Relationship stress and epigenetic age acceleration among older U.S. adults in the Midlife in the United States study.

BackgroundHealth conditions of participants can significantly affect longitudinal drop-out in population-based epidemiological surveys, yet few studies have examined the association between chronic pain (CP) and follow-up attrition.MethodsThe Midlife in the...

The current study examined whether informal caregivers performed worse, better, or similar to non-caregivers on cognitive tests of executive functioning and episodic memory over 10years. Methods: Data were from waves 2 (2003-04) and 3 (2013-14) of the Midlife in the United States (MIDUS) study (N = 2086). Multiple linear regression models examined whether caregiving at both waves 2 and 3 predicted better cognitive functioning at wave 3, than caregiving at only one time point or no caregiving (reference) while controlling for baseline covariates (i.e., sociodemographic, health, and functional status). After controlling for covariates, caregiving at both waves was independently associated with better performance in episodic memory (b = .24, SE = .10, p = .013) but not executive function (b = -.06, SE = .05, p = .246). Discussion:The findings partially supported both healthy caregiver and stress process models, indicating caregiving may be associated with better episodic memory but not executive functioning over time among the middle-aged and older adults.

Objectives: Informal caregiving has been associated with higher stress and lower levels of subjective well-being. Mind-body practices including yoga, tai chi, and Pilates also incorporate stress reducing activities. The current study aimed to examine the association between mind-body practice and subjective well-being among informal family caregivers. Methods: A sample of informal caregivers were identified in the Midlife in the United States study (N = 506, M ± SDage = 56 ± 11, 67% women). We coded mind-body practice into three categories, including regular practice (participating in one or more of them "a lot" or "often"), irregular (participating "sometimes" and "rarely") and no practice ("never"). Subjective well-being was measured using the 5-item global life satisfaction scale and the 9-item mindfulness scale. We used multiple linear regression models to examine associations between mind-body practice and caregivers' subjective well-being, controlling for covariates of sociodemographic factors, health, functional status, and caregiving characteristics. Results: Regular practice was associated with both better mindfulness-related well-being (b = 2.26, p < .05) and better life satisfaction (b = 0.43, p < .05), after controlling for covariates. Discussion: Future research should examine whether there is a selection effect of caregivers with higher well-being being more likely to choose these activities, and/or if mind-body practices are effective non-pharmacological interventions to improve family caregivers' quality of life.

Epigenetic aging measures are novel molecular indicators of biological aging that predict age-related chronic disease. We examined whether several established indices of epigenetic aging mediated the association between life course socioeconomic status (SES) and decrements in kidney function across a decade. Biomarker data were from 252 non-Hispanic (NH) Black and white participants who had consented to genetic analyses in Wave 2 (2004-2009) and 3 (2014-2021) of the Midlife in the United States study (MIDUS). Life course SES included parental education, a proxy of early life SES, and a composite score of adult SES based on the highest education level, household income to poverty line ratio, health insurance coverage, perception of the availability of money to meet needs, and difficulty level paying monthly bills. We included five measures of epigenetic age accelerations (EAA), based on the residuals after each epigenetic clock was regressed on chronological age (Horvath, Horvath blood and skin, Hannum, PhenoAge, and GrimAge) and one measure of the pace of aging (DunedinPACE) obtained during MIDUS 2. Kidney function was based on serum creatinine-based estimated glomerular filtration rate (eGFR), calculated using the CKD-EPI formula (without race adjustment). We calculated absolute decrements in eGFR across 11 years between MIDUS waves 2 and 3. Analyses were adjusted for age, sex, and health-related covariates (currently smoking, obese, hypertension, and insulin resistance). Lower adult SES and accelerated epigenetic aging, especially accelerated GrimAge and faster DunedinPACE pace of aging, mediated the association between lower parental education and larger decrements in eGFR. Accelerated epigenetic aging is associated with larger decrements in kidney function across a decade and may be one of the critical explanatory pathways for the higher burden of chronic kidney disease (CKD) among lower SES individuals.

