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Background: Understanding the impact of clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) on solid tumor risk and mortality can shed light on novel cancer pathways. Methods: The authors analyzed whole genome sequencing data from the Trans‐Omics for Precision Medicine Women's Health Initiative study (n = 10,866). They investigated the presence of CHIP and mCA and their association with the development and mortality of breast, lung, and colorectal cancers. Results: CHIP was associated with higher risk of breast (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.03–1.64; p =.02) but not colorectal (p =.77) or lung cancer (p =.32). CHIP carriers who developed colorectal cancer also had a greater risk for advanced‐stage (p =.01), but this was not seen in breast or lung cancer. CHIP was associated with increased colorectal cancer mortality both with (HR, 3.99; 95% CI, 2.41–6.62; p <.001) and without adjustment (HR, 2.50; 95% CI, 1.32–4.72; p =.004) for advanced‐stage and a borderline higher breast cancer mortality (HR, 1.53; 95% CI, 0.98–2.41; p =.06). Conversely, mCA (cell fraction [CF] >3%) did not correlate with cancer risk. With higher CFs (mCA >5%), autosomal mCA was associated with increased breast cancer risk (HR, 1.39; 95% CI, 1.06–1.83; p =.01). There was no association of mCA (>3%) with breast, colorectal, or lung mortality except higher colon cancer mortality (HR, 2.19; 95% CI, 1.11–4.3; p =.02) with mCA >5%. Conclusions: CHIP and mCA (CF >5%) were associated with higher breast cancer risk and colorectal cancer mortality individually. These data could inform on novel pathways that impact cancer risk and lead to better risk stratification. In the Women's Health Initiative Trans‐Omics for Precision Medicine study, participants with clonal hematopoiesis of indeterminate potential (CHIP) had higher breast cancer incidence and a higher colorectal cancer mortality than women without CHIP. The presence of autosomal mosaic chromosomal alterations with >5% cell fraction was associated with higher incidence of breast cancer but no other cancers. [ABSTRACT FROM AUTHOR]

BACKGROUND: Evidence linking gaseous air pollution to late-life brain health is mixed. OBJECTIVE: We explored associations between exposure to gaseous pollutants and brain magnetic resonance imaging (MRI) markers among Atherosclerosis Risk in Communities (ARIC) Study participants, with attention to the influence of exposure estimation method and confounding by site. METHODS: We considered data from 1,665 eligible ARIC participants recruited from four US sites in the period 1987–1989 with valid brain MRI data from Visit 5 (2011–2013). We estimated 10-y (2001–2010) mean carbon monoxide (CO), nitrogen dioxide (NO2), nitrogen oxides (NOx), and 8- and 24-h ozone (O3) concentrations at participant addresses, using multiple exposure estimation methods. We estimated site-specific associations between pollutant exposures and brain MRI outcomes (total and regional volumes; presence of microhemorrhages, infarcts, lacunes, and severe white matter hyperintensities), using adjusted linear and logistic regression models. We compared meta-analytically combined site-specific associations to analyses that did not account for site. RESULTS: Within-site exposure distributions varied across exposure estimation methods. Meta-analytic associations were generally not statistically significant regardless of exposure, outcome, or exposure estimation method; point estimates often suggested associations between higher NO2 and NOx and smaller temporal lobe, deep gray, hippocampal, frontal lobe, and Alzheimer disease signature region of interest volumes and between higher CO and smaller temporal and frontal lobe volumes. Analyses that did not account for study site more often yielded significant associations and sometimes different direction of associations. DISCUSSION: Patterns of local variation in estimated air pollution concentrations differ by estimation method. Although we did not find strong evidence supporting impact of gaseous pollutants on brain changes detectable by MRI, point estimates suggested associations between higher exposure to CO, NOx, and NO2 and smaller regional brain volumes. Analyses of air pollution and dementia-related outcomes that do not adjust for location likely underestimate uncertainty and may be susceptible to confounding bias. [ABSTRACT FROM AUTHOR]

Background Heterogeneity in ageing rates drives the need for research into lifestyle secrets of successful agers. Biological age, predicted by epigenetic clocks, has been shown to be a more reliable measure of ageing than chronological age. Dietary habits are known to affect the ageing process. However, much remains to be learnt about specific dietary habits that may directly affect the biological process of ageing. Objective To identify food groups that are directly related to biological ageing, using Copula Graphical Models. Methods We performed a preregistered analysis of 3,990 postmenopausal women from the Women's Health Initiative, based in North America. Biological age acceleration was calculated by the epigenetic clock PhenoAge using whole-blood DNA methylation. Copula Graphical Modelling, a powerful data-driven exploratory tool, was used to examine relations between food groups and biological ageing whilst adjusting for an extensive amount of confounders. Two food group–age acceleration networks were established: one based on the MyPyramid food grouping system and another based on item-level food group data. Results Intake of eggs, organ meat, sausages, cheese, legumes, starchy vegetables, added sugar and lunch meat was associated with biological age acceleration, whereas intake of peaches/nectarines/plums, poultry, nuts, discretionary oil and solid fat was associated with decelerated ageing. Conclusion We identified several associations between specific food groups and biological ageing. These findings pave the way for subsequent studies to ascertain causality and magnitude of these relationships, thereby improving the understanding of biological mechanisms underlying the interplay between food groups and biological ageing. [ABSTRACT FROM AUTHOR]

Background: Elevated psychosocial stress has been linked with accelerated biological aging, including composite DNA methylation (DNAm) markers that predict aging‐related outcomes ("epigenetic age"). However, no study has examined whether stressful life events (SLEs) are associated with epigenetic age acceleration in postmenopausal women, an aging population characterized by increased stress burden and disease risk. Methods: We leveraged the Women's Health Initiative, a large muti‐ancestry cohort of postmenopausal women with available psychosocial stress measures over the past year and epigenomic data. SLEs and social support were ascertained via self‐report questionnaires. Whole blood DNAm array (450 K) data were used to calculate five DNAm‐based predictors of chronological age, health span and life span, and telomere length (HorvathAge, HannumAge, PhenoAge, GrimAge, DNAmTL). Results: After controlling for potential confounders, higher SLE burden was significantly associated with accelerated epigenetic aging, as measured by GrimAge (β: 0.34, 95% CI: 0.08, 0.59) and DNAmTL (β: −0.016, 95% CI: −0.028, −0.004). Exploratory analyses showed that SLEs‐GrimAge associations were stronger in Black women as compared to other races/ethnicities and in those with lower social support levels. In women with lower social support, SLEs‐DNAmTL associations showed opposite association in Hispanic women as compared to other race/ethnicity groups. Conclusions: Our findings suggest that elevated stress burden is associated with accelerated epigenetic aging in postmenopausal women. Lower social support and/or self‐reported race/ethnicity may modify the association of stress with epigenetic age acceleration. These findings advance understanding of how stress may contribute to aging‐related outcomes and have important implications for disease prevention and treatment in aging women. [ABSTRACT FROM AUTHOR]

