Do Loneliness and Per Capita Income Combine to Increase the Pace of Biological Aging for Black Adults across Late Middle Age?

In a sample of 685 late middle-aged Black adults (M age at 2019 = 57.17 years), we examined the effects of loneliness and per capita income on accelerated aging using a newly developed DNA-methylation based index: the DunedinPACE. First, using linear, mixed effects regression in a growth curve framework, we found that change in DunedinPACE was dependent on age, with a linear model best fitting the data (b = 0.004, p < 0.001), indicating that average pace of change increased among older participants. A quadratic effect was also tested, but was non-significant. Beyond the effect of age, both change in loneliness (b = 0.009, p < 0.05) and change in per capita income (b = -0.016, p < 0.001) were significantly associated with change in DunedinPACE across an 11-year period, accounting for significant between person variability observed in the unconditional model. Including non-self-report indices of smoking and alcohol use did not reduce the association of loneliness or per capita income with DunedinPACE. However, change in smoking was strongly associated with change in DunedinPACE such that those reducing their smoking aged less rapidly than those continuing to smoke. In addition, both loneliness and per capita income were associated with DunedinPACE after controlling for variation in cell-types.

Epigenetic and Proteomic Biomarkers of Elevated Alcohol Use Predict Epigenetic Aging and Cell-Type variation Better Than Self-Report.

Excessive alcohol consumption (EAC) has a generally accepted effect on morbidity and mortality, outcomes thought to be reflected in measures of epigenetic aging (EA). As the association of self-reported EAC with EA has not been consistent with these expectations, underscoring the need for readily employable non-self-report tools for accurately assessing and monitoring the contribution of EAC to accelerated EA, newly developed alcohol consumption DNA methylation indices, such as the Alcohol T Score (ATS) and Methyl DetectR (MDR), may be helpful. To test that hypothesis, we used these new indices along with the carbohydrate deficient transferrin (CDT), concurrent as well as past self-reports of EAC, and well-established measures of cigarette smoking to examine the relationship of EAC to both accelerated EA and immune cell counts in a cohort of 437 young Black American adults. We found that MDR, CDT, and ATS were intercorrelated, even after controlling for gender and cotinine effects. Correlations between EA and self-reported EAC were low or non-significant, replicating prior research, whereas correlations with non-self-report indices were significant and more substantial. Comparing non-self-report indices showed that the ATS predicted more than four times as much variance in EA, CDT4 cells and B-cells as for both the MDR and CDT, and better predicted indices of accelerated EA. We conclude that each of the non-self-report indices have differing predictive capacities with respect to key alcohol-related health outcomes, and that the ATS may be particularly useful for clinicians seeking to understand and prevent accelerated EA. The results also underscore the likelihood of substantial underestimates of problematic use when self-report is used and a reduction in correlations with EA and variance in cell-types.

Methylation of FKBP5 is associated with accelerated DNA methylation ageing and cardiometabolic risk: replication in young-adult and middle-aged Black Americans.

Methylation of FKBP5 is involved in the regulation of the stress response and is influenced by early stress exposure. Two CpG sites, cg20813374 and cg00130530, have been identified as potential reporters of early stress. We examined whether FKBP5 methylation was associated with accelerated DNA methylation ageing and indirectly predicted poorer cardiovascular health among both young adult and middle-aged Black Americans. Four hundred and forty-nine young adults, with a mean age of 28.67 and N = 469 middle-age parents and their current partners with a mean age of 57.21, provided self-reports, biometric assessments, and blood draws. Methylation values were obtained using the Illumina Epic Array. Cardiometabolic risk was calculated by summing the standardized log-transformed scores for the body mass index, mean arterial blood pressure, and HbA1c. We also used a more standard index of risk, the Framingham 10-year cardiometabolic risk index, as an alternative measure of cardiometabolic risk. To measure accelerated ageing, four widely used indices of accelerated, DNA methylation-based ageing were used controlling sex, age, other variation in FKBP5, and cell-type. Exposure to community danger was associated with demethylation of FKBP5. FKBP5 methylation was significantly associated with accelerated ageing for both young-adult and middle-aged samples, with significant indirect effects from FKBP5 methylation to cardiometabolic risk through accelerated ageing for both. Early exposure to danger may influence FKBP5 methylation. In turn, FKBP5 methylation may help explain intrinsic accelerated ageing and elevated cardiometabolic risk in adulthood for Black Americans.

