A novel DNA methylation-based surrogate biomarker for chronic systemic inflammation (InfLaMeS): results from the Health and Retirement Study.

Chronic low-grade systemic inflammation is a risk factor for chronic diseases and mortality and is an important biomarker in health research. DNA methylation (DNAm) surrogate biomarkers are valuable exposure, risk factor and health outcome predictors in studies where the measures cannot be measured directly and often perform as well or better than direct measure. We generated a DNAm surrogate biomarker for chronic, systemic inflammation from a systemic inflammation latent variable of seven inflammatory markers and evaluated its performance relative to measured inflammatory biomarkers in predicting several age-associated outcomes of interest, including mortality, activities of daily living and multimorbidity in the Health and Retirement Study (HRS). The DNAm surrogate, Inflammation Latent Variable Methylation Surrogate (InfLaMeS), correlated with seven individual inflammation markers (r= -0.2-0.6) and performed as well or better to the systemic inflammation latent variable measure when predicting multimorbidity, disability, and 4-year mortality in HRS. Findings were validated in an external cohort, The Irish Longitudinal Study of Ageing. These results suggest that InfLaMeS provides a robust alternative to measured blood-chemistry measures of inflammation with broad applicability in instances where values of inflammatory markers are not measured but DNAm data is available.

Home Mortgage Lending and Neighborhood Mental Health: A Spatial Econometric Analysis of 18 U.S. Metropolitan Statistical Areas.

This study investigates the relationship between home mortgages and neighborhood mental health across the 18 largest metropolitan statistical areas (MSAs) in the United States. Home mortgages, a primary avenue to homeownership, contribute to housing security and stability. Moreover, their issuance reflects local investment and potential improvements in the built environment, hypothesized to positively influence community mental well-being. Using census tract-level data from multiple sources, we employed a spatial econometric approach, specifically spatial error modeling, to account for spatial dependency and estimate the association between home mortgage lending (2011 to 2020) and the prevalence of self-reported poor mental health in 2020. Our findings indicate a statistically significant negative association between mortgage issuance and self-reported poor mental health across all 18 MSAs, suggesting that increased mortgage lending is associated with improved neighborhood mental health. Comparisons between standard linear models and spatial error models highlight the influence of unmeasured, spatially correlated factors on neighborhood mental health outcomes. This study underscores mortgage lending as a crucial factor in community well-being and emphasizes the necessity of addressing spatial dependency in neighborhood health studies for accurate estimations. The findings offer valuable insights for researchers and policymakers aiming to enhance community mental health and address health disparities through informed housing policies.

Childhood Maltreatment and Longitudinal Epigenetic Aging: NIMHD Social Epigenomics Program.

Importance: Child physical and emotional abuse and neglect may affect epigenetic signatures of accelerated aging several years after the exposure. Objective: To examine the longitudinal outcomes of early-childhood and midchildhood exposures to maltreatment on later childhood and adolescent profiles of epigenetic accelerated aging. Design, Setting, and Participants: This cohort study used data from the Future of Families and Child Wellbeing Study (enrolled 1998-2000), a US birth cohort study with available DNA methylation (DNAm) data at ages 9 and 15 years (assayed between 2017 and 2020) and phenotypic data at birth (wave 1), and ages 3 (wave 3), 5 (wave 4), 9 (wave 5), and 15 (wave 6) years. Data were analyzed between June 18 and December 10, 2023. Exposures: Emotional aggression, physical assault, emotional neglect, and physical neglect via the Parent-Child Conflict Tactics Scale at ages 3 and 5 years. Main Outcomes and Measures: Epigenetic accelerated aging (DNAmAA) was measured using 3 machine learning-derived surrogates of aging (GrimAge, PhenoAge, and DunedinPACE) and 2 machine learning-derived surrogates of age (Horvath and PedBE), residualized for age in months. Results: A total of 1971 children (992 [50.3%] male) representative of births in large US cities between 1998 and 2000 were included. Physical assault at age 3 years was positively associated with DNAmAA for PhenoAge (ß = 0.073; 95% CI, 0.019-0.127), and emotional aggression at age 3 years was negatively associated with PhenoAge DNAmAA (ß = -0.107; 95% CI, -0.162 to -0.052). Emotional neglect at age 5 years was positively associated with PhenoAge DNAmAA (ß = 0.051; 95% CI, 0.006-0.097). Cumulative exposure to physical assault between ages 3 and 5 years was positively associated with PhenoAge DNAmAA (ß = 0.063; 95% CI, 0.003-0.123); emotional aggression was negatively associated with PhenoAge DNAmAA (ß = -0.104; 95% CI, -0.165 to -0.043). The association of these measures with age 15 years PhenoAge DNAmAA was almost fully mediated by age 9 years PhenoAge DNAm age acceleration. Similar patterns were found for GrimAge, DunedinPACE, and PhenoAge, but only those for PhenoAge remained after adjustments for multiple comparisons. Conclusions and Relevance: In this cohort study, altered patterns of DNAmAA were sensitive to the type and timing of child maltreatment exposure and appeared to be associated with more proximate biological embedding of stress.

