychopathology conceptualization and analysis.

Self-reported affective biases, but not all affective performance biases, are present in depression remission.

OBJECTIVE: Individuals with active major depressive disorder (MDD) have shown affective biases in cognitive flexibility and memory, particularly for negatively valenced stimuli. We evaluated whether impairments in affective flexibility would remain even during remission (rMDD), potentially representing trait- or scar-like effects of illness. METHOD: Participants completed the Emotion Card Sort Test (ECST), a measure of cognitive flexibility containing emotionally valenced stimuli, and the Emotion Word Stimulus Test (EWST), a measure of affective biases in delayed recall and recognition memory, and several self-report measures. RESULTS: Healthy controls (HCs; n = 35) and individuals with rMDD (n = 93) did not differ on performance for any of the three word types on the ECST or EWT. However, individuals with rMDD demonstrated greater negative bias on EWT recognition trials relative to HCs (d = .36). On self-report measures, individuals with rMDD exhibited greater levels of neuroticism, problems with attentional control, pessimistic attributional style, and negative automatic thoughts compared to HCs. CONCLUSIONS: These results provide initial evidence that some performance, but not self-reported, indices of affective bias may improve during remission from MDD. Results of this study could suggest that some components of affective bias may represent state feature of illness and others trait-like risk or scar features. PRACTITIONER POINTS: This study suggests that self-reported affective biases may persist in remission of major depressive disorder (rMDD). Affective attentional biases and affective memory biases were not demonstrated in individuals with rMDD, with the exception of a bias for recognizing negatively versus neutrally valenced stimuli. CAUTIONS OR LIMITATIONS: A limitation of this study was its cross-sectional design. Under ideal conditions, the same individuals would be studied in both the active and remitted phases of illness. Another limitation of this study was the smaller number of healthy controls relative to individuals with rMDD.

Predictors of Attrition in Longitudinal Neuroimaging Research: Inhibitory Control, Head Movement, and Resting-State Functional Connectivity.

Attrition is a major problem in longitudinal neuroimaging studies, as it may lead to unreliable estimates of the stability of trait-like processes over time, of the identification of risk factors for clinical outcomes, and of the effects of treatment. Identification of characteristics associated with attrition has implications for participant recruitment and participant retention to achieve representative longitudinal samples. We investigated inhibitory control deficits, head motion, and resting-state functional connectivity within the cognitive control network (CCN) as predictors of attrition. Ninety-seven individuals with remitted major depressive disorder or healthy controls completed a functional magnetic resonance imaging scan, which included a go/no-go task and resting-state functional connectivity. Approximately 2 months later, participants were contacted and invited to return for a second scan. Seventeen individuals were lost to follow-up or declined to participate in the follow-up scan. Worse inhibitory control was correlated with greater movement within the scanner, and each predicted a greater likelihood of attrition, with movement mediating the effects of inhibitory control on attrition. Individuals who dropped out of the study exhibited greater movement than nondropouts across 9 of the 14 runs of the scan, with medium-to-large effect sizes. Finally, exploratory analyses suggested that attenuated resting-state connectivity with the CCN (particularly in bilateral dorsolateral prefrontal cortex) was associated with greater likelihood of attrition after accounting for head motion at several levels of analysis. Inhibitory control and movement within the scanner are associated with attrition, and should be considered for strategic oversampling and participant retention strategies to ensure generalizability of results in longitudinal studies.