Childhood adversity predicts black young adults' DNA methylation-based accelerated aging: A dual pathway model.

We expand upon prior work (Gibbons et al., ) relating childhood stressor effects, particularly harsh childhood environments, to risky behavior and ultimately physical health by adding longer-term outcomes - deoxyribonucleic acid (DNA) methylation-based measures of accelerated aging (DNAm-aging). Further, following work on the effects of early exposure to danger (McLaughlin et al., ), we also identify an additional pathway from harsh childhood environments to DNAm-aging that we label the danger/FKBP5 pathway, which includes early exposure to dangerous community conditions that are thought to impact glucocorticoid regulation and pro-inflammatory mechanisms. Because different DNAm-aging indices provide different windows on accelerated aging, we contrast effects on early indices of DNAm-aging based on chronological age with later indices that focused on predicting biological outcomes. We utilize data from Family and Community Health Study participants (N = 449) from age 10 to 29. We find that harshness influences parenting, which, in turn, influences accelerated DNAm-aging through the risky cognitions and substance use (i.e., behavioral) pathway outlined by Gibbons et al. (). Harshness is also associated with increased exposure to threat/danger, which, in turn, leads to accelerated DNAm-aging through effects on FKBP5 activity and enhanced pro-inflammatory tendencies (i.e., the danger/FKBP5 pathway).

The effects of social adversity, discrimination, and health risk behaviors on the accelerated aging of African Americans: Further support for the weathering hypothesis.

BACKGROUND: The weathering hypothesis views the elevated rates of illness, disability, and mortality seen among Black Americans as a physiological response to the structural barriers, material hardships, and identity threats that comprise the Black experience. While granting that lifestyle may have some significance, the fundamental explanation for heath inequalities is seen as race-related stressors that accelerate biological aging. OBJECTIVE: The present study tests the weathering hypothesis by examining the impact on accelerated aging of four types of adversity frequently experienced by Black Americans. Further, we investigate whether health risk behaviors mediate the effect of these conditions. METHOD: Our analyses utilize data from 494 middle-age, African American men and women participating in the Family and Community Healthy Study. The newly developed GrimAge index of accelerated aging is used as an indicator of weathering. Education, income, neighborhood disadvantage, and discrimination serve as the independent variables. Three health risk behaviors - diet, exercise, and alcohol consumption - are included as potential mediators of the four types of adversity. Marital status and gender are entered as controls. RESULTS: Multivariate analyses indicated that the four types of adversity predicted acceleration whereas marriage predicted deceleration in speed of aging. Males showed greater accelerated aging than females, but there was no evidence that gender conditioned the effect of adversity. The health risk behaviors were unrelated to accelerated aging and did not mediate the effect of the stressors. CONCLUSION: Modern medicine's emphasis on life style as the primary explanation for race-based health disparities ignores the way race-related adversity rooted in structural and cultural conditions serves to accelerate biological decline, thereby increasing risk of early onset of illness and death. Importantly, these social conditions can only be addressed through social policies and programs that target institutional racism and promote economic equity.

Childhood adversity is linked to adult health among African Americans via adolescent weight gain and effects are genetically moderated.

Identifying the mechanisms linking early experiences, genetic risk factors, and their interaction with later health consequences is central to the development of preventive interventions and identifying potential boundary conditions for their efficacy. In the current investigation of 412 African American adolescents followed across a 20-year period, we examined change in body mass index (BMI) across adolescence as one possible mechanism linking childhood adversity and adult health. We found associations of childhood adversity with objective indicators of young adult health, including a cardiometabolic risk index, a methylomic aging index, and a count of chronic health conditions. Childhood adversities were associated with objective indicators indirectly through their association with gains in BMI across adolescence and early adulthood. We also found evidence of an association of genetic risk with weight gain across adolescence and young adult health, as well as genetic moderation of childhood adversity's effect on gains in BMI, resulting in moderated mediation. These patterns indicated that genetic risk moderated the indirect pathways from childhood adversity to young adult health outcomes and childhood adversity moderated the indirect pathways from genetic risk to young adult health outcomes through effects on weight gain during adolescence and early adulthood.