Cognition and Wealth Changes in Mid-to-later Life: A Latent Class Trajectories Approach Using the Health and Retirement Study.

ObjectivesTo assess how cognitive trajectories from mid-to-later life relate to wealth change, overall and by mid-life income. Methods: Data were from participants (51-64 years) in the 2000-2018 U.S. Health and Retirement Study who were cognitively healthy at baseline (year 2000; unweighted n = 3821). Longitudinal latent class analyses generated cognitive and wealth trajectories, independently, and multinomial logistic regressions estimated the association between cognitive trajectories and wealth profiles, overall and by median income. Results: We identified three cognitive: cognitively healthy (CH), increasing cognitive impairment (ICI), and increasing dementia (ID) and four wealth profiles: stable wealth loss (SWL), delayed gradual wealth loss (DGWL), stable wealth gain (SWG), and gradual wealth gain (GWG). The ID group had higher probability of being in the SWL group and lower probability of SWG, which was more pronounced in respondents with greater median income. Discussion: Individuals with ID may be vulnerable to wealth loss, particularly for middle-class households.

Immune cells are associated with mortality: the Health and Retirement Study.

Introduction: Age-related immunosenescence is characterized by changes in immune cell subsets and is associated with mortality. However, since immunosenescence is associated with other concurrent age-related changes such as inflammation and multi-organ dysfunction, it is unclear whether the association between age-related immunosenescence and mortality is independent of other concurrent age-related changes. To address these limitations, we evaluated the independent association between immune cell subsets and mortality after adjustment for age-related inflammation and biologic age. Methods: Data for this study was obtained from the 2016 interview of the Health and Retirement Study (N=6802). Cox proportional hazards regression models were used to estimate the association between 25 immune cell subsets (11 T-cell subsets, 4 B-cell subsets, 3 monocyte subsets, 3 natural killer cell subsets, 3 dendritic cell subsets, and neutrophils) and 4-year mortality adjusting for covariates such as the Klemera-Doubal algorithm biological age, chronological age, gender, race/ethnicity, BMI, smoking status, comorbidity index, CMV seropositivity, and inflammatory latent variable comprising C-reactive protein, and 4 cytokines (interleukin-10, interleukin-1 receptor antagonist, interleukin-6, and soluble tumor necrosis factor). Results: Four hundred and seventy-six participants died during the study period with an overall median follow up time of 2.5 years. After controlling for covariates and adjustment for sample-weights, total T cells [HR: 0.86, p=0.004], NK CD56LO cells [HR: 0.88, p=0.005], and neutrophils [HR: 1.22, p=0.004] were significantly associated with mortality. Conclusions: These findings support the idea that an aging immune system is associated with short-term mortality independent of age-related inflammation or other age-related measures of physiological dysfunction. If replicated in other external cohorts, these findings could identify novel targets for both monitoring and intervention to reduce the age-related mortality.

Cohabitation as a determinant of adaptive and innate immune cell profiles: Findings from the Health and Retirement Study.