Background Epigenetic age acceleration (EAA), a measure of accelerated biological aging, has been associated with an increased risk of several age-related chronic conditions. This is the first study to prospectively examine the relationship between EAA and both multimorbidity count and a weighted multimorbidity score among long-lived postmenopausal women. Methods We included 1 951 women from the Women's Health Initiative who could have survived to age 90. EAA was estimated using the Horvath pan-tissue, Hannum, PhenoAge, and GrimAge "clocks." Twelve chronic conditions were included in the multimorbidity count. The multimorbidity score was weighted for each morbidity's relationship with mortality in the study population. Using mixed-effects Poisson and linear regression models that included baseline covariates associated with both EAA and multimorbidity, we estimated relative risks (RRs) and 95% confidence intervals (CIs) for the relationships between each EAA measure at the study baseline with both multimorbidity count and weighted multimorbidity score at age 90, respectively. Results For every one standard deviation increase in AgeAccelPheno, the rate of multimorbidity accumulation increased 6% (RR = 1.06; 95% CI = 1.01–1.12; p  = .025) and the multimorbidity score by 7% (RR = 1.07; 95% CI = 1.01–1.13; p  = .014) for women who survived to age 90. The results for a one standard deviation increase in AgeAccelHorvath, AgeAccelHannum, and AgeAccelGrim with multimorbidity accumulation and score were weaker compared to AgeAccelPheno, and the latter 2 did not reach statistical significance. Conclusion AgeAccelPheno and AgeAccelHannum may predict multimorbidity count and score at age 90 in older women and, thus, may be useful as a biomarker predictor of multimorbidity burden in the last decades of life. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in atherosclerotic coronary heart disease (CHD) and all-cause mortality, but its association with incident type 2 diabetes (T2D) is unknown. We hypothesized that CHIP is associated with elevated risk of T2D. RESEARCH DESIGN AND METHODS: CHIP was derived from whole-genome sequencing of blood DNA in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) prospective cohorts. We performed analysis for 17,637 participants from six cohorts, without prior T2D, cardiovascular disease, or cancer. We evaluated baseline CHIP versus no CHIP prevalence with incident T2D, including associations with DNMT3A, TET2, ASXL1, JAK2, and TP53 variants. We estimated multivariable-adjusted hazard ratios (HRs) and 95% CIs with adjustment for age, sex, BMI, smoking, alcohol, education, self-reported race/ethnicity, and combined cohorts' estimates via fixed-effects meta-analysis. RESULTS: Mean (SD) age was 63.4 (11.5) years, 76% were female, and CHIP prevalence was 6.0% (n = 1,055) at baseline. T2D was diagnosed in n = 2,467 over mean follow-up of 9.8 years. Participants with CHIP had 23% (CI 1.04, 1.45) higher risk of T2D than those with no CHIP. Specifically, higher risk was for TET2 (HR 1.48; CI 1.05, 2.08) and ASXL1 (HR 1.76; CI 1.03, 2.99) mutations; DNMT3A was nonsignificant (HR 1.15; CI 0.93, 1.43). Statistical power was limited for JAK2 and TP53 analyses. CONCLUSIONS: CHIP was associated with higher incidence of T2D. CHIP mutations located on genes implicated in CHD and mortality were also related to T2D, suggesting shared aging-related pathology. [ABSTRACT FROM AUTHOR]

Background: Multisystem dysregulation (Dm) shows promise as a metric of aging and predicts mortality. However, Dm needs to be studied with less severe endpoints indicating modifiable aging stages. Physical function, reflecting healthy longevity rather than just longevity, is more relevant to the goals of geroscience but has not been well investigated.Methods: We tested the association of midlife Dm and its change over ~20 years with physical function in later life in 5,583 ARIC cohort participants (baseline mean age 54.7). Dm quantifies the multivariate statistical deviation of 17 physiologically motivated biomarkers relative to their distribution in a young healthy sample at baseline. Physical function was assessed from grip strength and the Short Physical Performance Battery (SPPB). Associations were quantified using linear regression and ordinal logistic regression adjusting for age, sex, race, and education.Results: Each unit increment in midlife Dm was associated with 1.71 times the odds of having a lower SPPB score. Compared to the 1 st quartile of midlife Dm, the odds ratios of having a lower SPPB score were 1.25, 1.56, and 2.45, respectively, for the 2 nd-4 th quartiles. Similar graded association patterns were observed for each SPPB component test and grip strength. An inverse monotonic relationship also was observed between annual growth rate of Dm and physical function.Conclusions: Greater multisystem dysregulation and progression in midlife were associated with lower physical function in later life. Future studies on the factors that lead to progression of multisystem dysregulation may highlight opportunities to preserve physical function. [ABSTRACT FROM AUTHOR]

BACKGROUND: During the 2010 Deepwater Horizon (DWH) disaster, response and cleanup workers were potentially exposed to toxic volatile components of crude oil. However, to our knowledge, no study has examined exposure to individual oil spill–related chemicals in relation to cardiovascular outcomes among oil spill workers. OBJECTIVES: Our aim was to investigate the association of several spill-related chemicals [benzene, toluene, ethylbenzene, xylene, 푛-hexane (BTEX-H)] and total hydrocarbons (THC) with incident coronary heart disease (CHD) events among workers enrolled in a prospective cohort. METHODS: Cumulative exposures to THC and BTEX-H across the cleanup period were estimated via a job-exposure matrix that linked air measurement data with self-reported DWH spill work histories. We ascertained CHD events following each worker’s last day of cleanup work as the first self-reported physician-diagnosed myocardial infarction (MI) or a fatal CHD event. We estimated hazard ratios (HR) and 95% confidence intervals for the associations of exposure quintiles (Q) with risk of CHD. We applied inverse probability weights to account for bias due to confounding and loss to follow-up. We used quantile g-computation to assess the joint effect of the BTEX-H mixture. RESULTS: Among 22,655 workers with no previous MI diagnoses, 509 experienced an incident CHD event through December 2019. Workers in higher quintiles of each exposure agent had increased CHD risks in comparison with the referent group (Q1) of that agent, with the strongest associations observed in Q5 (range of HR = 1.14–1:44). However, most associations were nonsignificant, and there was no evidence of exposure–response trends. We observed stronger associations among ever smokers, workers with =high school education, and workers with body mass index <30 kg/m². No apparent positive association was observed for the BTEX-H mixture. CONCLUSIONS: Higher exposures to volatile components of crude oil were associated with modest increases in risk of CHD among oil spill workers, although we did not observe exposure–response trends. [ABSTRACT FROM AUTHOR]