Inflammatory biomarker relationships with helper T cell GPR15 expression and cannabis and tobacco smoking.

OBJECTIVE: Smoking is associated with numerous inflammatory and autoimmune conditions. The goal of this study was to examine whether increased expression of G-protein-coupled receptor 15 (GPR15) on helper T cells in smokers could predispose to these conditions through its relationship with inflammatory biomarkers. METHODS: We used flow cytometric measurement of GPR15+CD3+CD4+ helper T cells and serum assays for C-reactive protein (CRP) and 17 cytokines drawn from peripheral blood samples from a cohort of n = 62 primarily African American young adults (aged 27-35 years). These variables were examined cross-sectionally in conjunction with serum biomarkers of tobacco (cotinine) and cannabis (tetrahydrocannabinol) use and lifestyle factors potentially impacting immune function in correlational analyses and linear regression models. RESULTS: Tobacco and cannabis smoking were strongly associated with increased GPR15 expression on helper T cells (p < 0.001), which was in turn was strongly associated with the ratio of pro-inflammatory to anti-inflammatory cytokines (p < 0.001). Mediation analyses indicated increased GPR15 expression accounted for roughly half of the relationship between smoking variables and pro-inflammatory to anti-inflammatory cytokine balance. CRP was not associated with cannabis or tobacco use or GPR15+ expression, but was associated with body mass index (p < 0.001). These relationships persisted after controlling for lifestyle and medical factors impacting immune function. CONCLUSIONS: Increased expression of GPR15 by helper T cells in smokers may mediate some of the relationship between smoking and a pro-inflammatory cytokine milieu. Better understanding of this relationship may help uncover how smoking increases the risk of inflammatory diseases.

The Effect of Tobacco Smoking Differs across Indices of DNA Methylation-Based Aging in an African American Sample: DNA Methylation-Based Indices of Smoking Capture These Effects.

Smoking is one of the leading preventable causes of morbidity and mortality worldwide, prompting interest in its association with DNA methylation-based measures of biological aging. Considerable progress has been made in developing DNA methylation-based measures that correspond to self-reported smoking status. In addition, assessment of DNA methylation-based aging has been expanded to better capture individual differences in risk for morbidity and mortality. Untested to date, however, is whether smoking is similarly related to older and newer indices of DNA methylation-based aging, and whether DNA methylation-based indices of smoking can be used in lieu of self-reported smoking to examine effects on DNA methylation-based aging measures. In the current investigation we examine mediation of the impact of self-reported cigarette consumption on accelerated, intrinsic DNA methylation-based aging using indices designed to predict chronological aging, phenotypic aging, and mortality risk, as well as a newly developed DNA methylation-based measure of telomere length. Using a sample of 500 African American middle aged smokers and non-smokers, we found that a) self-reported cigarette consumption was associated with accelerated intrinsic DNA methylation-based aging on some but not all DNA methylation-based aging indices, b) for those aging outcomes associated with self-reported cigarette consumption, DNA methylation-based indicators of smoking typically accounted for greater variance than did self-reported cigarette consumption, and c) self-reported cigarette consumption effects on DNA methylation-based aging indices typically were fully mediated by DNA methylation-based indicators of smoking (e.g., PACKYRS from GrimAge; or cg05575921 CpG site). Results suggest that when DNA methylation-based indices of smoking are substituted for self-reported assessments of smoking, they will typically fully reflect the varied impact of cigarette smoking on intrinsic, accelerated DNA methylation-based aging.

Cigarette and Cannabis Smoking Effects on GPR15+ Helper T Cell Levels in Peripheral Blood: Relationships with Epigenetic Biomarkers.