Introduction: Non-genetic factors are important but poorly understood determinants of immune profiles. Age and Cytomegalovirus (CMV) infection remain two well documented non-genetic determinants of the immune profile. Recently, one study identified cohabitation in the same household as an important determinant of immune profiles. Methods: We used immunophenotyping data from the Health and Retirement Study (HRS) to evaluate the association between cohabitation and the adaptive (subsets of T-cells, B-cells) and innate immune profiles (subsets of monocytes, natural killer cells and neutrophils). We compared adaptive and innate immune cell profiles using immunophenotyping data from 1184 same-household pairs (cohabitating partners) to 1184 non-household pairs to evaluate the association between cohabitation and adaptive immune cell profiles. We used data from 1737 same-household pairs and 1737 non-household pairs to evaluate the association between cohabitation and innate cell profiles. Household and non-household pairs were matched on age (±2years), educational background and race/ethnicity to minimize confounding due to these factors. The adaptive immune cells and innate immune cell profiles were compressed to two coordinates using multidimensional scaling (MDS). The Euclidean distances between same-household pairs were compared to the distances between non-household pairs for the adaptive and innate cell profiles separately using two sample independent t-tests. We also performed additional adjustment for age and BMI differences, CMV serostatus and smoking concordance/discordance status among household members. Results: For adaptive immune cell profiles, the mean Euclidean distance between same-household pairs was 4% lower than the non-household pairs (p = 0.03). When stratified by concordance for CMV serostatus among household pairs, the Euclidean distance was significantly lower by 8% in the same-household pairs as compared to non-household pairs among those who were discordant for CMV serostatus (p = 0.01) and among same-household pairs who were CMV seronegative (p = 0.02) after covariate adjustment. The mean Euclidian distance between same-household pairs was also 8% lower than non-household pairs for the innate immune cell profiles (p-value <0.0001) and this difference remained consistent across all strata of CMV infection. Discussion: This study confirms that cohabitation is associated with similarity in immune cell profiles. The differential effects of cohabitation on the adaptive and innate immune profiles suggest that further studies into the common environmental factors that influence individual immune cell subsets need to be evaluated in greater detail.

Systemic inflammation and biological aging in the Health and Retirement Study.

Chronic, low-level systemic inflammation associated with aging, or inflammaging, is a risk factor for several chronic diseases and mortality. Using data from the Health and Retirement Study, we generated a continuous latent variable for systemic inflammation from seven measured indicators of inflammation and examined associations with another biomarker of biological aging, DNA methylation age acceleration measured by epigenetic clocks, and 4-year mortality (N = 3,113). We found that greater systemic inflammation was positively associated with DNA methylation age acceleration for 10 of the 13 epigenetic clocks, after adjustment for sociodemographics and chronic disease risk factors. The latent variable for systemic inflammation was associated with 4-year mortality independent of DNA methylation age acceleration and was a better predictor of 4-year mortality than any of the epigenetic clocks examined, as well as mortality risk factors, including obesity and multimorbidity. Inflammaging and DNA methylation age acceleration may represent different biological processes contributing to mortality risk. Leveraging multiple measured inflammation markers to capture inflammaging is important for biology of aging research.

Age-related Differences in T-cell Subsets and Markers of Subclinical Inflammation in Aging Are Independently Associated With Type 2 Diabetes in the Health and Retirement Study.

OBJECTIVES: Age-related changes in adaptive immunity and subclinical inflammation are both important risk factors for diabetes in older adults. We evaluated the independent association between T-cell subsets, subclinical inflammation, and diabetes risk in the Health and Retirement Study (HRS). METHODS: We measured 11 T-cell subsets, 5 pro-inflammatory markers, and 2 anti-inflammatory markers from the 2016 wave of the HRS (baseline). Diabetes/prediabetes status was estimated at the 2016, 2018, and 2020 waves of HRS, based on levels of blood glucose/glycated hemoglobin in plasma or self-reported status. We used survey generalized logit models to evaluate the cross-sectional associations and Cox proportional hazard models to evaluate longitudinal associations. RESULTS: Among 8,540 participants (56 to 107 years of age), 27.6% had prevalent type 2 diabetes and 31.1% had prediabetes in the 2016 survey. After adjusting for age, sex, race/ethnicity, education, obesity, smoking, comorbidity index, and cytomegalovirus seropositivity, individuals with type 2 diabetes had lower naive T cells and higher memory and terminal effector T cells as compared with normoglycemic individuals. Among 3,230 normoglycemic participants in the 2016 survey, the incidence of diabetes was 1.8% over 4 years of follow-up. The baseline percentage of CD4+ effector memory T cells was associated with a lower risk of incident diabetes (hazard ratio [HR]=0.63, 95% confidence interval [CI] 0.49 to 0.80, p=0.0003) after adjustment for covariates. Baseline level of interleukin-6 (IL-6) was associated with risk of incident diabetes (HR=1.52, 95% CI 1.18 to 1.97, p=0.002). The associations between age-related changes in CD4+ effector memory T cells and risk of incident diabetes remained unchanged after adjustment for subclinical inflammation, although adjusting for CD4+ effector memory T cells nullified the association between IL-6 and incident diabetes. CONCLUSIONS: This study showed that the baseline percentage of CD4+ effector memory T cells was inversely associated with incident diabetes independent of subclinical inflammation, but CD4+ effector memory T-cell subsets affected the relationship between IL-6 and incident diabetes. Further studies are needed to confirm and investigate mechanisms by which T-cell immunity affects diabetes risk.