BackgroundThe relative predictive utility for specific forms of internalizing psychopathology (anxiety and depression syndromes) vs. the overall internalizing spectrum has not received extensive attention in the study of epigenetic aging. Here, we took a Hierarchical Taxonomy of Psychopathology (HiTOP) perspective on examining this issue, comparing specific syndromes with the overall internalizing spectrum.Aims & ObjectivesTo compare the predictive utility of specific internalizing syndromes (i.e., major depression, generalized anxiety, and panic disorder) with the overall internalizing spectrum in understanding epigenetic age acceleration (EAA).MethodIn a national sample of American adults from the Midlife in the United States Study (MIDUS; n=1,309), we compared the prediction of EAA by symptom counts for specific mood and anxiety syndromes (i.e., major depression, generalized anxiety, and panic disorder) with the overall internalizing spectrum (representing the variance in common among these syndromes).ResultsLater-generation EAA clocks (GrimAge and DunedinPACE) were more strongly associated with the internalizing spectrum than with specific syndromic symptom counts. EAA indices were not significantly associated with the symptom counts net of the internalizing spectrum.Discussion & ConclusionsMuch of the health-relevant variability within anxiety and depressive disorders is captured by the overarching internalizing spectrum.

Cortisol has been widely used as biomarker of stress and aging, but confounding effects and disruption of the hypothalamic–pituitary–adrenal axis can lead to misinterpretation of results based on a single measurement. A possible alternative is the co-measurement of cortisol and the adrenal hormone dehydroepiandrosterone-sulfate (DHEAS), a glucocorticoid antagonist that modulates the stress response. Using data from 969 individuals from the Midlife in the United States study, this study aimed to investigate the influence of age, sex, and self-identified biosocial group (SIBG) on DHEAS, cortisol, and the cortisol/DHEAS ratio, to test whether these hormones add predictive power to epigenetic age estimates, and to compare the performance of these three hormonal measures in predicting epigenetic age acceleration (EAA) using sex epigenetic clocks: Horvath, Horvath’s skin & blood (Horvath2), Hannum, PhenoAge, GrimAge, and DunedinPACE. Our findings revealed that age, sex and SIBG significantly influenced all three hormonal measures. Controlling for these biodemographic factors, we found that the cortisol/DHEAS was the best predictor of epigenetic clocks. There was a significant and positive correlation between cortisol and Hannum epigenetic age, and between cortisol/DHEAS ratio in three out of the six clocks (Hannum, Horvath2, PhenoAge), but no significant associations between DHEAS and epigenetic age. The cortisol/DHEAS ratio also had a significant and positive correlation with Hannum EAA. DHEAS and cortisol were not significantly associated with EAA for any epigenetic clock. Our results reinforce the importance of co-measuring cortisol and DHEAS in studies investigating the effect of stress in aging processes.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10522-025-10307-x.

A known association exists between exposure to gestational diabetes mellitus (GDM) and epigenetic age acceleration (EAA) in GDM-exposed offspring compared to those without GDM exposure. This association has not been assessed previously in mothers with pregnancies complicated by GDM. A total of 137 mother-child dyads with an index pregnancy 4–10 years before study enrollment were included. Clinical data and whole blood samples were collected and quantified to obtain DNA methylation (DNAm) estimates using the Illumina MethylEPIC 850K array in mothers and offspring. DNAm age and age acceleration were evaluated using the Horvath and Hannum clocks. Multivariable linear regression models were performed to determine the association between EAA and leptin, high-density lipoprotein cholesterol (HDL-C), fasting glucose, fasting insulin, and HOMA-IR. Mothers with a GDM and non-GDM pregnancy had strong correlations between chronological age and DNAm age (r > 0.70). Offspring of GDM mothers had moderate to strong correlations, whereas offspring of non-GDM mothers had moderate correlations between chronological age and DNAm age. Association analyses revealed a significant association between EAA and fasting insulin in offspring (FDR < 0.05), while HDL-C was the only metabolic marker significantly associated with EAA in mothers (FDR < 0.05). Mothers in the GDM group had a higher predicted epigenetic age and age acceleration than mothers in the non-GDM group. The association between EAA with elevated fasting insulin in offspring and elevated HDL-C in mothers suggests possible biomarkers that can better elucidate the effects of exposure to a GDM pregnancy and future cardiometabolic outcomes.