Background: Smoking causes widespread epigenetic changes that have been linked with an increased risk of smoking-associated diseases and elevated mortality. Of particular interest are changes in the level of T cells expressing G-protein-coupled receptor 15 (GPR15), a chemokine receptor linked with multiple autoimmune diseases, including inflammatory bowel disease, multiple sclerosis and psoriasis. Accordingly, a better understanding of the mechanisms by which smoking influences variation in the GPR15+ helper T cell subpopulation is of potential interest. Methods: In the current study, we used flow cytometry and digital PCR assays to measure the GPR15+CD3+CD4+ populations in peripheral blood from a cohort of n = 62 primarily African American young adults (aged 27-35 years) with a high rate of tobacco and cannabis use. Results: We demonstrated that self-reported tobacco and cannabis smoking predict GPR15+CD3+CD4+ helper T cell levels using linear regression models. Further, we demonstrated that methylation of two candidate CpGs, cg19859270, located in GPR15, and cg05575921, located in the gene Aryl Hydrocarbon Receptor Repressor (AHRR), were both significant predictors of GPR15+CD3+CD4+ cell levels, mediating the relationship between smoking habits and increases in GPR15+CD3+CD4+ cells. As hypothesized, the interaction between cg05575921 and cg19859270 was also significant, indicating that low cg05575921 methylation was more strongly predictive of GPR15+CD3+CD4+ cell levels for those who also had lower cg19859270 methylation. Conclusions: Smoking leads changes in two CpGs, cg05575921 and cg19859270, that mediate 38.5% of the relationship between tobacco and cannabis smoking and increased GPR15+ Th levels in this sample. The impact of cg19859270 in amplifying the association between cg05575921 and increased GPR15+ Th levels is of potential theoretical interest given the possibility that it reflects a permissive interaction between different parts of the adaptive immune system.

AHRR Methylation is a Significant Predictor of Mortality Risk in Framingham Heart Study.

Background.-The ability to predict mortality is useful to clinicians, policy makers and insurers. At the current time, prediction of future mortality is still an inexact process with some proposing that epigenetic assessments could play a role in improving prognostics. In past work, we and others have shown that DNA methylation status at cg05575921, a well-studied measure of smoking intensity, is also a predictor of mortality. However, the exact extent of that predictive capacity and its independence of other commonly measured mortality risk factors are unknown. Objective.-To determine the capacity of methylation to predict mortality. Method.-We analyzed the relationship of methylation at cg05575921 and cg04987734, a recently described quantitative marker of heavy alcohol consumption, to mortality in the Offspring Cohort of the Framingham Heart Study using proportional hazards survival analysis. Results.-In this group of participants (n = 2278) whose average age was 66 ± 9 years, we found that the inclusion of both cg05575921 and cg04987734 methylation to a base model consisting of age and sex only, or to a model containing 11 commonly used mortality risk factors, improved risk prediction. What is more, prediction accuracy for the base model plus methylation data was increased compared to the base model plus known predictors of mortality (CHD, COPD, or stroke). Conclusion.-Cg05575921, and to a smaller extent cg04987734, are strong predictors of mortality risk in older Americans and that incorporation of DNA methylation assessments to these and other loci may be useful to population scientists, actuaries and policymakers to better understand the relationship of environmental risk factors, such as smoking and drinking, to mortality.

Testing Life Course Models Whereby Juvenile and Adult Adversity Combine to Influence Speed of Biological Aging.

The present study extends prior research on the links between social adversity and aging by employing more comprehensive measures of adversity and a new gene expression index of aging. Hierarchical regression and 20 years of data from a sample of 381 black Americans were used to test models regarding the impact of social adversity on speed of aging. Consistent with the early life sensitivity model, early adversity continued to predict accelerated aging after controlling for adult adversity. Contrary to the pathway model, adult adversity was not related to aging following controls for early adversity. The cumulative stress model received partial support as high adversity during adulthood amplified the effect of early adversity on aging. Finally, consonant with the social change model, low adversity during adulthood buffered the effect of early adversity on aging. These findings held after controlling for health behaviors such as smoking, diet, and exercise.

Inflammation mediates the effect of discrimination, religiosity, and friendship network on expression of the Tp53 cancer suppressor gene.