Association between prenatal socioeconomic disadvantage, adverse birth outcomes, and inflammatory response at birth.

Prenatal socioeconomic disadvantage is associated with inflammation in mid- to late-life, yet whether a pro-inflammatory phenotype is present at birth and the role of adverse birth outcomes in this pathway remains unclear. We utilized data on prenatal socioeconomic disadvantage at the individual- (i.e., mother's and father's education level, insurance type, marital status, and Women, Infants, and Children benefit receipt) and census-tract level as well as preterm (< 37 weeks gestation) and small-for-gestational-age (SGA) (i.e., < 10th percentile of sex-specific birth weight for gestational age) birth status, and assessed inflammatory markers (i.e., C-reactive protein, serum amyloid p, haptoglobin, and α-2 macroglobulin) in archived neonatal bloodspots from a Michigan population-based cohort of 1000 neonates. Continuous latent variables measuring individual- and combined individual- and neighborhood-level prenatal socioeconomic disadvantage were constructed and latent profile analysis was used to create a categorical inflammatory response variable (high versus low) based on continuous inflammatory marker levels. Structural equation models were used to estimate the total and direct effect of prenatal socioeconomic disadvantage on the inflammatory response at birth as well as indirect effect via preterm or SGA birth (among term neonates only), adjusting for mother's age, race/ethnicity, body mass index, smoking status, comorbidities, and antibiotic use/infection as well as grandmother's education level. There was a statistically significant total effect of both individual- and combined individual- and neighborhood-level prenatal socioeconomic disadvantage on high inflammatory response among all neonates as well as among term neonates only, and a positive but not statistically significant direct effect in both groups. The indirect effects via preterm and SGA birth were both negative, but not statistically significant. Our findings suggest prenatal socioeconomic disadvantage contributes to elevated neonatal inflammatory response, but via pathways outside of these adverse birth outcomes.

Grip strength is inversely associated with DNA methylation age acceleration.

BACKGROUND: There is a large body of evidence linking muscular weakness, as determined by low grip strength, to a host of negative ageing-related health outcomes. Given these links, grip strength has been labelled a 'biomarker of aging'; and yet, the pathways connecting grip strength to negative health consequences are unclear. The objective of this study was to determine whether grip strength was associated with measures of DNA methylation (DNAm) age acceleration. METHODS: Middle age and older adults from the 2006 to 2008 waves of the Health and Retirement Study with 8-10 years of follow-up were included. Cross-sectional and longitudinal regression modelling was performed to examine the association between normalized grip strength (NGS) and three measures of DNAm age acceleration, adjusting for cell composition, sociodemographic variables and smoking. Longitudinal modelling was also completed to examine the association between change in absolute grip strength and DNAm age acceleration. The three DNAm clocks used for estimating age acceleration include the established DunedinPoAm, PhenoAge and GrimAge clocks. RESULTS: There was a robust and independent cross-sectional association between NGS and DNAm age acceleration for men using the DunedinPoAm (ß: -0.36; P < 0.001), PhenoAge (ß: -8.27; P = 0.01) and GrimAge (ß: -4.56; P = 0.01) clocks and for women using the DunedinPoAm (ß: -0.36; P < 0.001) and GrimAge (ß: -4.46; P = 0.01) clocks. There was also an independent longitudinal association between baseline NGS and DNAm age acceleration for men (ß: -0.26; P < 0.001) and women (ß: -0.36; P < 0.001) using the DunedinPoAm clock and for women only using the PhenoAge (ß: -8.20; P < 0.001) and GrimAge (ß: -5.91; P < 0.001) clocks. Longitudinal modelling revealed a robust association between change in grip strength from wave 1 to wave 3 was independently associated with PhenoAgeAA (ß: -0.13; 95% CI: -0.23, -0.03) and GrimAgeAA (ß: -0.07; 95% CI: -0.14, -0.01) in men only (both P < 0.05). CONCLUSIONS: Our findings provide some initial evidence of age acceleration among men and women with lower NGS and loss of strength over time. Future research is needed to understand the extent to which DNAm age mediates the association between grip strength and chronic disease, disability and mortality.