Disrupted engagement of networks supporting hot and cold cognition in remitted major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is characterized by dysfunction in cognitive and emotional systems. However, the neural network correlates of cognitive control (cold cognition) and emotion processing (hot cognition) during the remitted state of MDD (rMDD) remain unclear and not fully probed, which has important implications for identifying intermediate phenotypes of depression risk. METHODS: 43 young adults with rMDD and 33 healthy controls (HCs) underwent fMRI while completing separate tasks of cold cognition (Parametric Go/No-Go test) and hot cognition (Facial Emotion Processing Test). Two 2 group (rMDD, HC) × 2 event (sad/fearful faces, correct rejections) factorial models of activation were calculated in SPM8. Functional activation was evaluated in the salience and emotional network (SEN) and the cognitive control network (CCN), including hypothesized interaction between group and task within the CCN. RESULTS: Individuals with rMDD demonstrated greater spatial extent of suprathreshold activation within the SEN during sad faces relative to HCs. There were several regions within the CCN in which HCs showed greater activation than rMDD during correct rejections of lures, whereas individuals with rMDD showed greater activation than HCs during sad or fearful faces. LIMITATIONS: Results were not directly compared with active MDD. CONCLUSIONS: These results provide evidence of deficient CCN engagement during cognitive control in rMDD (dysfunctional cold cognition). Elevated SEN activation during sad faces could represent heightened salience of negative emotional faces in rMDD; elevated CCN activation during emotional faces in rMDD could represent compensatory regulatory control. These group differences may represent vulnerability factors, scars of prior depressive episodes, or processes maintaining wellness.

Pubertal Development, Emotion Regulatory Styles, and the Emergence of Sex Differences in Internalizing Disorders and Symptoms in Adolescence.

Adolescence marks the emergence of sex differences in internalizing symptoms and disorders, with girls at increased risk for depression and anxiety during the pubertal transition. However, the mechanisms through which puberty confers risk for internalizing psychopathology for girls, but not boys, remain unclear. We examined two pubertal indicators (pubertal status and timing) as predictors of the development of emotion regulation styles (rumination and emotional clarity) and depressive and anxiety symptoms and disorders in a three-wave study of 314 adolescents. Path analyses indicated that early pubertal timing, but not pubertal status, predicted increased rumination, but not decreased emotional clarity, in adolescent girls, but not boys. Additionally, rumination mediated the association between early pubertal timing and increased depressive, but not anxiety, symptoms and disorder onset among adolescent girls. These findings suggest that the sex difference in depression may result partly from early maturing girls' greater tendency to develop ruminative styles than boys.

INFLEXIBLE COGNITION PREDICTS FIRST ONSET OF MAJOR DEPRESSIVE EPISODES IN ADOLESCENCE.

BACKGROUND: Major depressive disorder often is characterized by a lack of cognitive and emotional flexibility, resulting in an impaired ability to adapt to situational demands. Adolescence is an important period of risk for the first onset of depression, yet relatively little is known about whether aspects of inflexibility, such as rumination and deficits in attentional shifting, could confer risk for the development of the disorder during this time. METHOD: In the present study, a sample of 285 never-depressed adolescents completed self-report and behavioral measures of rumination and attentional shifting at a baseline visit, followed by up to 4 years of annual prospective follow-up diagnostic assessments. RESULTS: Survival analyses indicated that adolescents with greater levels of rumination or poorer attentional shifting experienced a shorter time until the first onset of major depressive episodes, even after accounting for baseline symptoms and demographic characteristics. Although girls were twice as likely as boys to experience the first onset of depression, rumination predicted a shorter time until depression onset only for boys. Rumination and attentional shifting were not correlated and predicted time until onset of major depression independently of one another. CONCLUSIONS: These results provide evidence that components of cognition that are characterized by rigidity and perseveration confer risk for the first onset of major depression during adolescence. Evaluating rumination and attentional shifting in adolescence may be useful in identifying individuals who are at risk for depression and who may benefit from interventions that target or alter the development of these characteristics.

Assessment and Treatment of Bipolar Spectrum Disorders in Emerging Adulthood: Applying the Behavioral Approach System Hypersensitivity Model.

Bipolar disorder is associated with a host of negative physical and interpersonal outcomes including suicide. Emerging adulthood is an age of risk for the onset of bipolar spectrum disorders (BSD) and there has been increased effort to focus on early identification and subsequent intervention for BSDs during this developmental period. Recent research on the behavioral approach system (BAS) hypersensitivity model of bipolar disorder may have implications for the assessment and treatment of BSD in emerging adulthood. We summarize relevant findings on the BAS hypersensitivity model that support the use of reward sensitivity in the early identification of BSDs and suggest evidence-based strategies for clinical work with emerging adults with bipolar spectrum disorders.