OBJECTIVE: Chronic inflammation and expression of the TP53 gene are two biomarkers that have been identified as particularly important in the etiology and progression of cancer. While much is known about the determinants of inflammation, there is currently little information regarding the causes of variation in the functioning of TP53, even though it has been recognized for 40 years as the most potent of the cancer suppressor genes. The current paper explores the interrelationship between these two biomarkers and investigates the extent to which they are influenced by the social environment. METHODS: Using structural equation modeling (SEM) and longitudinal observational data from a sample of several hundred African Americans, we tested the hypothesis that adversity - operationalized as racial discrimination- and coping resources - operationalized as religiosity and black friends - influence expression of TP53, for better or worse, through their impact on inflammation. RESULTS: Correlational analysis showed inflammation and TP53 to be inversely related. Further, discrimination was positively related to inflammation and negatively related to TP53 expression, whereas religiosity and black friends were both negatively related to inflammation and positively related to TP53 expression. Finally, SEM indicated that the effect of the social environmental variables on TP53 expression was indirect through level of inflammation. CONCLUSIONS: In addition to its established contribution to cancer through DNA damage and cell proliferation, inflammation likely increases cancer risk indirectly by inhibiting expression of the TP53 cancer suppressor gene. Hence environmental and stress management interventions may do more than reduce inflammation's cell damaging effects; they may also lessen the chances of cancer by increasing expression of TP53.

Perceived relationship support moderates the association of contextual stress with inflammation among African Americans.

We followed 402 African American young adults from ages 24 to 29, a period of emerging committed relationships, to examine the association of contextual stress (CS), for example, experiences of financial strain, victimization, and racial discrimination, with inflammation, and to test predictions that greater perceived relationship warmth and support (PRWS) at age 29 would moderate the association between earlier CS and inflammation, using a multiplex assessment of cytokines to construct an index of the ratio between predominantly proinflammatory cytokines versus predominantly anti-inflammatory cytokines. CS experienced at age 24 was associated with greater inflammation at age 29 in the full sample (b = .112, p = .004). PRWS at age 29 moderated the association of earlier CS with inflammation (b = -.114, p = .011), but there was no significant main effect of PRWS (b = -.053, p = .265). Finally, using an internal moderator approach, we compared the association of CS with inflammation among those not in a committed relationship to those in more or less supportive relationships, showing a significant and stronger association of CS with inflammation for those with low PRWS (-1 SD; b = .182, p < .001), a weaker and nonsignificant association of CS with inflammation among those with higher PRWS (+1 SD; b = -.002, p = .975), and an intermediate and nonsignificant association of CS with inflammation among those with no committed romantic relationship (b = .077, p = .227). Results were robust to number of cytokines included in the inflammation index. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Neighborhood Disadvantage and Biological Aging: Using Marginal Structural Models to Assess the Link Between Neighborhood Census Variables and Epigenetic Aging.

OBJECTIVES: Past research has reported an association between neighborhood disadvantage and healthy aging, but most of these studies utilize self-report measures of health or physical functioning and do not properly account for neighborhood selection effects, creating concerns regarding inflated associations. To overcome these limitations and provide a more stringent estimate of effects, the current study investigated the effect of neighborhood disadvantage on aging using newly developed epigenetic methods to assess rate of biological aging and marginal structural modeling (MSM) to account for potential confounds due to neighborhood selection. METHODS: We tested the hypothesis that neighborhood disadvantage accelerates aging using U.S. census data and five waves of interview data from a sample of 100 middle-aged African American women. Using a recently developed epigenetic index of aging, biological age was measured using weighted methylation values at 71 CpG sites. We calculated a measure of accelerated methylomic aging (in years) based upon the residual scores resulting from a regression of methylomic age on chronological age. RESULTS: Controlling for a variety of individual difference factors that could be confounded with neighborhood effects, including various health behaviors, neighborhood disadvantage was associated with accelerated biological aging. Using MSM to account for selection effects, a standard deviation increase in neighborhood disadvantage accelerated aging an average of 9 months. CONCLUSIONS: Our findings converge with prior work to provide strong evidence that neighborhood context is a significant determinant of healthy aging.

Blood-Based Biomarkers for Predicting the Risk for Five-Year Incident Coronary Heart Disease in the Framingham Heart Study via Machine Learning.

An improved approach for predicting the risk for incident coronary heart disease (CHD) could lead to substantial improvements in cardiovascular health. Previously, we have shown that genetic and epigenetic loci could predict CHD status more sensitively than conventional risk factors. Herein, we examine whether similar machine learning approaches could be used to develop a similar panel for predicting incident CHD. Training and test sets consisted of 1180 and 524 individuals, respectively. Data mining techniques were employed to mine for predictive biosignatures in the training set. An ensemble of Random Forest models consisting of four genetic and four epigenetic loci was trained on the training set and subsequently evaluated on the test set. The test sensitivity and specificity were 0.70 and 0.74, respectively. In contrast, the Framingham risk score and atherosclerotic cardiovascular disease (ASCVD) risk estimator performed with test sensitivities of 0.20 and 0.38, respectively. Notably, the integrated genetic-epigenetic model predicted risk better for both genders and very well in the three-year risk prediction window. We describe a novel DNA-based precision medicine tool capable of capturing the complex genetic and environmental relationships that contribute to the risk of CHD, and being mapped to actionable risk factors that may be leveraged to guide risk modification efforts.

