Association of midlife air pollution exposures and residential road proximity with incident dementia: The Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Increasing evidence links higher air pollution exposures to increased risk of cognitive impairment. While midlife risk factors are often most strongly linked to dementia risk, few studies have considered associations between midlife roadway proximity or ambient air pollution exposure and incident dementia decades later, in late life. OBJECTIVES: Our objective was to determine if midlife exposures to ambient air pollution or roadway proximity are associated with increased risk of dementia in the Atherosclerosis Risk in Communities (ARIC) study over up to 29 years of follow-up. METHODS: Our eligible sample included Black and White ARIC participants without dementia at Visit 2 (1990-1992). Participants were followed through Visit 7 (2018-2019), with dementia status and onset date defined based on formal dementia ascertainment at study visits, informant interviews, and surveillance efforts. We used adjusted Weibull survival models to assess the associations of midlife ambient air pollution and road proximity with incident dementia. RESULTS: The median age at baseline (1990-1992, Visit 2) of the 12,700 eligible ARIC participants was 57.0 years; 56.0% were female, 24.2% were Black, and 78.9% had at least a high school education. Over up to 29 years of follow-up, 2511 (19.8%) persons developed dementia. No associations were found between ambient air pollutants and proximity to major roadways with risk of incident dementia. In exploratory analyses, living closer to roadways in midlife increased dementia risk in individuals younger at baseline and those without midlife hypertension, and there was evidence of increased risk of dementia with increased midlife exposure to NOx, several PM2.5 components, and trace metals among those with diabetes in midlife. CONCLUSIONS: Midlife exposure to ambient air pollution and midlife roadway proximity was not associated with dementia risk over decades of follow-up. Further investigation to explore potential for greater susceptibility among specific subgroups identified here is needed.

Association of Gaseous Ambient Air Pollution and Dementia-Related Neuroimaging Markers in the ARIC Cohort, Comparing Exposure Estimation Methods and Confounding by Study Site.

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. https://doi.org/10.1289/EHP13906.

A comparison of PM2.5 exposure estimates from different estimation methods and their associations with cognitive testing and brain MRI outcomes.

BACKGROUND: Reported associations between particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5) and cognitive outcomes remain mixed. Differences in exposure estimation method may contribute to this heterogeneity. OBJECTIVES: To assess agreement between PM2.5 exposure concentrations across 11 exposure estimation methods and to compare resulting associations between PM2.5 and cognitive or MRI outcomes. METHODS: We used Visit 5 (2011-2013) cognitive testing and brain MRI data from the Atherosclerosis Risk in Communities (ARIC) Study. We derived address-linked average 2000-2007 PM2.5 exposure concentrations in areas immediately surrounding the four ARIC recruitment sites (Forsyth County, NC; Jackson, MS; suburbs of Minneapolis, MN; Washington County, MD) using 11 estimation methods. We assessed agreement between method-specific PM2.5 concentrations using descriptive statistics and plots, overall and by site. We used adjusted linear regression to estimate associations of method-specific PM2.5 exposure estimates with cognitive scores (n = 4678) and MRI outcomes (n = 1518) stratified by study site and combined site-specific estimates using meta-analyses to derive overall estimates. We explored the potential impact of unmeasured confounding by spatially patterned factors. RESULTS: Exposure estimates from most methods had high agreement across sites, but low agreement within sites. Within-site exposure variation was limited for some methods. Consistently null findings for the PM2.5-cognitive outcome associations regardless of method precluded empirical conclusions about the potential impact of method on study findings in contexts where positive associations are observed. Not accounting for study site led to consistent, adverse associations, regardless of exposure estimation method, suggesting the potential for substantial bias due to residual confounding by spatially patterned factors. DISCUSSION: PM2.5 estimation methods agreed across sites but not within sites. Choice of estimation method may impact findings when participants are concentrated in small geographic areas. Understanding unmeasured confounding by factors that are spatially patterned may be particularly important in studies of air pollution and cognitive or brain health.

Radon Exposure and Incident Stroke Risk in the Women's Health Initiative.