Background: Many commonly used prescription medications have cardiovascular adverse effects, yet the cumulative risk of cardiovascular events associated with the concurrent use of these medications is unknown. We examined the association between the concurrent use of prescription medications with known risk of a major adverse cardiovascular event (MACE) ("MACE medications") and the risk of such events among older adults. Methods: A multi‐center, population‐based study from the Atherosclerosis Risk in Communities (ARIC) study of a cohort of 3669 community‐dwelling adults aged 61–86 years with no history of cardiovascular disease who reported the use of at least one medication between September 2006 and August 2013 were followed up until August 2015. Exposure defined as time‐varying and time‐fixed use of 1, 2 or ≥3 MACE medications with non‐MACE medications serving as negative control. Primary outcome was incident MACE defined as coronary artery revascularization, myocardial infarction, fatal coronary heart disease, stroke, cardiac arrest, or death. Results: In fully adjusted models, there was an increased risk of MACE associated with use of 1, 2, or ≥3 MACE medications (1 MACE: hazards ratio [HR], 1.21; 95% confidence interval [CI], 0.94–1.57); 2 MACE: HR 1.89, CI 1.42–2.53; ≥3 MACE: HR 2.22, CI 1.61–3.07) compared to use of non‐MACE medications. These associations persisted in propensity score‐matched analyses and among new users of MACE medications, never users of cardiovascular medications and subgroups of participants with increased risk of MACE. There was no association between the number of non‐MACE medications used and MACE. Conclusions and Relevance: In this community‐based cohort of older adults with no prior cardiovascular disease, the use of MACE medications was independently and consistently associated with an increased risk of such events in a dose–response fashion. [ABSTRACT FROM AUTHOR]

It has been reported that residents of low–socioeconomic-status (SES) neighborhoods have a higher risk of developing cardiovascular disease (CVD). However, most of the previous studies focused on 1-time measurement of neighborhood SES in middle-to-older adulthood and lacked demographic diversity to allow for comparisons across different race/ethnicity and sex groups. We examined neighborhood SES in childhood and young, middle, and older adulthood in association with CVD risk among Black and White men and women in the Atherosclerosis Risk in Communities Study (1996–2019). We found that lower neighborhood SES in young, middle, and older adulthood, but not in childhood, was associated with a higher risk of CVD later in life. When compared with the highest quartile, the lowest quartile of neighborhood SES in young, middle, and older adulthood was associated with 18% (hazard ratio (HR) = 1.18, 95% confidence interval (CI): 1.02, 1.36), 21% (HR = 1.21, 95% CI: 1.04, 1.39), and 12% (HR = 1.12, 95% CI: 0.99, 1.26) increases in the hazard of total CVD, respectively. The association between lower neighborhood SES in older adulthood and higher CVD hazard was particularly strong among Black women. Our study findings support the role of neighborhood SES in cardiovascular health in both Black and White adults. [ABSTRACT FROM AUTHOR]

Dietary copper intake may be associated with cognitive decline and dementia. We used data from 10,269 participants of the Atherosclerosis Risks in Communities Study to study the associations of dietary copper intake with 20-year cognitive decline and incident dementia. Dietary copper intake from food and supplements was quantified using food frequency questionnaires. Cognition was assessed using 3 cognitive tests at study visits; dementia was ascertained at study visits and via surveillance. Multiple imputation by chained equations was applied to account for the missing information of cognitive function during follow-up. Survival analysis with parametric models and mixed-effect models were used to estimate the associations for incident dementia and cognitive decline, respectively. During 20 years of follow-up (1996–1998 to 2016–2017), 1,862 incident cases of dementia occurred. Higher intake of dietary copper from food was associated with higher risk of incident dementia among those with high intake of saturated fat (hazard ratio = 1.49, 95% confidence interval: 1.04, 1.95). Higher intake of dietary copper from food was associated with greater decline in language overall (beta = −0.12, 95% confidence interval: −0.23, −0.02). Therefore, a diet high in copper, particularly when combined with a diet high in saturated fat, may increase the risk of cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Epigenetic age acceleration (AgeAccel), which indicates faster biological aging relative to chronological age, has been associated with lower cognitive function. However, the association of AgeAccel with mild cognitive impairment (MCI) or dementia is not well-understood. We examined associations of 4 AgeAccel measures with incident MCI and dementia.Methods: This prospective analysis included 578 older women from the Women's Health Initiative Memory Study selected for a case-cohort study of coronary heart disease (CHD). Women were free of CHD and cognitive impairment at baseline. Associations of AgeAccel measures (intrinsic AgeAccel [IEAA], extrinsic AgeAccel [EEAA], AgeAccelPheno, and AgeAccelGrim) with risks for incident adjudicated diagnoses of MCI and dementia overall and stratified by incident CHD status were evaluated.Results: IEAA was not significantly associated with MCI (HR, 1.23; 95% CI, 0.99-1.53), dementia (HR, 1.10; 95% CI, 0.88-1.38), or cognitive impairment (HR, 1.18; 95% CI, 0.99-1.40). In stratified analysis by incident CHD status, there was a 39% (HR, 1.39; 95% CI, 1.07-1.81) significantly higher risk of MCI for every 5-year increase in IEAA among women who developed CHD during follow-up. Other AgeAccel measures were not significantly associated with MCI or dementia.Conclusions: IEAA was not significantly associated with cognitive impairment overall but was associated with impairment among women who developed CHD. Larger studies designed to examine associations of AgeAccel with cognitive impairment are needed, including exploration of whether associations are stronger in the setting of underlying vascular pathologies. [ABSTRACT FROM AUTHOR]

Background: Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of mutant hematopoietic stem cells, confers risk for multiple diseases of aging including hematologic cancer and cardiovascular disease. Whole-exome or genome sequencing can detect CHIP, but due to those assays' high cost, most population studies have been cross-sectional, sequencing only a single timepoint per individual. Results: We developed and validated a cost-effective single molecule molecular inversion probe sequencing (smMIPS) assay for detecting CHIP, targeting the 11 most frequently mutated genes in CHIP along with 4 recurrent mutational hotspots. We sequenced 548 multi-timepoint samples collected from 182 participants in the Women's Health Initiative cohort, across a median span of 16 years. We detected 178 driver mutations reaching variant allele frequency ≥ 2% in at least one timepoint, many of which were detectable well below this threshold at earlier timepoints. The majority of clonal mutations (52.1%) expanded over time (with a median doubling period of 7.43 years), with the others remaining static or decreasing in size in the absence of any cytotoxic therapy. Conclusions: Targeted smMIPS sequencing can sensitively measure clonal dynamics in CHIP. Mutations that reached the conventional threshold for CHIP (2% frequency) tended to continue growing, indicating that after CHIP is acquired, it is generally not lost. The ability to cost-effectively profile CHIP longitudinally will enable future studies to investigate why some CHIP clones expand, and how their dynamics relate to health outcomes at a biobank scale. [ABSTRACT FROM AUTHOR]