Socioeconomic status and immune aging in older US adults in the health and retirement study.

Socioeconomic and demographic factors including educational attainment, race and ethnicity, and childhood socioeconomic status (SES) are powerful predictors of inequalities in aging, morbidity, and mortality. Immune aging, including accumulation of late-differentiated, senescent-like lymphocytes and lower levels of naïve lymphocytes, may play a role in the development of the age-related health inequalities. This study used nationally representative data from more than 9,000 US adults from the Health and Retirement Study to investigate associations between educational attainment, race and ethnicity, and childhood SES and lymphocyte percentages. Respondents with lower educational attainment, Hispanic adults, and those who had a parent with less than a high school education had lymphocyte percentages consistent with more immune aging compared to those with greater educational attainment, non-Hispanic White adults, and respondents who had parents with a high school education, respectively. Associations between education, Hispanic ethnicity, and parents' education and late differentiated senescent-like T lymphocytes (TemRA) and B cells were largely driven by cytomegalovirus (CMV), suggesting it is a factor in observed SES inequalities in immunosenescence. Naïve T lymphocytes may be particularly affected by socioeconomic position and may therefore be of particular interest to research interested in inequalities in health and aging.

Historic redlining in Columbus, Ohio associated with stroke prevalence.

BACKGROUND: Racial disparities exist in stroke and stroke outcomes. In an ecologic study, using the Home Owners' Loan Corporation (HOLC) "redlining" scores, as indicator of historic racialized lending practices, we hypothesized that census tracts with high historic redlining are associated with higher stroke prevalence. METHODS: Weighted historic redlining scores (HRS) were calculated using the proportion of 1930s HOLC residential security grades contained within 2010 census tract boundaries of Columbus, Ohio. Stroke prevalence (adults >=18) was obtained at the census tract-level from the CDC's 500 Cities Project. Sociodemographic census tract level data (American Community Survey 2014-2018) were considered mediators in the causal association between historic redlining and stroke prevalence and were not controlled for in regression analysis. HRS and stroke prevalence associations were evaluated with and without adjustment for proportion of census tract 65 years and older. RESULTS: Census tracts in the highest quartile of HRS (greater redlining) had 1.73% higher stroke prevalence compared to those in the lowest quartile (95% CI:0.41,3.05) adjusting for proportion 65 years and older. No other interquartile differences were observed. CONCLUSIONS: Historic redlining practices are a form of structural racism that established geographic systems of disadvantage and consequently, poor health outcomes. Our findings demonstrate disparate stroke prevalence by degree of historic redlining in census tracts across Columbus, Ohio.

Benzophenone-3 and antinuclear antibodies in U.S. adolescents and adults ages 12-39 years.

Background: Between 1988 and 2012, prevalence of antinuclear antibodies (ANA) increased in the U.S., especially in adolescents and non-Hispanic Whites. Female predominance of ANA suggests a role for hormonal factors, including xenobiotic exposures that may disrupt endocrine signaling. Benzophenone-3 (BP-3) is one such chemical with increasing exposure through sunscreen use. We investigated whether urinary BP-3 levels were related to ANA in adolescents and young adults. Methods: In a sample of 1,785 individuals ages 12-39 years in the National Health and Nutrition Examination Survey (NHANES; 2003-4, 2011-12), we examined cross-sectional associations of ANA (N=192; 3+ or 4+ at the 1:80 dilution, measured by HEp-2 immunofluorescence) with urinary BP-3, and other phenols bisphenol-A, triclosan, and parabens. Adjusted prevalence odds ratios (POR) were calculated in season-stratified models [winter (November-April) and summer (May-October)], given differences in sunscreen use and BP-3 concentrations. Results: BP-3 concentrations (detected in >98.5% of individuals) did not differ by ANA positivity in the summer (geometric mean, GM 30.6 ng/ml ANA-positive vs. 35.3 ANA-negative; GM ratio 1.15), but in winter were higher among ANA-positives (50.2 vs. 20.1 ANA-negative; GM ratio 2.50). ANA was associated with log10BP-3 in winter (POR 1.57; 95%CI 1.07-2.30 per unit increase) but not summer (0.94; 0.61, 1.44; interaction p=0.09). Triclosan, parabens, and bisphenol-A levels were unrelated to ANA overall or by season (ORs 0.64 to 1.33). Conclusions: The association of urinary BP-3 with ANA in the winter may reflect different exposure patterns or unmeasured confounders. Findings warrant replication in prospective studies and including past and year-round exposures.