BACKGROUND AND OBJECTIVES: Little is known about the role of radon in the epidemiology of stroke among women. We therefore examined the association between home radon exposure and risk of stroke among middle-aged and older women in the United States. METHODS: We conducted a prospective cohort study of postmenopausal women aged 50-79 years at baseline (1993-1998) in the Women's Health Initiative. We measured exposures as 2-day, indoor, lowest living-level average radon concentrations in picocuries per liter (pCi/L) as estimated in 1993 by the US Geological Survey and reviewed by the Association of American State Geologists under the Indoor Radon Abatement Act. We used Cox proportional hazards models to estimate risk of incident, neurologist-adjudicated stroke during follow-up through 2020 as a hazard ratio and 95% CI, adjusting for study design and participant demographic, social, behavioral, and clinical characteristics. RESULTS: Among 158,910 women without stroke at baseline (mean age 63.2 years; 83% white), 6,979 incident strokes were identified over follow-up (mean 13.4 years). Incidence rates were 333, 343, and 349 strokes per 100,000 woman-years at radon concentrations of <2, 2-4, and >4 pCi/L, respectively. Compared with women living at concentrations <2 pCi/L, those at 2-4 and >4 pCi/L had higher covariate-adjusted risks of incident stroke: hazard ratio (95% CI) 1.06 (0.99-1.13) and 1.14 (1.05-1.22). Using nonlinear spline functions to model radon, stroke risk was significantly elevated at concentrations ranging from 2 to 4 pCi/L (p = 0.0004), that is, below the United States Environmental Protection Agency Radon Action Level for mitigation (4 pCi/L). Associations were slightly stronger for ischemic (especially cardioembolic, small vessel occlusive, and large artery atherosclerotic) than hemorrhagic stroke, but otherwise robust in sensitivity analyses. DISCUSSION: Radon exposure is associated with moderately increased stroke risk among middle-aged and older women in the United States, suggesting that promulgation of a lower Radon Action Level may help reduce the domestic impact of cerebrovascular disease on public health.

Diet Quality and Epigenetic Aging in the Women's Health Initiative.

BACKGROUND: Higher diet quality scores are associated with a lower risk for many chronic diseases and all-cause mortality; however, it is unclear if diet quality is associated with aging biology. OBJECTIVE: This study aimed to examine the association between diet quality and a measure of biological aging known as epigenetic aging. DESIGN: A cross-sectional data analysis was used to examine the association between three diet quality scores based on self-reported food frequency questionnaire data and five measures of epigenetic aging based on DNA methylation (DNAm) data from peripheral blood. PARTICIPANTS/SETTING: This study included 4,500 postmenopausal women recruited from multiple sites across the United States (1993-98), aged 50 to 79 years, with food frequency questionnaire and DNAm data available from the Women's Health Initiative baseline visit. MAIN OUTCOME MEASURES: Five established epigenetic aging measures were generated from HumanMethylation450 Beadchip DNAm data, including AgeAccelHannum, AgeAccelHorvath, AgeAccelPheno, AgeAccelGrim, and DunedinPACE. STATISTICAL ANALYSES PERFORMED: Linear mixed models were used to test for associations between three diet quality scores (Healthy Eating Index, Dietary Approaches to Stop Hypertension, and alternate Mediterranean diet scores) and epigenetic aging measures, adjusted for age, race and ethnicity, education, tobacco smoking, physical activity, Women's Health Initiative substudy from which DNAm data were obtained, and DNAm-based estimates of leukocyte proportions. RESULTS: Healthy Eating Index, Dietary Approaches to Stop Hypertension, and alternate Mediterranean diet scores were all inversely associated with AgeAccelPheno, AgeAccelGrim, and DunedinPACE (P < 0.05), with the largest effects with DunedinPACE. A one standard deviation increment in diet quality scores was associated with a decrement (ß ± SE) in DunedinPACE z score of -0.097 ± 0.014 (P = 9.70 x 10-13) for Healthy Eating Index, -0.107 ± 0.014 (P = 1.53 x 10-14) for Dietary Approaches to Stop Hypertension, and -0.068 ± 0.013 (P = 2.31 x 10-07) for the alternate Mediterranean diet. CONCLUSIONS: In postmenopausal women, diet quality scores were inversely associated with DNAm-based measures of biological aging, particularly DunedinPACE.

Comparison of PM2.5 Air Pollution Exposures and Health Effects Associations Using 11 Different Modeling Approaches in the Women's Health Initiative Memory Study (WHIMS).