Background: Ambient PM2.5 is a ubiquitous air pollutant with demonstrated adverse health impacts in population. Hemodialysis patients are a highly vulnerable population and may be particularly susceptible to the effects of PM2.5 exposure. This study examines associations between short-term PM2.5 exposure and cardiovascular disease (CVD) and mortality among patients receiving maintenance in-center hemodialysis.Methods: Using the United State Renal Data System (USRDS) registry, we enumerated a cohort of all US adult kidney failure patients who initiated in-center hemodialysis between 1/1/2011 and 12/31/2016. Daily ambient PM2.5 exposure estimates were assigned to cohort members based on the ZIP code of the dialysis clinic. CVD incidence and mortality were ascertained through 2016 based on USRDS records. Discrete time hazards regression was used to estimate the association between lagged PM2.5 exposure and CVD incidence, CVD-specific mortality, and all-cause mortality 1 t adjusting for temperature, humidity, day of the week, season, age at baseline, race, employment status, and geographic region. Effect measure modification was assessed for age, sex, race, and comorbidities.Results: Among 314,079 hemodialysis patients, a 10 µg/m3 increase in the average lag 0-1 daily PM2.5 exposure was associated with CVD incidence (HR: 1.03 (95% CI: 1.02, 1.04)), CVD mortality (1.05 (95% CI: 1.03, 1.08)), and all-cause mortality (1.04 (95% CI: 1.03, 1.06)). The association was larger for people who initiated dialysis at an older age, while minimal evidence of effect modification was observed across levels of sex, race, or baseline comorbidities.Conclusions: Short-term ambient PM2.5 exposure was positively associated with incident CVD events and mortality among patients receiving in-center hemodialysis. Older patients appeared to be more susceptible to PM2.5-associated CVD events than younger hemodialysis patients. [ABSTRACT FROM AUTHOR]

Background: Late-life exposure to ambient air pollution is a modifiable risk factor for dementia, but epidemiological studies have shown inconsistent evidence for cognitive decline. Air quality (AQ) improvement has been associated with improved cardiopulmonary health and decreased mortality, but to the best of our knowledge, no studies have examined the association with cognitive function. We examined whether AQ improvement was associated with slower rate of cognitive decline in older women aged 74 to 92 years. Methods and findings: We studied a cohort of 2,232 women residing in the 48 contiguous US states that were recruited from more than 40 study sites located in 24 states and Washington, DC from the Women's Health Initiative (WHI) Memory Study (WHIMS)-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO) study. They were predominantly non-Hispanic White women and were dementia free at baseline in 2008 to 2012. Measures of annual (2008 to 2018) cognitive function included the modified Telephone Interview for Cognitive Status (TICSm) and the telephone-based California Verbal Learning Test (CVLT). We used regionalized universal kriging models to estimate annual concentrations (1996 to 2012) of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) at residential locations. Estimates were aggregated to the 3-year average immediately preceding (recent exposure) and 10 years prior to (remote exposure) WHIMS-ECHO enrollment. Individual-level improved AQ was calculated as the reduction from remote to recent exposures. Linear mixed effect models were used to examine the associations between improved AQ and the rates of cognitive declines in TICSm and CVLT trajectories, adjusting for sociodemographic (age; geographic region; race/ethnicity; education; income; and employment), lifestyle (physical activity; smoking; and alcohol), and clinical characteristics (prior hormone use; hormone therapy assignment; depression; cardiovascular disease (CVD); hypercholesterolemia; hypertension; diabetes; and body mass index [BMI]). For both PM2.5 and NO2, AQ improved significantly over the 10 years before WHIMS-ECHO enrollment. During a median of 6.2 (interquartile range [IQR] = 5.0) years of follow-up, declines in both general cognitive status (β = −0.42/year, 95% CI: −0.44, −0.40) and episodic memory (β = −0.59/year, 95% CI: −0.64, −0.54) were observed. Greater AQ improvement was associated with slower decline in TICSm (βPM2.5improvement = 0.026 per year for improved PM2.5 by each IQR = 1.79 μg/m3 reduction, 95% CI: 0.001, 0.05; βNO2improvement = 0.034 per year for improved NO2 by each IQR = 3.92 parts per billion [ppb] reduction, 95% CI: 0.01, 0.06) and CVLT (βPM2.5 improvement = 0.070 per year for improved PM2.5 by each IQR = 1.79 μg/m3 reduction, 95% CI: 0.02, 0.12; βNO2improvement = 0.060 per year for improved NO2 by each IQR = 3.97 ppb reduction, 95% CI: 0.005, 0.12) after adjusting for covariates. The respective associations with TICSm and CVLT were equivalent to the slower decline rate found with 0.9 to 1.2 and1.4 to 1.6 years of younger age and did not significantly differ by age, region, education, Apolipoprotein E (ApoE) e4 genotypes, or cardiovascular risk factors. The main limitations of this study include measurement error in exposure estimates, potential unmeasured confounding, and limited generalizability. Conclusions: In this study, we found that greater improvement in long-term AQ in late life was associated with slower cognitive declines in older women. This novel observation strengthens the epidemiologic evidence of an association between air pollution and cognitive aging. Diana Younan and colleagues investigate whether air quality improvement is associated with rate of cognitive decline in community-dwelling older women in the United States. Author summary: Why was this study done?: Although studies have shown that late-life exposure to outdoor air pollution is a modifiable risk factor for dementia, the epidemiological evidence for cognitive decline has been inconsistent. Epidemiological studies have demonstrated that improved air quality (AQ) may decrease mortality and improve respiratory health, strengthening the evidence of a relationship between ambient air pollution and these health outcomes. To our knowledge, no previous studies have examined the potential benefit of slowing cognitive aging by AQ improvement. What did the researchers do and find?: Using a US cohort of 2,232 older women followed up to 20 years, we explored whether women living in locations with greater AQ improvement had slower decline in their cognitive function. AQ improvement was defined as the difference in air pollution levels over 2 time points that were 10 years apart. Living in locations with greater AQ improvement was associated with slower cognitive declines in older women, equivalent to women who were 0.9 to 1.6 years younger. The associations were similar across age groups, geographic region, education, Apolipoprotein E (ApoE) e4 genotypes, and cardiovascular risk factors. What do these findings mean?: These findings strengthen the contribution of outdoor air pollution on cognitive aging. These results highlight the potential benefits of reducing outdoor air pollution levels. Key study limitations include measurement error in exposure estimates, potential unmeasured confounders, and limited generalizability. [ABSTRACT FROM AUTHOR]