Early life trauma and adult leucocyte telomere length.

BACKGROUND: Telomere length, a biomarker of cell division and cellular aging, has been associated with multiple chronic disease endpoints. Experienced trauma over the life course may contribute to telomere shortening via mechanisms of stress embodiment. However, it is unclear how patterns of co-occurring trauma during sensitive periods (e.g., early life) throughout the life course may influence telomere shortening. We examine the relationship between co-occurring early life trauma on adult telomere length and the extent to which adulthood trauma, socioeconomic position, and health and lifestyle factors may mediate this relationship. METHODS: We use data from a sample of participants in the Sister Study (N = 740, analytic sample: n = 602), a prospective cohort of U.S. self-identified females aged 35-74 years at enrollment (2003-2009) for whom leukocyte telomere length was measured in baseline blood samples. Participants reported their experience of 20 different types of trauma, from which we identified patterns of co-occurring early life trauma (before age 18) using latent class analysis. We estimated the direct and indirect effects of early life trauma on leukocyte telomere length using structural equation modeling, allowing for mediating adult pathways. RESULTS: Approximately 47 % of participants reported early life trauma. High early life trauma was associated with shorter telomere length compared to low early life trauma (ß = -0.11; 95 % CI: -0.22, -0.004) after adjusting for age and childhood socioeconomic position. The inverse association between early life trauma and adult leukocyte telomere length was largely attributable to the direct effect of early life trauma on telomere length (ß = -0.12; 95 %CI: -0.23, -0.01). Mediating indirect pathways via adult trauma, socioeconomic position, and health metrics did not substantively contribute the overall association. CONCLUSIONS: These findings highlight the role of patterns of co-occurring early life trauma on shortened telomere length independent of adult pathways.

Prenatal Socioeconomic Disadvantage and Epigenetic Alterations at Birth Among Children Born to White British and Pakistani Mothers in the Born in Bradford Study.

Prenatal socioeconomic disadvantage (SD) has been linked to DNA methylation (DNAm) in adulthood, but whether such epigenetic alterations are present at birth remains unclear. We carried out an epigenome-wide analysis of the association between several measures of individual- and area-level prenatal SD and DNAm assessed in neonatal cord blood via the Infinium EpicBeadChip among offspring born to mothers of White British (N = 455) and Pakistani (N = 493) origin in the Born in Bradford Study. Models were adjusted for mother's age, ethnicity, and education level as well as cell-type fractions and then for maternal health behaviours and neonate characteristics, and last, stratified by mother's ethnicity. P-values were corrected for multiple testing and a permutation-based approach was used to account for small cell sizes. Among all children, housing tenure (owning versus renting) as well as father's occupation (manual versus non-manual) were each associated with DNAm of one CpG site and index of multiple deprivation (IMD) was associated with DNAm of 11 CpG sites. Among children born to White British mothers, father's occupation (student or unemployed versus non-manual) was associated with DNAm of 1 CpG site and IMD with DNAm of 3 CpG sites. Among children born to Pakistani mothers, IMD was associated with DNAm of 1 CpG site. Associations were largely unchanged after further adjustment for maternal health behaviours or neonate characteristics and remained statistically significant. Our findings suggest that individual- and area-level prenatal SD may shape alterations to the neonatal epigenome, but associations vary across ethnic groups.

Evaluation of T-cell aging-related immune phenotypes in the context of biological aging and multimorbidity in the Health and Retirement Study.