BACKGROUND: Many approaches to quantifying air pollution exposures have been developed. However, the impact of choice of approach on air pollution estimates and health-effects associations remains unclear. OBJECTIVES: Our objective is to compare particulate matter with aerodynamic diameter ≤2.5µm (PM2.5) concentrations and resulting health effects associations using multiple estimation approaches previously used in epidemiologic analyses. METHODS: We assigned annual PM2.5 exposure estimates from 1999 to 2004 derived from 11 different approaches to Women's Health Initiative Memory Study (WHIMS) participant addresses within the contiguous US. Approaches included geostatistical interpolation approaches, land-use regression or spatiotemporal models, satellite-derived approaches, air dispersion and chemical transport models, and hybrid models. We used descriptive statistics and plots to assess relative and absolute agreement among exposure estimates and examined the impact of approach on associations between PM2.5 and death due to natural causes, cardiovascular disease (CVD) mortality, and incident CVD events, adjusting for individual-level covariates and climate-based region. RESULTS: With a few exceptions, relative agreement of approach-specific PM2.5 exposure estimates was high for PM2.5 concentrations across the contiguous US. Agreement among approach-specific exposure estimates was stronger near PM2.5 monitors, in certain regions of the country, and in 2004 vs. 1999. Collectively, our results suggest but do not quantify lower agreement at local spatial scales for PM2.5. There was no evidence of large differences in health effects associations with PM2.5 among estimation approaches in analyses adjusted for climate region. CONCLUSIONS: Different estimation approaches produced similar spatial patterns of PM2.5 concentrations across the contiguous US and in areas with dense monitoring data, and PM2.5-health effects associations were similar among estimation approaches. PM2.5 estimates and PM2.5-health effects associations may differ more in samples drawn from smaller areas or areas without substantial monitoring data, or in analyses with finer adjustment for participant location. Our results can inform decisions about PM2.5 estimation approach in epidemiologic studies, as investigators balance concerns about bias, efficiency, and resource allocation. Future work is needed to understand whether these conclusions also apply in the context of other air pollutants of interest. https://doi.org/10.1289/EHP12995.

Radon Exposure, Clonal Hematopoiesis, and Stroke Susceptibility in the Women's Health Initiative.

BACKGROUND AND OBJECTIVES: Studies suggest that clonal hematopoiesis of indeterminate potential (CHIP) may increase risk of hematologic malignancy and cardiovascular disease, including stroke. However, few studies have investigated plausible environmental risk factors for CHIP such as radon, despite the climate-related increases in and documented infrequency of testing for this common indoor air pollutant.The purpose of this study was to estimate the risk of CHIP related to radon, an established environmental mutagen. METHODS: We linked geocoded addresses of 10,799 Women's Health Initiative Trans-Omics for Precision Medicine (WHI TOPMed) participants to US Environmental Protection Agency-predicted, county-level, indoor average screening radon concentrations, categorized as follows: Zone 1 (>4 pCi/L), Zone 2 (2-4 pCi/L), and Zone 3 (<2 pCi/L). We defined CHIP as the presence of one or more leukemogenic driver mutations with variant allele frequency >0.02. We identified prevalent and incident ischemic and hemorrhagic strokes; subtyped ischemic stroke using Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria; and then estimated radon-related risk of CHIP as an odds ratio (OR) and 95% CI using multivariable-adjusted, design-weighted logistic regression stratified by age, race/ethnicity, smoking status, and stroke type/subtype. RESULTS: The percentages of participants with CHIP in Zones 1, 2, and 3 were 9.0%, 8.4%, and 7.7%, respectively (ptrend = 0.06). Among participants with ischemic stroke, Zones 2 and 1 were associated with higher estimated risks of CHIP relative to Zone 3: 1.39 (1.15-1.68) and 1.46 (1.15-1.87), but not among participants with hemorrhagic stroke: 0.98 (0.68-1.40) and 1.03 (0.70-1.52), or without stroke: 1.04 (0.74-1.46) and 0.95 (0.63-1.42), respectively (pinteraction = 0.03). Corresponding estimates were particularly high among TOAST-subtyped cardioembolism: 1.78 (1.30-2.47) and 1.88 (1.31-2.72), or other ischemic etiologies: 1.37 (1.06-1.78) and 1.50 (1.11-2.04), but not small vessel occlusion: 1.05 (0.74-1.49) and 1.00 (0.68-1.47), respectively (pinteraction = 0.10). Observed patterns of association among strata were insensitive to attrition weighting, ancestry adjustment, prevalent stroke exclusion, separate analysis of DNMT3A driver mutations, and substitution with 3 alternative estimates of radon exposure. DISCUSSION: The robust elevation of radon-related risk of CHIP among postmenopausal women who develop incident cardioembolic stroke is consistent with a potential role of somatic genomic mutation in this societally burdensome form of cerebrovascular disease, although the mechanism has yet to be confirmed.