Associations between Epigenetic Age Acceleration and Psychoneurological Symptoms in Sickle Cell Disease

Differential associations between relationship stressors and natural killer cell gene expression by race/ethnicity and sex among older U.S. adults.

Background: Obesity is associated with increased risk of cardiovascular and other age-related diseases that may represent accelerated aging. As methylation levels in DNA change with aging, epigenetic age (EA), which integrates whole-genome methylation has emerged as a novel biomarker of aging and has been associated with mortality and age-related morbidity. Epigenetic age acceleration (EAA), is based on the residual value of 353 previously defined methylation markers regressed on chronologic age (CA), and is thus independent of CA. Therefore, we sought to examine the association of obesity and EAA in midlife. Methods: A subset of participants in the CARDIA cohort (n=1200) randomly selected (balanced on race and sex) underwent genome-wide DNA methylation profiling with the Illumina EPIC array from exam year 15 (2000-01 [age 33-45 years]) and 20 (2005-06 [38-50 years] for calculation of EAA. Body mass index (BMI) was measured at Y15 and Y20, respectively. We used linear regression to examine the association of obesity (independent variable) with EAA after adjusting for CA, race, sex, education, study center, smoking status, physical activity, and alcohol intake. Results: Participants were 52% female and 41% black and had mean BMI 28.5±6.2 kg/m 2 at Y15 and 29.2±6.4 kg/m 2 at Y20. At Y15, participants who were obese had 1.04 (0.38) years higher EAA compared to normal BMI participants (p&lt;0.01, Figure) . Similar results were observed at Y20. Results were similar when evaluating the association of BMI continuously with EAA (p&lt;0.05). Conclusions: EAA is a promising molecular biomarker of aging associated with obesity. Changes in DNA methylation may serve as an intermediate phenotype prior to the onset of age-associated pathologies related to obesity.