BACKGROUND: Cellular changes in adaptive immune system accompany the process of aging and contribute to an aging-related immune phenotype (ARIP) characterized by decrease in naïve T-cells (TN) and increase in memory T-cells (TM). A population-representative marker of ARIP and its associations with biological aging and age-related chronic conditions have not been studied previously. METHODS: We developed two ARIP indicators based on well understood age-related changes in T cell distribution: TN/(TCM (Central Memory) + TEM (Effector Memory) + TEFF (Effector)) (referred as TN/TM) in CD4 + and CD8 + T-cells. We compared them with existing ARIP measures including CD4/CD8 ratio and CD8 + TN cells by evaluating associations with chronological age and the Klemera Doubal measure of biological age (measured in years) using linear regression, multimorbidity using multinomial logistic regression and two-year mortality using logistic regression. RESULTS: CD8 + TN and CD8 + TN/TM had the strongest inverse association with chronological age (beta estimates: -3.41 and -3.61 respectively; p-value < 0.0001) after adjustment for sex, race/ethnicity and CMV status. CD4 + TN/TM and CD4 + TN had the strongest inverse association with biological age (ß = -0.23; p = 0.003 and ß = -0.24; p = 0.004 respectively) after adjustment for age, sex, race/ethnicity and CMV serostatus. CD4/CD8 ratio was not associated with chronological age or biological age. CD4 + TN/TM and CD4 + TN was inversely associated with multimorbidity. For CD4 + TN/TM, people with 2 chronic conditions had an odds ratio of for 0.74 (95%CI: 0.63-0.86 p = 0.0003) compared to those without any chronic conditions while those with 3 chronic conditions had an odds ratio of 0.75 (95% CI: 0.63-0.90; p = 0.003) after adjustment for age, sex, race/ethnicity, CMV serostatus, smoking, and BMI. The results for the CD4 + TN subset were very similar to the associations seen with the CD4 + TN/TM. CD4 + TN/TM and CD4 + TN were both associated with two-year mortality (OR = 0.80 (95% CI: 0.67-0.95; p = 0.01) and 0.81 (0.70-0.94; p = 0.01), respectively). CONCLUSION: CD4 + TN/TM and CD4 + TN had a stronger association with biological age, age-related morbidity and mortality compared to other ARIP measures. Future longitudinal studies are needed to evaluate the utility of the CD4 + subsets in predicting the risk of aging-related outcomes.

Latent Class Models of Early-life Trauma and Incident Breast Cancer.

BACKGROUND: Psychosocial trauma has been hypothesized to influence breast cancer risk, but little is known about how co-occurring traumas-particularly during early life-may impact incidence. We examine the relationship between multiple measures of early-life trauma and incident breast cancer. METHODS: The Sister Study is a prospective cohort study of US women (n = 50,884; enrollment 2003-2009; ages 35-74). Of 45,961 eligible participants, 3,070 developed invasive breast cancer or ductal carcinoma in situ through 2017. We assessed trauma before age 18 using previously studied measures (cumulative score, individual trauma type, and substantive domain) and a six-class latent variable to evaluate co-occurring traumas. We accounted for missing data using multiple imputation and estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional-hazards models. RESULTS: Approximately 49% of participants reported early-life trauma. Using the latent class variable approach, breast cancer hazard was higher among participants who had sexual trauma or household dysfunction (HR = 1.1; CI = 0.93, 1.3) or moderate (HR = 1.2; CI = 0.99, 1.4) but not high trauma (HR = 0.66; CI = 0.44, 0.99) compared to low trauma. Breast cancer HRs associated with sexual early-life trauma or household dysfunction were elevated for pre- and postmenopausal breast cancer and by estrogen receptor status. We found no effect modification by race-ethnicity. Estimated effects were attenuated with report of constant childhood social support. CONCLUSIONS: Breast cancer incidence varied by latent patterns of co-occurring early-life trauma. Models capturing childhood social support and trauma patterning, rather than cumulative or discrete indicators, may be more meaningful in breast cancer risk assessment.

Hygiene Hypothesis Indicators and Prevalence of Antinuclear Antibodies in US Adolescents.