Individual and Neighborhood-level Socioeconomic Status and Somatic Mutations Associated With Increased Risk of Cardiovascular Disease and Mortality: A Cross-Sectional Analysis in the Women's Health Initiative.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), the expansion of leukemogenic mutations in white blood cells, has been associated with increased risk of atherosclerotic cardiovascular diseases, cancer, and mortality. OBJECTIVE: We examined the relationship between individual- and neighborhood-level socioeconomic status (SES) and CHIP and evaluated effect modification by interpersonal and intrapersonal resources. METHODS: The study population included 10,799 postmenopausal women from the Women's Health Initiative without hematologic malignancy or antineoplastic medication use. Individual- and neighborhood (Census tract)-level SES were assessed across several domains including education, income, and occupation, and a neighborhood-level SES summary z-score, which captures multiple dimensions of SES, was generated. Interpersonal and intrapersonal resources were self-reports. CHIP was ascertained based on a prespecified list of leukemogenic driver mutations. Weighted logistic regression models adjusted for covariates were used to estimate risk of CHIP as an odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: The interval-scale neighborhood-level SES summary z-score was associated with a 3% increased risk of CHIP: OR (95% CI) = 1.03 (1.00-1.05), p = .038. Optimism significantly modified that estimate, such that among women with low/medium and high levels of optimism, the corresponding ORs (95% CIs) were 1.03 (1.02-1.04) and 0.95 (0.94-0.96), pInteraction < .001. CONCLUSIONS: Our findings suggest that reduced risk of somatic mutation may represent a biological pathway by which optimism protects contextually advantaged but at-risk women against age-related chronic disease and highlight potential benefits of long-term, positive psychological interventions.

Stressful life events, social support, and epigenetic aging in the Women's Health Initiative.

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 (ß: 0.34, 95% CI: 0.08, 0.59) and DNAmTL (ß: -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.

The association of long-term exposure to criteria air pollutants, fine particulate matter components, and airborne trace metals with late-life brain amyloid burden in the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Studies suggest associations between long-term ambient air pollution exposure and outcomes related to Alzheimer's disease (AD). Whether a link exists between pollutants and brain amyloid accumulation, a biomarker of AD, is unclear. We assessed whether long-term air pollutant exposures are associated with late-life brain amyloid deposition in Atherosclerosis Risk in Communities (ARIC) study participants. METHODS: We used a chemical transport model with data fusion to estimate ambient concentrations of PM2.5 and its components, NO2, NOx, O3 (24-hour and 8-hour), CO, and airborne trace metals. We linked concentrations to geocoded participant addresses and calculated 10-year mean exposures (2002 to 2011). Brain amyloid deposition was measured using florbetapir amyloid positron emission tomography (PET) scans in 346 participants without dementia in 2012-2014, and we defined amyloid positivity as a global cortical standardized uptake value ratio ≥ the sample median of 1.2. We used logistic regression models to quantify the association between amyloid positivity and each air pollutant, adjusting for putative confounders. In sensitivity analyses, we considered whether use of alternate air pollution estimation approaches impacted findings for PM2.5, NO2, NOx, and 24-hour O3. RESULTS: At PET imaging, eligible participants (N = 318) had a mean age of 78 years, 56% were female, 43% were Black, and 27% had mild cognitive impairment. We did not find evidence of associations between long-term exposure to any pollutant and brain amyloid positivity in adjusted models. Findings were materially unchanged in sensitivity analyses using alternate air pollution estimation approaches for PM2.5, NO2, NOx, and 24-hour O3. CONCLUSIONS: Air pollution may impact cognition and dementia independent of amyloid accumulation, though whether air pollution influences AD pathogenesis later in the disease course or at higher exposure levels deserves further consideration.

Long-term exposure to ambient particulate matter and stroke etiology: Results from the Women's Health Initiative.