Background: The epigenetic clock becomes an important biomarker in aging research, where epigenetic age (EA) approximates chronological age with high accuracy and epigenetic age acceleration (EAA) demonstrates superior performance in predicting health outcomes in the general population. The utility of EAA among adult survivors of childhood cancer is largely unknown. We aimed to compare EAA between childhood cancer survivors and non-cancer controls, and evaluate associations between EAA, treatment exposures, health behaviors, and chronic health conditions (CHCs) among survivors. Methods: Genome-wide methylation data were generated with Infinium EPIC BeadChip on blood derived DNA from 2139 survivors and 282 community controls with no prior history of cancer. EAA was estimated as the residual value from the fit of a simple linear regression of EA (using Levine's clock) on chronological age (i.e., age at DNA sampling). Cumulative doses of chemotherapy and region-specific radiation exposures were abstracted from medical records. Health behaviors including physical activity, diet, tobacco smoking, and alcohol consumption were assessed from questionnaires and categorized as favorable, intermediate and unfavorable. Multivariable piecewise-exponential regression model was employed to evaluate associations of EAA with 59 clinically assessed CHCs. Results: EA was highly correlated with chronological age with the same Pearson coefficient (r = 0.88) in survivors and controls; however, EAA was significantly higher in survivors than controls, overall (adjusted least square mean [ALSM] = 0.63 vs. -3.61 years, P&amp;lt;0.001) and across primary diagnoses (ranging from ALSM = -1.27 in central nervous system tumor to 4.61 in Hodgkin lymphoma). Among survivors, significantly higher EAA was associated with exposures to chest RT, abdomen/pelvic RT, alkylating agents, glucocorticoids, or epipodophyllotoxins. Compared to survivors with favorable health behaviors (ALSM = 0.26), EAA was higher in survivors with intermediate (1.07, P = 0.04) or unfavorable health behaviors (1.45, P = 0.03). After adjusting for attained age, sex, age at diagnosis, and treatment, significant linear trends across tertiles of EAA were identified in associations with occurrences of five CHCs: hypertension (Relative Rate = 1.83 for survivors with EAA in the 3rd vs. the 1st tertile, 95% CI = 1.17-2.83); myocardial infraction (2.91, 1.27-7.21); obesity (1.39, 1.17-1.66); obstructive pulmonary deficit (1.86, 0.95-3.77); and peripheral sensory neuropathy (2.04, 0.99-4.26). Conclusion: EAA is significantly higher in childhood cancer survivors than non-cancer controls and is associated with treatment exposures, health behaviors, and CHCs. Clinically, EAA may inform intervention strategies including health coaching to prevent or delay the onset of CHCs among survivors of childhood cancer. Citation Format: Na Qin, Zhenghong Li, Nan Song, John Easton, Heather Mulder, Emily Plyler, Geoffery Neale, Emily Walker, Carmen L. Wilson, Melissa M. Hudson, Yutaka Yasui, Leslie L. Robison, Jinghui Zhang, Kirsten K. Ness, Zhaoming Wang. Epigenetic age acceleration and chronic health conditions among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5414.

Neighborhood disadvantage and elevated CD14 gene expression among middle-aged adults: Findings from the Midlife in the United States study.

Psychological and physical health are often conceptualized as the absence of disease; there is less research that addresses positive psychological and physical functioning. For example, optimism has been linked with reduced disease risk and biological dysfunction, but very little research has evaluated associations with markers of healthy biological functioning. Thus, we investigated the association between two indicators of positive health: optimism and serum antioxidants. The cross-sectional association between optimism and antioxidant concentrations was evaluated in 982 men and women from the Midlife in the United States study. Primary measures included self-reported optimism (assessed with the revised Life Orientation Test) and serum concentrations of nine different antioxidants (carotenoids and vitamin E). Regression analyses evaluated the relationship between optimism and antioxidant concentrations in models adjusted for demographics, health status, and health behaviors. For every standard deviation increase in optimism, carotenoid concentrations increased by 3% to 13% in age-adjusted models. Controlling for demographic characteristics and health status attenuated this association. Fruit and vegetable consumption and smoking status were identified as potential pathways underlying the association between optimism and serum carotenoids. Optimism was not significantly associated with vitamin E. Optimism was associated with greater carotenoid concentrations, and this association was partially explained by diet and smoking status. The direction of effects cannot be conclusively determined. Effects may be bidirectional given that optimists are likely to engage in health behaviors associated with more serum antioxidants, and more serum antioxidants are likely associated with better physical health that enhances optimism.