Autoimmunity prevalence, as measured by antinuclear antibodies (ANA), is increasing in U.S. adolescents. Improved hygiene and cleaner environments in childhood may reduce exposure to infections and other immune challenges, resulting in improper immune responses to later-life exposures. We examined associations of hygiene hypothesis indicators, including asthma, allergies, and antibodies to infectious agents, with ANA prevalence, measured by HEp-2 immunofluorescence, in adolescents (aged 12-19 years) over a 25-year time span in the National Health and Nutrition Examination Survey (NHANES) (N=2,709), adjusting for age, sex, race/ethnicity, body mass index, education and survey cycle, overall and within individual time periods, using logistic regression. Prevalence of ANA in adolescents increased from 5.0% in 1988-1991 to 12.8% in 2011-2012. ANA were positively associated with diagnosis of asthma in early childhood (OR: 2.07, CI: 1.09-3.99) and the effect estimate for current hay fever was elevated but not statistically significant (OR: 1.55, CI: 0.85-2.84). Fewer than 2% of those with ANA in 1988-1991 had been diagnosed with asthma, compared with 18% in 1999-2000, and 27% in 2003-2004 and 2011-2012. ANA trended negatively with Helicobacter pylori antibodies (OR: 0.49, CI: 0.24-0.99). ANA may be useful as an additional indicator of inadequate immune education in adolescence, a critical period of growth and development.

The legacy of structural racism: Associations between historic redlining, current mortgage lending, and health.

Structural racism, which is embedded in past and present operations of the U.S. housing market, is a fundamental cause of racial health inequities. We conducted an ecologic study to 1) examine historic redlining in relation to current neighborhood lending discrimination and three key indicators of societal health (mental health, physical health, and infant mortality rate (IMR)) and 2) investigate sustained lending disinvestment as a determinant of current neighborhood health in one of the most hypersegregated metropolitan areas in the United States, Milwaukee, Wisconsin. We calculated weighted historic redlining scores from the proportion of 1930s Home Owners' Loan Corporation residential security grades contained within 2010 census tract boundaries. We combined two lending indicators from 2018 Home Mortgage Disclosure Act data to capture current neighborhood lending discrimination: low lending occurrence and high cost loans (measured via loan rate spread). Using historic redlining score and current lending discrimination, we created a 4-level hierarchical measure of lending trajectory. In Milwaukee neighborhoods, greater historic redlining was associated with current lending discrimination (OR = 1.73, 95%CI: 1.16, 2.58) and increased prevalence of poor physical health (ß = 1.34, 95%CI: 0.40, 2.28) and poor mental health (ß = 1.26, 95%CI: 0.51, 2.01). Historic redlining was not associated with neighborhood IMR (ß = -0.48, 95%CI: -2.12, 1.15). A graded association was observed between lending trajectory and health: neighborhoods with high sustained disinvestment had worse physical and mental health than neighborhoods with high investment (poor physical health: ß = 5.33, 95%CI: 3.05, 7.61; poor mental health: ß = 4.32, 95%CI: 2.44, 6.20). IMR was highest in 'disinvested' neighborhoods (ß = 5.87, 95%CI: 0.52, 11.22). Our findings illustrate ongoing legacies of government sponsored historic redlining. Structural racism, as manifested in historic and current forms of lending disinvestment, predicts poor health in Milwaukee's hypersegregated neighborhoods. We endorse equity focused policies that dismantle and repair the ways racism is entrenched in America's social fabric.

Objective and subjective childhood socioeconomic disadvantage and incident depression in adulthood: a longitudinal analysis in the Sister Study.

Understanding of the role of objective versus subjective childhood socioeconomic disadvantage (SD) in depression onset in adulthood among women, independent of later life SD, and across birth cohorts, is limited. We examined the association between objective (i.e., household education level) and subjective (i.e., rank of family income and report of not enough food to eat) SD during childhood and diagnosis of clinical depression after age 30 among 47,055 women in the Sister Study. We used Cox proportional hazard models adjusting for women's race/ethnicity, childhood household composition, mother's age at her birth adulthood educational attainment, and calendar year of birth. Analyses were repeated stratified by 10-year birth group. A total of 8036 (17.1%) women were diagnosed with clinical depression over a mean follow-up of 24.0 (± 9.9) years. Those reporting being poor (versus well-off) or not having enough food to eat in childhood had a 1.28 (95% confidence interval (CI) 1.13, 1.44) and 1.30 (95% CI 1.21, 1.41) times higher rate of depression diagnosis, respectively, with consistent associations observed across birth year groups. An inverse association between low household education level and incident depression was observed at baseline (i.e., age 30) becoming positive over time in the total sample but only among women born between 1935-1954 in analyses stratified by 10-year birth group. Our findings suggest that subjective SD in childhood is a largely consistent predictor of depression onset among women in adulthood whereas the effects of household education level in childhood may vary across women born into different birth cohorts, and for some, across the lifecourse.