BACKGROUND: Ambient particulate matter (PM) air pollution is a leading cause of global disability and accounts for an annual 2.9 million deaths globally. PM is established as an important risk factor for cardiovascular disease, however the evidence supporting a link specifically between long-term exposure to ambient PM and incident stroke is less clear. We sought to evaluate the association of long-term exposure to different size fractions of ambient PM with incident stroke (overall and by etiologic subtypes) and cerebrovascular deaths within the Women's Health Initiative, a large prospective study of older women in the US. METHODS: We studied 155,410 postmenopausal women without previous cerebrovascular disease enrolled into the study between 1993 and 1998, with follow-up through 2010. We assessed geocoded participant address-specific concentrations of ambient PM (fine [PM2.5], respirable [PM10] and coarse [PM10-2.5]), as well as nitrogen dioxide [NO2] using spatiotemporal models. We classified hospitalization events into ischemic, hemorrhagic, or other/unclassified stroke. Cerebrovascular mortality was defined as death from any stroke etiology. We used Cox proportional hazard models to calculate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for individual and neighborhood-level characteristics. RESULTS: During a median follow-up time of 15 years, participants experienced 4,556 cerebrovascular events. The hazard ratio for all cerebrovascular events was 2.14 (95% CI: 1.87, 2.44) comparing the top versus bottom quartiles of PM2.5. Similarly, there was a statistically significant increase in events comparing the top versus bottom quartiles of PM10 and NO2 (HR: 1.17; 95% CI: 1.03, 1.33 and HR:1.26; 95% CI: 1.12, 1.42). The strength of association did not vary substantially by stroke etiology. There was little evidence of an association between PMcoarse and incident cerebrovascular events. CONCLUSIONS: Long-term exposure to fine (PM2.5) and respirable (PM10) particulate matter as well as NO2 was associated with a significant increase of cerebrovascular events among postmenopausal women. Strength of the associations were consistent by stroke etiology.

Short-term Air Pollution Levels and Blood Pressure in Older Women.

BACKGROUND: Evidence of associations between daily variation in air pollution and blood pressure (BP) is varied and few prior longitudinal studies adjusted for calendar time. METHODS: We studied 143,658 postmenopausal women 50 to 79 years of age from the Women's Health Initiative (1993-2005). We estimated daily atmospheric particulate matter (PM) (in three size fractions: PM2.5, PM2.5-10, and PM10) and nitrogen dioxide (NO2) concentrations at participants' residential addresses using validated lognormal kriging models. We used linear mixed-effects models to estimate the association between air pollution concentrations and repeated measures of systolic and diastolic BP (SBP, DBP) adjusting for confounders and calendar time. RESULTS: Short-term PM2.5 and NO2 were each positively associated with DBP {0.10 mmHg [95% confidence interval (CI): 0.04, 0.15]; 0.13 mmHg (95% CI: 0.09, 0.18), respectively} for interquartile range changes in lag 3-5 day PM2.5 and NO2. Short-term NO2 was negatively associated with SBP [-0.21 mmHg (95%CI: -0.30, -0.13)]. In two-pollutant models, the NO2-DBP association was slightly stronger, but for PM2.5 was attenuated to null, compared with single-pollutant models. Associations between short-term NO2 and DBP were more pronounced among those with higher body mass index, lower neighborhood socioeconomic position, and diabetes. When long-term (annual) and lag 3-5 day PM2.5 were in the same model, associations with long-term PM2.5 were stronger than for lag 3-5 day. CONCLUSIONS: We observed that short-term PM2.5 and NO2 levels were associated with increased DBP, although two-pollutant model results suggest NO2 was more likely responsible for observed associations. Long-term PM2.5 effects were larger than short-term.

Air pollution and decreased bone mineral density among Women's Health Initiative participants.

Background: Osteoporosis heavily affects postmenopausal women and is influenced by environmental exposures. Determining the impact of criteria air pollutants and their mixtures on bone mineral density (BMD) in postmenopausal women is an urgent priority. Methods: We conducted a prospective observational study using data from the ethnically diverse Women's Health Initiative Study (WHI) (enrollment, September 1994-December 1998; data analysis, January 2020 to August 2022). We used log-normal, ordinary kriging to estimate daily mean concentrations of PM10, NO, NO2, and SO2 at participants' geocoded addresses (1-, 3-, and 5-year averages before BMD assessments). We measured whole-body, total hip, femoral neck, and lumbar spine BMD at enrollment and follow-up (Y1, Y3, Y6) via dual-energy X-ray absorptiometry. We estimated associations using multivariable linear and linear mixed-effects models and mixture effects using Bayesian kernel machine regression (BKMR) models. Findings: In cross-sectional and longitudinal analyses, mean PM10, NO, NO2, and SO2 averaged over 1, 3, and 5 years before the visit were negatively associated with whole-body, total hip, femoral neck, and lumbar spine BMD. For example, lumbar spine BMD decreased 0.026 (95% CI: 0.016, 0.036) g/cm2/year per a 10% increase in 3-year mean NO2 concentration. BKMR suggested that nitrogen oxides exposure was inversely associated with whole-body and lumbar spine BMD. Interpretation: In this cohort study, higher levels of air pollutants were associated with bone damage, particularly on lumbar spine, among postmenopausal women. These findings highlight nitrogen oxides exposure as a leading contributor to bone loss in postmenopausal women, expanding previous findings of air pollution-related bone damage. Funding: US National Institutes of Health.