Adverse childhood experiences (ACEs) are associated with the risk of poorer health, and identifying molecular mechanisms may lay the foundation for health promotion in people with ACEs. To investigate the associations of ACEs with changes in epigenetic age acceleration (EAA), a biomarker associated with various health outcomes in middle-aged adults, in a population with balanced race and sex demographics. Data for this cohort study were from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Participants in CARDIA underwent 8 follow-up exams from baseline (year 0 [Y0]; 1985-1986) to Y30 (2015-2016), and participant blood DNA methylation information was obtained at Y15 (2000-2001) and Y20 (2005-2006). Individuals from Y15 and Y20 with available DNA methylation data and complete variables for ACEs and covariates were included. Data were analyzed from September 2021 to August 2022. Participant ACEs (general negligence, emotional negligence, physical violence, physical negligence, household substance abuse, verbal and emotional abuse, and household dysfunction) were obtained at Y15. The primary outcome consisted of results from 5 DNA methylation-based EAA measurements known to be associated with biological aging and long-term health: intrinsic EAA (IEAA), extrinsic EAA (EEAA), PhenoAge acceleration (PhenoAA), GrimAge acceleration (GrimAA), and Dunedin Pace of Aging Calculated From the Epigenome (DunedinPACE), measured at Y15 and Y20. Linear regression and generalized estimating equations were used to assess associations of the burden of ACEs (≥4 vs <4 ACEs) with EAA adjusting for demographics, health-related behaviors, and early life and adult socioeconomic status. A total of 895 participants for Y15 (mean [SD] age, 40.4 [3.5] years; 450 males [50.3%] and 445 females [49.7%]; 319 Black [35.6%] and 576 White [64.4%]) and 867 participants for Y20 (mean [SD] age, 45.4 [3.5] years; 432 males [49.8%] and 435 females [50.2%]; 306 Black [35.3%] and 561 White [64.7%]) were included after excluding participants with missing data. There were 185 participants with (20.7%) vs 710 participants without (79.3%) 4 or more ACEs at Y15 and 179 participants with (20.6%) vs 688 participants without (79.4%) 4 or more ACEs at Y20. Having 4 or more ACEs was positively associated with EAA in years at Y15 (EEAA: β = 0.60 years; 95% CI, 0.18-1.02 years; PhenoAA: β = 0.62 years; 95% CI = 0.13-1.11 years; GrimAA: β = 0.71 years; 95% CI, 0.42-1.00 years; DunedinPACE: β = 0.01; 95% CI, 0.01-0.02) and Y20 (IEAA: β = 0.41 years; 95% CI, 0.05-0.77 years; EEAA: β = 1.05 years; 95% CI, 0.66-1.44 years; PhenoAA: β = 0.57 years; 95% CI, 0.08-1.05 years; GrimAA: β = 0.57 years; 95% CI, 0.28-0.87 years; DunedinPACE: β = 0.01; 95% CI, 0.01-0.02) after adjusting for demographics, health-related behaviors, and socioeconomic status. In this cohort study, ACEs were associated with EAA among middle-aged adults after controlling for demographics, behavior, and socioeconomic status. These findings of the associations between early life experience and the biological aging process in midlife may contribute to health promotion in a life course perspective.

Background We sought to assess changes in episodic memory and executive functioning among men and women in the Midlife in the United States (MIDUS) cohort study; and to delineate variations in episodic memory and executive functioning by gender; and to determine the impact of discrimination on longitudinal changes in episodic memory and executive functioning. Methods We used data from the MIDUS study - a national probability sample of non-institutionalized, English speaking respondents aged 25-74 living in the 48 contiguous states of the United States. The initial wave in our study (1995) included 4963 non-institutionalized adults aged 32 to 84 (M = 55, SD = 12.4). Dependent variables are episodic memory and executive functioning, assessed with the Brief Test for Cognition. The independent variables were discrimination (lifetime and daily discrimination) variables. Furthermore, we investigated baseline cognition score, race/ethnicity (White, Hispanic, other), education (some college or more vs high school of less), whether or not living with partner, income (per 100% above Federal Poverty Level), unemployed (vs employed), retired (vs employed), physical health (self-reported), vigorous physical activity, depression (continuous scale), anxiety (continuous scale). To assess cognition changes we estimated adjusted linear regression models. Results Cross-sectional, work discrimination was associated with cognition in men and women. Longitudinally, adjusting for baseline cognition score, race/ethnicity, education, living situation, income, (un)employed, (not)retired, physical health, vigorous physical activity, depression, and anxiety, we found an association of family strain with cognition changes in high-income men, and an association of daily discrimination with cognition changes in men (Beta 0.01, P-value: 0.001). Conclusions Reducing discrimination might be an important measure to support cognitive function in ageing populations.