Late-life ambient air pollution is a risk factor for brain aging, but it remains unknown if improved air quality (AQ) lowers dementia risk. We studied a geographically diverse cohort of older women dementia free at baseline in 2008 to 2012 (n = 2,239, aged 74 to 92). Incident dementia was centrally adjudicated annually. Yearly mean concentrations of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) were estimated using regionalized national universal kriging models and averaged over the 3-y period before baseline (recent exposure) and 10 y earlier (remote exposure). Reduction from remote to recent exposures was used as the indicator of improved AQ. Cox proportional hazard ratios (HRs) for dementia risk associated with AQ measures were estimated, adjusting for sociodemographic, lifestyle, and clinical characteristics. We identified 398 dementia cases during follow up (median = 6.1 y). PM2.5 and NO2 reduced significantly over the 10 y before baseline. Larger AQ improvement was associated with reduced dementia risks (HRPM2.5 0.80 per 1.78 μg/m³, 95% CI 0.71–0.91; HRNO2 0.80 per 3.91 parts per billion, 95% CI 0.71–0.90), equivalent to the lower risk observed in women 2.4 y younger at baseline. Higher PM2.5 at baseline was associated with higher dementia risk (HRPM2.5 1.16 per 2.90 μg/m³, 95% CI 0.98–1.38), but the lower dementia risk associated with improved AQ remained after further adjusting for recent exposure. The observed associations did not substantially differ by age, education, geographic region, Apolipoprotein E e4 genotypes, or cardiovascular risk factors. Long-term AQ improvement in late life was associated with lower dementia risk in older women. [ABSTRACT FROM AUTHOR]

Background: Body mass index (BMI), a well-known risk factor for poor cardiovascular outcomes, is associated with differential DNA methylation (DNAm). Similarly, metabolic health has also been associated with changes in DNAm. It is unclear how overall metabolic health outside of BMI may modify the relationship between BMI and methylation profiles, and what consequences this may have on downstream cardiovascular disease. The purpose of this study was to identify cytosine-phosphate-guanine (CpG) sites at which the association between BMI and DNAm could be modified by overall metabolic health. Results: The discovery study population was derived from three Women's Health Initiative (WHI) ancillary studies (n = 3977) and two Atherosclerosis Risk in Communities (ARIC) ancillary studies (n = 3520). Findings were validated in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (n = 1200). Generalized linear models regressed methylation β values on the interaction between BMI and metabolic health Z score (BMI × MHZ) adjusted for BMI, MHZ, cell composition, chip number and location, study characteristics, top three ancestry principal components, smoking, age, ethnicity (WHI), and sex (ARIC). Among the 429,566 sites examined, differential associations between BMI × MHZ and DNAm were identified at 22 CpG sites (FDR q < 0.05), with one site replicated in MESA (cg18989722, in the TRAPPC9 gene). Three of the 22 sites were associated with incident coronary heart disease (CHD) in WHI. For each 0.01 unit increase in DNAm β value, the risk of incident CHD increased by 9% in one site and decreased by 6–10% in two sites over 25 years. Conclusions: Differential associations between DNAm and BMI by MHZ were identified at 22 sites, one of which was validated (cg18989722) and three of which were predictive of incident CHD. These sites are located in several genes related to NF-kappa-B signaling, suggesting a potential role for inflammation between DNA methylation and BMI-associated metabolic health. [ABSTRACT FROM AUTHOR]

Background: Elucidating associations between exposures to ambient air pollutants and profiles of cognitive performance may provide insight into neurotoxic effects on the aging brain.Objective: We examined associations between empirically derived profiles of cognitive performance and residential concentrations of particulate matter of aerodynamic diameter < 2.5 (PM2.5) and nitrogen dioxide (NO2) in older women.Method: Women (N = 2,142) from the Women's Health Initiative Study of Cognitive Aging completed a neuropsychological assessment measuring attention, visuospatial, language, and episodic memory abilities. Average yearly concentrations of PM2.5 and NO2 were estimated at the participant's addresses for the 3 years prior to the assessment. Latent profile structural equation models identified subgroups of women exhibiting similar profiles across tests. Multinomial regressions examined associations between exposures and latent profile classification, controlling for covariates.Result: Five latent profiles were identified: low performance across multiple domains (poor multi-domain; n = 282;13%), relatively poor verbal episodic memory (poor memory; n = 216; 10%), average performance across all domains (average multi-domain; n = 974; 45%), superior memory (n = 381; 18%), and superior attention (n = 332; 15%). Using women with average cognitive ability as the referent, higher PM2.5 (per interquartile range [IQR] = 3.64μg/m3) was associated with greater odds of being classified in the poor memory (OR = 1.29; 95% Confidence Interval [CI] = 1.10-1.52) or superior attention (OR = 1.30; 95% CI = 1.10-1.53) profiles. NO2 (per IQR = 9.86 ppb) was associated with higher odds of being classified in the poor memory (OR = 1.38; 95% CI = 1.17-1.63) and lower odds of being classified with superior memory (OR = 0.81; 95% CI = 0.67-0.97).Conclusion: Exposure to PM2.5 and NO2 are associated with patterns of cognitive performance characterized by worse verbal episodic memory relative to performance in other domains. [ABSTRACT FROM AUTHOR]

BACKGROUND: Previous studies suggest that certain dietary patterns and constituents may be beneficial to brain health. Airborne exposures to fine particulate matter [particulate matter with aerodynamic diameter ≤2.5 μm (PM2.5)] are neurotoxic, but the combined effects of dietary patterns and PM2.5 have not been investigated. OBJECTIVES: We examined whether previously reported association between PM2.5 exposure and lower white matter volume (WMV) differed between women whose usual diet during the last 3 months before baseline was more or less consistent with a Mediterranean–DASH Intervention for Neurodegenerative Delay (MIND)-like diet, a dietary pattern that may slow neurodegenerative changes. METHODS: This study included 1,302 U.S. women who were 65–79 y old and free of dementia in the period 1996–1998 (baseline). In the period 2005–2006, structural brain magnetic resonance imaging (MRI) scans were performed to estimate normal-appearing brain volumes (excluding areas with evidence of small vessel ischemic disease). Baseline MIND diet scores were derived from a food frequency questionnaire. Three-year average PM2.5 exposure prior to MRI was estimated using geocoded participant addresses and a spatiotemporal model. RESULTS: Average total and temporal lobe WMVs were 0.74 cm³ [95% confidence interval (CI): 0.001, 1.48) and 0.19 cm³ (95% CI: 0.002, 0.37) higher, respectively, with each 0.5-point increase in the MIND score and were 4.16 cm³ (95% CI: -6.99, -1.33) and 1.46 cm³ (95% CI: -2.16, -0.76) lower, respectively, with each interquartile range (IQR) (IQR = 3.22 μg/m³) increase in PM2.5. The inverse association between PM2.5 per IQR and WMV was stronger (p-interaction <0.001) among women with MIND scores below the median (for total WMV, -12.47 cm³; 95% CI: -17.17, -7.78), but absent in women with scores above the median (0.16 cm³; 95% CI: -3.41, 3.72), with similar patterns for WMV in the frontal, parietal, and temporal lobes. For total cerebral and hippocampus brain volumes or WMV in the corpus callosum, the associations with PM2.5 were not significantly different for women with high MIND scores and women with low MIND scores. DISCUSSION: In this cohort of U.S. women, PM2.5 exposure was associated with lower MRI-based WMV, an indication of brain aging, only among women whose usual diet was less consistent with the MIND-like dietary pattern at baseline. [ABSTRACT FROM AUTHOR]