Long-term aircraft noise exposure and risk of hypertension in postmenopausal women.

BACKGROUND: Studies of the association between aircraft noise and hypertension are complicated by inadequate control for potential confounders and a lack of longitudinal assessments, and existing evidence is inconclusive. OBJECTIVES: We evaluated the association between long-term aircraft noise exposure and risk of hypertension among post-menopausal women in the Women's Health Initiative Clinical Trials, an ongoing prospective U.S. METHODS: Day-night average (DNL) and night equivalent sound levels (Lnight) were modeled for 90 U.S. airports from 1995 to 2010 in 5-year intervals using the Aviation Environmental Design Tool and linked to participant geocoded addresses from 1993 to 2010. Participants with modeled exposures ≥45 A-weighted decibels (dB [A]) were considered exposed, and those outside of 45 dB(A) who also did not live in close proximity to unmodeled airports were considered unexposed. Hypertension was defined as systolic/diastolic blood pressure ≥140/90 mmHg or inventoried/self-reported antihypertensive medication use. Using time-varying Cox proportional hazards models, we estimated hazard ratios (HRs) for incident hypertension when exposed to DNL or Lnight ≥45 versus <45 dB(A), controlling for sociodemographic, behavioral, and environmental/contextual factors. RESULTS/DISCUSSION: There were 18,783 participants with non-missing DNL exposure and 14,443 with non-missing Lnight exposure at risk of hypertension. In adjusted models, DNL and Lnight ≥45 db(A) were associated with HRs of 1.00 (95% confidence interval [CI]: 0.93, 1.08) and 1.06 (95%CI: 0.91, 1.24), respectively. There was no evidence supporting a positive exposure-response relationship, and findings were robust in sensitivity analyses. Indications of elevated risk were seen among certain subgroups, such as those living in areas with lower population density (HRinteraction: 0.84; 95%CI: 0.72, 0.98) or nitrogen dioxide concentrations (HRinteraction: 0.82; 95%CI: 0.71, 0.95), which may indicate lower ambient/road traffic noise. Our findings do not suggest a relationship between aircraft noise and incident hypertension among older women in the U.S., though associations in lower ambient noise settings merit further investigation.

The Association of Epigenetic Age Acceleration and Multimorbidity at Age 90 in the Women's Health Initiative.

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.

Epigenome-Wide Analysis of DNA Methylation and Optimism in Women and Men.

OBJECTIVE: Higher optimism is associated with reduced mortality and a lower risk of age-related chronic diseases. DNA methylation (DNAm) may provide insight into mechanisms underlying these relationships. We hypothesized that DNAm would differ among older individuals who are more versus less optimistic. METHODS: Using cross-sectional data from two population-based cohorts of women with diverse races/ethnicities ( n = 3816) and men (only White, n = 667), we investigated the associations of optimism with epigenome-wide leukocyte DNAm. Random-effects meta-analyses were subsequently used to pool the individual results. Significantly differentially methylated cytosine-phosphate-guanines (CpGs) were identified by the "number of independent degrees of freedom" approach: effective degrees of freedom correction using the number of principal components (PCs), explaining >95% of the variation of the DNAm data (PC-correction). We performed regional analyses using comb-p and pathway analyses using the Ingenuity Pathway Analysis software. RESULTS: We found that essentially all CpGs (total probe N = 359,862) were homogeneous across sex and race/ethnicity in the DNAm-optimism association. In the single CpG site analyses based on homogeneous CpGs, we identified 13 significantly differentially methylated probes using PC-correction. We found four significantly differentially methylated regions and two significantly differentially methylated pathways. The annotated genes from the single CpG site and regional analyses are involved in psychiatric disorders, cardiovascular disease, cognitive impairment, and cancer. Identified pathways were related to cancer, and neurodevelopmental and neurodegenerative disorders. CONCLUSION: Our findings provide new insights into possible mechanisms underlying optimism and health.

DNA methylation GrimAge version 2.

