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.

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.

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.

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.

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.

Rumination and overgeneral autobiographical memory in adolescents: an integration of cognitive vulnerabilities to depression.

During adolescence, rates of depression dramatically increase and girls become twice as likely as boys to develop depression. Research suggests that overgeneral autobiographical memory and rumination are vulnerability factors for depressive symptoms in adolescence that may be triggered by stressful life events. The current longitudinal study included 160 early adolescents (Mage = 12.44 years, 60.0 % African American, 40.0 % Caucasian, and 56.2 % female). At baseline, adolescents completed measures of current depressive symptoms, rumination, and specificity of autobiographical memories. Approximately 9 months later, the adolescents completed measures of current depressive symptoms and stressful life events that had occurred between baseline and follow-up. Analyses indicated that girls with more overgeneral autobiographical memories in combination with higher levels of rumination were most vulnerable to experiencing increases in depressive symptoms following stressful life events. Additionally, retrieving more specific autobiographical memories appeared to buffer against the impact of negative life events on depressive symptoms among both boys and girls. Memory specificity may play a protective role in depression risk, suggesting that memory specificity training interventions may prove beneficial for adolescents.

Pubertal Timing, Peer Victimization, and Body Esteem Differentially Predict Depressive Symptoms in African American and Caucasian Girls.

This study prospectively examined pubertal timing and peer victimization as interactive predictors of depressive symptoms in a racially diverse community sample of adolescents. We also expanded on past research by assessing body esteem as a mechanism by which pubertal timing and peer victimization confer risk for depression. In all, 218 adolescents (53.4% female, 49.3% African American, 50.7% Caucasian) completed both a baseline assessment and a follow-up assessment approximately 8 months later. Early maturing Caucasian girls and late maturing African American girls experienced the greatest increases in depressive symptoms at follow-up if they experienced higher levels of peer victimization between baseline and follow-up. Furthermore, body esteem significantly mediated the relationship between pubertal timing, peer victimization, and depressive symptoms for girls of both races. The interaction of pubertal timing and peer victimization did not predict depressive symptoms for boys of either race. These results support body esteem as a mechanism that contributes to increased depression among girls in adolescence-despite a differential impact of pubertal timing for Caucasian and African American girls.

Pubertal timing and vulnerabilities to depression in early adolescence: differential pathways to depressive symptoms by sex.

Although research implicates pubertal processes in the emergence of the sex difference in depression during adolescence, few studies have examined how cognitive and affective vulnerabilities influence the effect of pubertal timing on depressive symptoms. The current study prospectively examined whether early pubertal timing predicted increases in depressive symptoms among adolescents with more negative cognitive styles and lower emotional clarity, and whether this risk was specific to adolescent girls. In a diverse sample of 318 adolescents, early pubertal timing predicted increases in depressive symptoms among adolescent boys and girls with more negative cognitive styles and adolescent girls with poor emotional clarity. These findings suggest that earlier pubertal maturation may heighten the risk of depression for adolescents with pre-existing vulnerabilities to depression, and that early maturing adolescent girls with lower levels of emotional clarity may be particularly vulnerable to depressive symptoms, representing one pathway through which the sex difference in depression may emerge.

Cognitive vulnerabilities amplify the effect of early pubertal timing on interpersonal stress generation during adolescence.

Early pubertal timing has been found to confer risk for the occurrence of interpersonal stressful events during adolescence. However, pre-existing vulnerabilities may exacerbate the effects of early pubertal timing on the occurrence of stressors. Thus, the current study prospectively examined whether cognitive vulnerabilities amplified the effects of early pubertal timing on interpersonal stress generation. In a diverse sample of 310 adolescents (M age = 12.83 years, 55 % female; 53 % African American), early pubertal timing predicted higher levels of interpersonal dependent events among adolescents with more negative cognitive style and rumination, but not among adolescents with lower levels of these cognitive vulnerabilities. These findings suggest that cognitive vulnerabilities may heighten the risk of generating interpersonal stress for adolescents who undergo early pubertal maturation, which may subsequently place adolescents at greater risk for the development of psychopathology.

Emotional maltreatment, peer victimization, and depressive versus anxiety symptoms during adolescence: hopelessness as a mediator.

Extensive comorbidity between depression and anxiety has driven research to identify unique and shared risk factors. This study prospectively examined the specificity of three interpersonal stressors (emotional abuse, emotional neglect, and relationally oriented peer victimization) as predictors of depressive versus anxiety symptoms in a racially diverse community sample of adolescents. We expanded on past research by examining hopelessness as a mediator of the relationships between these interpersonal stressors and symptoms. Participants included 225 adolescents (55% African American; 59% female; M age = 12.84 years) who completed measures at baseline (Time 1) and two follow-up assessments (Times 2 and 3). Symptoms of depression and anxiety (social, physical, total) were assessed at Time 1 and Time 3, whereas intervening emotional maltreatment, peer victimization, and hopelessness were assessed at Time 2. Hierarchical linear regressions indicated that emotional abuse was a nonspecific predictor of increases in both depressive symptoms and symptoms of social, physical, and total anxiety, whereas relationally oriented peer victimization predicted depressive symptoms specifically. Emotional neglect did not predict increases in depressive or anxiety symptoms. In addition, hopelessness mediated the relationships between emotional abuse and increases in symptoms of depression and social anxiety. These findings suggest that emotional abuse and relationally oriented peer victimization are interpersonal stressors that are relevant to the development of internalizing symptoms in adolescence and that hopelessness may be one mechanism through which emotional abuse contributes to an increased risk of depression and social anxiety.

Overgeneral autobiographical memory, emotional maltreatment, and depressive symptoms in adolescence: evidence of a cognitive vulnerability-stress interaction.

Overgeneral autobiographical memory (OGM) is associated with depression and may confer risk for the development of depressed mood, but few longitudinal studies have evaluated OGM as a predictor of depressive symptoms in early adolescence, particularly in the context of environmental stressors. We investigated whether OGM and emotional maltreatment would interact to predict prospective increases in depressive symptoms in early adolescents and whether these effects differed by race. Among 174 seventh-graders, OGM and familial emotional abuse interacted to predict depressive symptoms eight months later, controlling for initial depressive symptoms. Specifically, emotional abuse predicted increases in depressive symptoms among Caucasian adolescents with more OGM, but not among those with less OGM. This association was not significant for African American adolescents. These results provide support for a cognitive vulnerability-stress relationship between OGM and emotional abuse in early adolescence and suggest that these mechanisms of risk for depression may be specific to Caucasian adolescents.

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.

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.

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.

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.

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.