Background: Identification of factors that may help to preserve cognitive function in late life could elucidate mechanisms and facilitate interventions to improve the lives of millions of people. However, the large number of potential factors associated with cognitive function poses an analytical challenge.Objective: We used data from the longitudinal Women's Health Initiative Memory Study (WHIMS) and machine learning to investigate 50 demographic, biomedical, behavioral, social, and psychological predictors of preserved cognitive function in later life.Methods: Participants in WHIMS and two consecutive follow up studies who were at least 80 years old and had at least one cognitive assessment following their 80th birthday were classified as cognitively preserved. Preserved cognitive function was defined as having a score ≥39 on the most recent administration of the modified Telephone Interview for Cognitive Status (TICSm) and a mean score across all assessments ≥39. Cognitively impaired participants were those adjudicated by experts to have probable dementia or at least two adjudications of mild cognitive impairment within the 14 years of follow-up and a last TICSm score < 31. Random Forests was used to rank the predictors of preserved cognitive function.Results: Discrimination between groups based on area under the curve was 0.80 (95%-CI-0.76-0.85). Women with preserved cognitive function were younger, better educated, and less forgetful, less depressed, and more optimistic at study enrollment. They also reported better physical function and less sleep disturbance, and had lower systolic blood pressure, hemoglobin, and blood glucose levels.Conclusion: The predictors of preserved cognitive function include demographic, psychological, physical, metabolic, and vascular factors suggesting a complex mix of potential contributors. [ABSTRACT FROM AUTHOR]

BACKGROUND: Atrial fibrillation (AF) is associated with substantial morbidity and mortality. Short-term exposures to air pollution have been associated with AF triggering; less is known regarding associations between long-term air pollution exposures and AF incidence. OBJECTIVES: Our objectivewas to assess the association between long-term exposures to air pollution and distance to road on incidence of AF in a cohort of U.S.women. METHODS: We assessed the association of high resolution spatiotemporal model predictions of long-term exposures to particulate matter (PM10 and PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), and distance to major roads with incidence of AF diagnosis, identified through Medicare linkage, among 83,117 women in the prospective Women's Health Initiative cohort, followed from enrollment in Medicare through December 2012, incidence of AF, or death. Using time-varying Cox proportional hazards models adjusted for age, race/ethnicity, study component, body mass index, physical activity, menopausal hormone therapy, smoking, diet quality, alcohol consumption, educational attainment, and neighborhood socioeconomic status, we estimated the relative risk of incident AF in association with each pollutant. METHODS: We assessed the association of high resolution spatiotemporal model predictions of long-term exposures to particulate matter (PM10 and PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), and distance to major roads with incidence of AF diagnosis, identified through Medicare linkage, among 83,117 women in the prospective Women's Health Initiative cohort, followed from enrollment in Medicare through December 2012, incidence of AF, or death. Using time-varying Cox proportional hazards models adjusted for age, race/ethnicity, study component, body mass index, physical activity, menopausal hormone therapy, smoking, diet quality, alcohol consumption, educational attainment, and neighborhood socioeconomic status, we estimated the relative risk of incident AF in association with each pollutant. RESULTS: A total of 16,348 incident AF cases were observed over 660,236 person-years of follow-up. Most exposure–response associations were nonlinear. NO2 was associated with risk of AF in multivariable adjusted models [Hazard Ratio (HR)=1.18; 95% confidence interval (CI): 1.13, 1.24, comparing the top to bottom quartile, 푝-for-trend= <0.0001]. Women living closer to roadways were at higher risk of AF (e.g., HR=1.07; 95% CI: 1.01, 1.13 for living within 50 m of A3 roads, compared with =1,000 m, 푝-for-trend=0.02), but we did not observe adverse associations with exposures to PM10, PM2.5, or SO2. There were adverse associations with PM10 (top quartile HR=1.10; 95% CI: 1.05, 1.16, 푝-for-trend= <0.0001) and PM2.5 (top quartile HR=1.09; 95% CI: 1.03, 1.14, 푝-for-trend=0:002) in sensitivity models adjusting for census region. DISCUSSION: In this study of postmenopausal women, NO2 and distance to road were consistently associated with higher risk of AF. [ABSTRACT FROM AUTHOR]

BACKGROUND: Episodic memory decline varies by age and underlying neuropathology. Whether ambient air pollution contributes to the heterogeneity of episodic memory decline in older populations remains unclear. OBJECTIVES: We estimated associations between air pollution exposures and episodic memory decline according to pollutant, exposure time window, age, and latent class subgroups defined by episodic memory trajectories. METHODS: Participants were from the Women's Health Initiative Memory Study-Epidemiology of Cognitive Health Outcomes. Older women (푛 = 2,056; 74-92 years of age) completed annual (2008-2018) episodic memory assessments using the telephone-based California Verbal Learning Test (CVLT). We estimated 3-y average fine particulate matter [PM with an aerodynamic diameter of = 2.5µm (PM2.5)] and nitrogen dioxide (NO2) exposures at baseline and 10 y earlier (recent and remote exposures, respectively), using regionalized national universal kriging. Separate latent class mixed models were used to estimate associations between interquartile range increases in exposures and CVLT trajectories in women ≤80 and >80 years of age, adjusting for covariates. RESULTS: Two latent classes were identified for women ≤80 years of age (푛 = 828), "slow-decliners" {slope=-0.12/y [95% confidence interval (CI): -0.23, -0.01] and "fast-decliners" [slope=-1.79/y (95% CI: -2.08, -1.50)]}. In the slow-decliner class, but not the fast-decliner class, PM2.5 exposures were associated with a greater decline in CVLT scores over time, with a stronger association for recent vs. remote exposures [-0.16/y (95% CI: -2.08, -0.03) per 2.88 μg/m³ and -0.11/y (95% CI: -0.22, 0.01) per 3.27μg/m³, respectively]. Among women ≥ 80 years of age (푛 = 1,128), the largest latent class comprised "steady-decliners" [slope=-1.35/y (95% CI: -1.53, -1.17)], whereas the second class, "cognitively resilient", had no decline in CVLT on average. PM2.5 was not associated with episodic memory decline in either class. A 6.25-ppb increase in recent NO2 was associated with nonsignificant acceleration of episodic memory decline in the = 80-y-old fast-decliner class [-0.21/y (95% CI: -0.45, 0.04)], and in the >80-y-old cognitively resilient class [-0.10/y (95% CI: -0.24, 0.03)] and steady-decliner class [-0.11/y (95% CI: -0.27, 0.05)]. Associations with recent NO2 exposure in women >80 years of age were stronger and statistically significant when 267 women with incident probable dementia were excluded [e.g., -0.12/y (95% CI: -0.22, -0.02) for the cognitively resilient class]. In contrast with changes in CVLT over time, there were no associations between exposures and CVLT scores during follow-up in any subgroup. DISCUSSION: In a community-dwelling U.S. population of older women, associations between late-life exposure to ambient air pollution and episodic memory decline varied by age-related cognitive trajectories, exposure time windows, and pollutants. [ABSTRACT FROM AUTHOR]