We previously described a DNA methylation (DNAm) based biomarker of human mortality risk DNAm GrimAge. Here we describe version 2 of GrimAge (trained on individuals aged between 40 and 92) which leverages two new DNAm based estimators of (log transformed) plasma proteins: high sensitivity C-reactive protein (logCRP) and hemoglobin A1C (logA1C). We evaluate GrimAge2 in 13,399 blood samples across nine study cohorts. After adjustment for age and sex, GrimAge2 outperforms GrimAge in predicting mortality across multiple racial/ethnic groups (meta P=3.6x10-167 versus P=2.6x10-144) and in terms of associations with age related conditions such as coronary heart disease, lung function measurement FEV1 (correlation= -0.31, P=1.1x10-136), computed tomography based measurements of fatty liver disease. We present evidence that GrimAge version 2 also applies to younger individuals and to saliva samples where it tracks markers of metabolic syndrome. DNAm logCRP is positively correlated with morbidity count (P=1.3x10-54). DNAm logA1C is highly associated with type 2 diabetes (P=5.8x10-155). DNAm PAI-1 outperforms the other age-adjusted DNAm biomarkers including GrimAge2 in correlating with triglyceride (cor=0.34, P=9.6x10-267) and visceral fat (cor=0.41, P=4.7x10-41). Overall, we demonstrate that GrimAge version 2 is an attractive epigenetic biomarker of human mortality and morbidity risk.

Analysis of Epigenetic Age Acceleration and Healthy Longevity Among Older US Women.

Importance: Accelerated biological aging is associated with decreased physical capability and cognitive functioning, which are associated with increased risk of morbidity and mortality. Objective: We investigated associations between epigenetic age acceleration (EAA), a biomarker associated with aging, and healthy longevity among older women. Design, Setting, and Participants: This cohort study was a secondary analysis of participants in the Women's Health Initiative (WHI) who were eligible to survive to age 90 years by September 30, 2020. Participants were located in multiple centers. This study was restricted to women with genome-wide DNA methylation data, generated from baseline blood samples within 3 WHI ancillary studies. Median (IQR) follow-up times from baseline were 21.6 (19.6-22.9) years and 21.4 (19.8-22.7) years for women who survived to age 90 years with and without intact mobility, respectively, and 13.2 (8.8-16.7) for women who did not survive to age 90 years. Data were analyzed from December 2020 to July 2021. Exposures: EAA was estimated using 4 established "clocks": Horvath pantissue, Hannum, Pheno, and Grim. Main Outcomes and Measures: Using multinomial logistic regression, odds ratios (ORs) and 95% CIs were estimated for 3 healthy longevity outcomes for each clock: survival to age 90 years with intact mobility, survival to age 90 years without intact mobility, and no survival to age 90 years. Results: Among 1813 women, there were 464 women (mean [SD] age at baseline, 71.6 [3.5] years) who survived to age 90 years with intact mobility and cognitive functioning, 420 women (mean [SD] age at baseline, 71.3 [3.2] years) who survived to age 90 years without intact mobility and cognitive functioning, and 929 women (mean [SD] age at baseline, 70.2 [3.4] years) who did not survive to age 90 years. Women who survived to age 90 years with intact mobility and cognitive function were healthier at baseline compared with women who survived without those outcomes or who did not survive to age 90 years (eg, 143 women [30.8%] vs 101 women [24.0%] and 202 women [21.7%] with 0 chronic conditions). The odds of surviving to age 90 years with intact mobility were lower for every 1 SD increase in EAA compared with those who did not survive to age 90 years as measured by AgeAccelHorvath (OR, 0.82; 95% CI, 0.69-0.96; P = .01), AgeAccelHannum (OR, 0.67; 95% CI, 0.56-0.80; P < .001), AgeAccelPheno (OR, 0.60; 95% CI, 0.51-0.72; P < .001), and AgeAccelGrim (OR, 0.68; 95% CI, 0.55-0.84; P < .001). ORs were similar for women who survived to age 90 years with intact mobility and cognitive function (eg, AgeAccelHorvath: OR per 1 SD increase in EAA, 0.83; 95% CI, 0.71-0.98; P = .03) compared with women who did not survive to age 90 years. Conclusions and Relevance: These findings suggest that EAA may be a valid biomarker associated with healthy longevity among older women and may be used for risk stratification and risk estimation of future functional and cognitive aging. Outcomes suggest that future studies may focus on the potential for public health interventions to counteract EAA and its association with poor health outcomes to lower disease burden while increasing longevity.