Discrimination, segregation, and chronic inflammation: Testing the weathering explanation for the poor health of Black Americans.

Several studies have reported a relation between race-related stressors and the poor health of Black Americans. Such findings raise questions regarding the mediating biological mechanisms that might account for this link. The present study investigated elevated systemic inflammation, a factor shown to be a strong predictor of chronic illness and mortality in all ethnic populations, as a possible factor. Using 7 waves of data from the Family and Community Health Study, collected over a 20-year period from over 400 Black Americans, we investigated the extent to which exposure to discrimination and segregation at various points in the life course predicted adult inflammation at age 28. Our analyses examined whether cumulative stress, stress generation, or predictive adaptive response (PAR) models best accounted for any associations that existed between these race-related stressors and adult inflammation. At every wave of data collection, assessments of discrimination and segregation were related to adult inflammation. However, multivariate analyses using structure equation modeling indicated that the PAR model best explained the effect of these race-related stressors on inflammation. Exposure to discrimination and segregation during the juvenile years predicted adult inflammation and amplified the inflammatory effect of adult exposure to these race-related stressors. These effects were considerably more robust than that of traditional health risk factors such as diet, exercise, smoking, and low SES. Implications of these findings are discussed, including the limitations of the widely accepted risk factor approach to increasing the health of Black Americans. (PsycINFO Database Record

Integrated genetic and epigenetic prediction of coronary heart disease in the Framingham Heart Study.

An improved method for detecting coronary heart disease (CHD) could have substantial clinical impact. Building on the idea that systemic effects of CHD risk factors are a conglomeration of genetic and environmental factors, we use machine learning techniques and integrate genetic, epigenetic and phenotype data from the Framingham Heart Study to build and test a Random Forest classification model for symptomatic CHD. Our classifier was trained on n = 1,545 individuals and consisted of four DNA methylation sites, two SNPs, age and gender. The methylation sites and SNPs were selected during the training phase. The final trained model was then tested on n = 142 individuals. The test data comprised of individuals removed based on relatedness to those in the training dataset. This integrated classifier was capable of classifying symptomatic CHD status of those in the test set with an accuracy, sensitivity and specificity of 78%, 0.75 and 0.80, respectively. In contrast, a model using only conventional CHD risk factors as predictors had an accuracy and sensitivity of only 65% and 0.42, respectively, but with a specificity of 0.89 in the test set. Regression analyses of the methylation signatures illustrate our ability to map these signatures to known risk factors in CHD pathogenesis. These results demonstrate the capability of an integrated approach to effectively model symptomatic CHD status. These results also suggest that future studies of biomaterial collected from longitudinally informative cohorts that are specifically characterized for cardiac disease at follow-up could lead to the introduction of sensitive, readily employable integrated genetic-epigenetic algorithms for predicting onset of future symptomatic CHD.

Sharing the Burden of the Transition to Adulthood: African American Young Adults' Transition Challenges and Their Mothers' Health Risk.

For many African American youth, the joint influences of economic and racial marginalization render the transition to stable adult roles challenging. We have gained much insight into how these challenges affect future life chances, yet we lack an understanding of what these challenges mean in the context of linked lives. Drawing on a life course framework, this study examines how young African Americans' experiences across a variety of salient domains during the transition to adulthood affect their mothers' health. Results suggest that stressors experienced by African Americans during the transition to adulthood (e.g., unemployment, troubled romantic relationships, arrest) heighten their mothers' cumulative biological risk for chronic diseases, or allostatic load, and reduce subjective health. These results suggest that the toll of an increasingly tenuous and uncertain transition to adulthood extends beyond young people to their parents. Hence, increased public investments during this transition may not only reduce inequality and improve life chances for young people themselves, but may also enhance healthy aging by relieving the heavy burden on parents to help their children navigate this transition.