Background: Electrocardiographic left ventricular hypertrophy (ECG‐LVH) represents preclinical cardiovascular disease and predicts cardiovascular disease morbidity and mortality. While the newly developed Peguero‐Lo Presti ECG‐LVH criteria have greater sensitivity for LVH than the Cornell voltage and Sokolow–Lyon criteria, its short‐term repeatability is unknown. Therefore, we characterized the short‐term repeatability of Peguero‐Lo Presti ECG‐LVH criteria and evaluate its agreement with Cornell voltage and Sokolow–Lyon ECG‐LVH criteria. Methods: Participants underwent two resting, standard, 12‐lead ECGs at each of two visits one week apart (n = 63). We defined a Peguero‐Lo Presti index as a sum of the deepest S wave amplitude in any single lead and lead V4 (i.e., SD + SV4) and defined Peguero‐Lo Presti LVH index as ≥ 2,300 µV among women and ≥ 2,800 µV among men. We estimated repeatability as an intraclass correlation coefficient (ICC), agreement as a prevalence‐adjusted bias‐adjusted kappa coefficient (κ), and precision using 95% confidence intervals (CIs). Results: The Peguero‐Lo Presti index was repeatable: ICC (95% CI) = 0.94 (0.91–0.97). Within‐visit agreement of Peguero‐Lo Presti LVH was high at the first and second visits: κ (95% CI) = 0.97 (0.91–1.00) and 1.00 (1.00–1.00). Between‐visit agreement of the first and second measurements at each visit was comparable: κ (95% CI) = 0.90 (0.80–1.00) and 0.93 (0.85–1.00). Agreement of Peguero‐Lo Presti and Cornell or Sokolow–Lyon LVH on any one of the four ECGs was slightly lower: κ (95% CI) = 0.71 (0.54–0.89). Conclusion: The Peguero‐Lo Presti index and LVH have excellent repeatability and agreement, which support their use in clinical and epidemiological studies. [ABSTRACT FROM AUTHOR]

Background: Diet quality is a risk factor for chronic disease and mortality. Differential DNA methylation across the epigenome has been associated with chronic disease risk. Whether diet quality is associated with differential methylation is unknown. This study assessed whether diet quality was associated with differential DNA methylation measured across 445 548 loci in the Women's Health Initiative (WHI) and the TwinsUK cohort.Design: The discovery cohort consisted of 4355 women from the WHI. The replication cohort consisted of 571 mono- and dizygotic twins from the TwinsUK cohort. DNA methylation was measured in whole blood using the Illumina Infinium HumanMethylation450 Beadchip. Diet quality was assessed using the Alternative Healthy Eating Index 2010 (AHEI-2010). A meta-analysis, stratified by study cohort, was performed using generalized linear models that regressed methylation on AHEI-2010, adjusting for cell composition, chip number and location, study characteristics, principal components of genetic relatedness, age, smoking status, race/ethnicity and body mass index (BMI). Statistical significance was defined as a false discovery rate < 0.05. Significant sites were tested for replication in the TwinsUK cohort, with significant replication defined by P < 0.05 and a consistent direction.Results: Diet quality was significantly associated with differential DNA methylation at 428 cytosine-phosphate-guanine (CpG) sites in the discovery cohort. A total of 24 CpG sites were consistent with replication in the TwinsUK cohort, more than would be expected by chance (P = 2.7x10-4), with one site replicated in both the blood and adipose tissue (cg16379999 located in the body of SEL1L).Conclusions: Diet quality was associated with methylation at 24 CpG sites, several of which have been associated with adiposity, inflammation and dysglycaemia. These findings may provide insight into pathways through which diet influences chronic disease. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular health (CVH) has been defined by the American Heart Association (AHA) as the presence of the "Life's Simple 7" ideal lifestyle and clinical factors. CVH is known to predict longevity and freedom from cardiovascular disease, the leading cause of death for women in the United States. DNA methylation markers of aging have been aggregated into a composite epigenetic age score, which is associated with cardiovascular morbidity and mortality. However, it is unknown whether poor CVH is associated with acceleration of aging as measured by DNA methylation markers in epigenetic age. Methods and results: We performed a cross-sectional analysis of racially/ethnically diverse post-menopausal women enrolled in the Women's Health Initiative cohort recruited between 1993 and 1998. Epigenetic age acceleration (EAA) was calculated using DNA methylation data on a subset of participants and the published Horvath and Hannum methods for intrinsic and extrinsic EAA. CVH was calculated using the AHA measures of CVH contributing to a 7-point score. We examined the association between CVH score and EAA using linear regression modeling adjusting for self-reported race/ethnicity and education. Among the 2,170 participants analyzed, 50% were white and mean age was 64 (7 SD) years. Higher or more favorable CVH scores were associated with lower extrinsic EAA (~ 6 months younger age per 1 point higher CVH score, p < 0.0001), and lower intrinsic EAA (3 months younger age per 1 point higher CVH score, p < 0.028). Conclusions: These cross-sectional observations suggest a possible mechanism by which ideal CVH is associated with greater longevity. [ABSTRACT FROM AUTHOR]

BACKGROUND/OBJECTIVES: Exposure to air pollution may contribute to both increasing depressive symptoms and decreasing episodic memory in older adulthood, but few studies have examined this hypothesis in a longitudinal context. Accordingly, we examined the association between air pollution and changes in depressive symptoms (DS) and episodic memory (EM) and their interrelationship in oldest‐old (aged 80 and older) women. DESIGN: Prospective cohort data from the Women's Health Initiative Memory Study‐Epidemiology of Cognitive Health Outcomes. SETTING: Geographically diverse community‐dwelling population. PARTICIPANTS: A total of 1,583 dementia‐free women aged 80 and older. MEASUREMENTS: Women completed up to six annual memory assessments (latent composite of East Boston Memory Test and Telephone Interview for Cognitive Status) and the 15‐item Geriatric Depression Scale (GDS‐15). We estimated 3‐year average exposures to regional particulate matter with aerodynamic diameter below 2.5 μm (PM2.5) (interquartile range [IQR] = 3.35 μg/m3) and gaseous nitrogen dioxide (NO2) (IQR = 9.55 ppb) at baseline and during a remote period 10 years earlier, using regionalized national universal kriging. RESULTS: Latent change structural equation models examined whether residing in areas with higher pollutant levels was associated with annual changes in standardized EM and DS while adjusting for potential confounders. Remote NO2 (β =.287 per IQR; P =.002) and PM2.5 (β =.170 per IQR; P =.019) exposure was significantly associated with larger increases in standardized DS, although the magnitude of the difference, less than 1 point on the GDS‐15, is of questionable clinical significance. Higher DS were associated with accelerated EM declines (β = −.372; P =.001), with a significant indirect effect of remote NO2 and PM2.5 exposure on EM declines mediated by DS. There were no other significant indirect exposure effects. CONCLUSION: These findings in oldest‐old women point to potential adverse effects of late‐life exposure to air pollution on subsequent interplay between DS and EM, highlighting air pollution as an environmental health risk factor for older women. [ABSTRACT FROM AUTHOR]