Examination of the independent contribution of rheumatic heart disease and congestive cardiac failure to the development and outcome of melioidosis in Far North Queensland, tropical Australia.

BACKGROUND: Patients with rheumatic heart disease (RHD) and congestive cardiac failure (CCF) are believed to have an increased risk of melioidosis and are thought to be more likely to die from the infection. This study was performed to confirm these findings in a region with a high incidence of all three conditions. PRINCIPAL FINDINGS: Between January 1998 and December 2021 there were 392 cases of melioidosis in Far North Queensland, tropical Australia; 200/392 (51.0%) identified as an Indigenous Australian, and 337/392 (86.0%) had a confirmed predisposing comorbidity that increased risk for the infection. Overall, 46/392 (11.7%) died before hospital discharge; the case fatality rate declining during the study period (p for trend = 0.001). There were only 3/392 (0.8%) with confirmed RHD, all of whom had at least one other risk factor for melioidosis; all 3 survived to hospital discharge. Among the 200 Indigenous Australians in the cohort, 2 had confirmed RHD; not statistically greater than the prevalence of RHD in the local general Indigenous population (1.0% versus 1.2%, p = 1.0). RHD was present in only 1/193 (0.5%) cases of melioidosis diagnosed after October 2016, a period which coincided with prospective data collection. There were 26/392 (6.6%) with confirmed CCF, but all 26 had another traditional risk factor for melioidosis. Patients with CCF were more likely to also have chronic lung disease (OR (95% CI: 4.46 (1.93-10.31), p<0.001) and chronic kidney disease (odds ratio (OR) (95% confidence interval (CI): 2.98 (1.22-7.29), p = 0.01) than those who did not have CCF. Two patients with melioidosis and CCF died before hospital discharge; both were elderly (aged 81 and 91 years) and had significant comorbidity. CONCLUSIONS: In this region of tropical Australia RHD and CCF do not appear to be independent risk factors for melioidosis and have limited prognostic utility.

Gaseous air pollutants and DNA methylation in a methylome-wide association study of an ethnically and environmentally diverse population of U.S. adults.

Epigenetic mechanisms may underlie air pollution-health outcome associations. We estimated gaseous air pollutant-DNA methylation (DNAm) associations using twelve subpopulations within Women's Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) cohorts (n = 8397; mean age 61.3 years; 83% female; 46% African-American, 46% European-American, 8% Hispanic/Latino). We used geocoded participant address-specific mean ambient carbon monoxide (CO), nitrogen oxides (NO2; NOx), ozone (O3), and sulfur dioxide (SO2) concentrations estimated over the 2-, 7-, 28-, and 365-day periods before collection of blood samples used to generate Illumina 450 k array leukocyte DNAm measurements. We estimated methylome-wide, subpopulation- and race/ethnicity-stratified pollutant-DNAm associations in multi-level, linear mixed-effects models adjusted for sociodemographic, behavioral, meteorological, and technical covariates. We combined stratum-specific estimates in inverse variance-weighted meta-analyses and characterized significant associations (false discovery rate; FDR<0.05) at Cytosine-phosphate-Guanine (CpG) sites without among-strata heterogeneity (PCochran's Q > 0.05). We attempted replication in the Cooperative Health Research in Region of Augsburg (KORA) study and Normative Aging Study (NAS). We observed a -0.3 (95% CI: -0.4, -0.2) unit decrease in percent DNAm per interquartile range (IQR, 7.3 ppb) increase in 28-day mean NO2 concentration at cg01885635 (chromosome 3; regulatory region 290 bp upstream from ZNF621; FDR = 0.03). At intragenic sites cg21849932 (chromosome 20; LIME1; intron 3) and cg05353869 (chromosome 11; KLHL35; exon 2), we observed a -0.3 (95% CI: -0.4, -0.2) unit decrease (FDR = 0.04) and a 1.2 (95% CI: 0.7, 1.7) unit increase (FDR = 0.04), respectively, in percent DNAm per IQR (17.6 ppb) increase in 7-day mean ozone concentration. Results were not fully replicated in KORA and NAS. We identified three CpG sites potentially susceptible to gaseous air pollution-induced DNAm changes near genes relevant for cardiovascular and lung disease. Further harmonized investigations with a range of gaseous pollutants and averaging durations are needed to determine the effect of gaseous air pollutants on DNA methylation and ultimately gene expression.