Background: Prior studies have shown insulin resistance is associated with reduced cardiac autonomic function measured at rest, but few studies have determined whether insulin resistance is associated with reduced cardiac autonomic function measured during daily activities.Methods: We examined older adults without diabetes with 48-h ambulatory electrocardiography (n = 759) in an ancillary study of the Atherosclerosis Risk in Communities Study. Insulin resistance, the exposure, was defined by quartiles for three indexes: 1) the homeostatic model assessment of insulin resistance (HOMA-IR), 2) the triglyceride and glucose index (TyG), and 3) the triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C). Low heart rate variability, the outcome, was defined by <25th percentile for four measures: 1) standard deviation of normal-to-normal R-R intervals (SDNN), a measure of total variability; 2) root mean square of successive differences in normal-to-normal R-R intervals (RMSSD), a measure of vagal activity; 3) low frequency spectral component (LF), a measure of sympathetic and vagal activity; and 4) high frequency spectral component (HF), a measure of vagal activity. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals weighted for sampling/non-response, adjusted for age at ancillary visit, sex, and race/study-site. Insulin resistance quartiles 4, 3, and 2 were compared to quartile 1; high indexes refer to quartile 4 versus quartile 1.Results: The average age was 78 years, 66% (n = 497) were women, and 58% (n = 438) were African American. Estimates of association were not robust at all levels of HOMA-IR, TyG, and TG/HDL-C, but suggest that high indexes were associated consistently with indicators of vagal activity. High HOMA-IR, high TyG, and high TG/HDL-C were consistently associated with low RMSSD (OR: 1.68 (1.00, 2.81), OR: 2.03 (1.21, 3.39), and OR: 1.73 (1.01, 2.91), respectively). High HOMA-IR, high TyG, and high TG/HDL-C were consistently associated with low HF (OR: 1.90 (1.14, 3.18), OR: 1.98 (1.21, 3.25), and OR: 1.76 (1.07, 2.90), respectively).Conclusions: In older adults without diabetes, insulin resistance was associated with reduced cardiac autonomic function - specifically and consistently for indicators of vagal activity - measured during daily activities. Primary prevention of insulin resistance may reduce the related risk of cardiac autonomic dysfunction. [ABSTRACT FROM AUTHOR]

DNA methylation (DNAm) has a well-established association with age in many tissues, including peripheral blood mononuclear cells (PBMCs). Compared to DNAm, the closely related epigenetic modification known as DNA hydroxymethylation (DNAhm) was much more recently discovered in mammals. Preliminary investigations have observed a positive correlation between gene body DNAhm and cis-gene expression. While some of these studies have observed an association between age and global DNAhm, none have investigated region-specific age-related DNAhm in human blood samples. In this study, we investigated DNAhm and gene expression in PBMCs of 10 young and 10 old, healthy female volunteers. Thousands of regions were differentially hydroxymethylated in the old vs. young individuals in gene bodies, exonic regions, enhancers, and promoters. Consistent with previous work, we observed directional consistency between age-related differences in DNAhm and gene expression. Further, age-related DNAhm and genes with high levels of DNAhm were enriched for immune system processes which may support a role of age-related DNAhm in immunosenescence. [ABSTRACT FROM AUTHOR]

BACKGROUND Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described. METHODS We conducted a case–control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (n EA = 931, n AA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (n EA = 14,210, n AA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (n EA = 5,266, n AA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case–control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL. RESULTS The known hypertension locus, CASZ1 , was a top finding among EAs (P = 1.1 × 10−8) and in the race-combined analysis (P = 1.5 × 10−9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6–0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls. CONCLUSION This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus. [ABSTRACT FROM AUTHOR]

Objectives. To test whether indicators of despair are rising among US adults as they age toward midlife and whether this rise is concentrated among low-educated Whites and in rural areas. Methods. We used data from the National Longitudinal Study of Adolescent to Adult Health, a nationally representative study of US adolescents in 1994. Our sample was restricted to individuals who participated in 1 or more of 5 waves (1994–2017) and self-identified as non-Hispanic White, non-Hispanic Black, or Hispanic (n = 18 446). We examined change in indicators of despair from adolescence to adulthood using multilevel regression analysis, testing for differences by race/ethnicity, education, and rurality. Results. We found evidence of rising despair among this cohort over the past decade. This increase was not restricted to low-educated Whites or to rural areas. Conclusions. Results suggest that generally rising despair among the young adult cohort now reaching midlife that cuts across racial/ethnic, educational, and geographic groups may presage rising midlife mortality for these subgroups in the next decade. [ABSTRACT FROM AUTHOR]

Background: Although social exposures have complex and dynamic relationships and interactions, the existing literature on the impact of rural–urban residence on stage at breast cancer diagnosis does not examine heterogeneity of effect. We examined the joint effect of social support, social relationship strain, and rural–urban residence on stage at breast cancer diagnosis. Methods: Using data from the Women's Health Initiative (WHI) (n = 161,808), we describe the distribution of social, behavioral, and clinical factors by rural–urban residence among postmenopausal women with incident breast cancer (n = 7,120). We used rural–urban commuting area (RUCA) codes to categorize baseline residential addresses as urban, large rural city/town, or small rural town, and the surveillance, epidemiology, and end results staging system to categorize breast cancer stage at diagnosis (dichotomized as early or late). We then used univariable and multivariable logistic regression to estimate odds ratios (ORs) and associated 95% confidence intervals (95% CI) for the relationship between rural–urban residence and stage at breast cancer diagnosis. We included separate interaction terms between rural–urban residence and social strain and social support to test for statistical interaction. Results: Of the social, behavioral, and clinical factors we examined, only younger age at WHI enrollment screening was significantly associated with late stage at breast cancer diagnosis (p = 0.003). Contrary to our hypothesis, rural–urban residence was not significantly associated with stage at breast cancer diagnosis among postmenopausal women ([adjusted OR, 95% CI] for urban compared with small town: 1.08 [0.76–1.53]; large town compared with small town: 1.16 [0.74–1.84]; and urban compared with large town: 0.93 [0.68–1.26]).The associations did not vary by social support or social strain (p for interaction between RUCA and social strain and social support, respectively: 0.99 and 0.17). Conclusions: Future studies should examine other potential effect modifiers to identify novel factors predictive or protective for late stage at breast cancer diagnosis associated with rural–urban residence. [ABSTRACT FROM AUTHOR]