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Discrimination is a social adversity that is linked to several age-related outcomes. However, the molecular drivers of these observations are poorly understood. Social adverse factors are associated with proinflammatory and interferon gene expression, but little is known about whether additional genes are associated with discrimination among both African American and White adults. In this study, we examined how perceived discrimination in African American and White adults was associated with genome-wide transcriptome differences using RNA sequencing. Perceived discrimination was measured based on responses to self-reported lifetime discrimination and racial discrimination. Differential gene expression and pathway analysis were conducted in a cohort (N = 59) stratified by race, sex, and overall discrimination level. We found 28 significantly differentially expressed genes associated with race among those reporting high discrimination. Several of the upregulated genes for African American versus White adults reporting discrimination were related to immune function IGLV2-11, S100B, IGKV3-20, and IGKV4-1; the most significantly downregulated genes were associated with immune modulation and cancer, LUCAT1, THBS1, and ARPIN. The most enriched gene ontology biological process between African American and White men reporting high discrimination was the regulation of cytokine biosynthetic processes. The immune response biological process was significantly lower for African American women compared to White women reporting high discrimination. Discrimination was associated with the expression of small nucleolar RNAs, long noncoding RNAs, and microRNAs associated with energy homeostasis, cancer, and actin. Understanding the pathways through which adverse social factors like discrimination are associated with gene expression is crucial in advancing knowledge of age-related health disparities., (© 2025 Federation of American Societies for Experimental Biology.)

Circulating cell-free mitochondrial DNA (ccf-mtDNA) acts as a damage-associated molecular pattern molecule and may be cargo within extracellular vesicles (EVs). ccf-mtDNA and select mitochondrial DNA (mtDNA) haplogroups are associated with cardiovascular disease. We hypothesized that ccf-mtDNA and plasma EV mtDNA would be associated with hypertension, sex, self-identified race, and mtDNA haplogroup ancestry. Participants were normotensive (n = 107) and hypertensive (n = 108) African American and White adults from the Healthy Aging in Neighborhoods of Diversity across the Life Span study. ccf-mtDNA levels were higher in African American participants compared with White participants in both plasma and EVs, but ccf-mtDNA levels were not related to hypertension. EV mtDNA levels were highest in African American participants with African mtDNA haplogroup. Circulating inflammatory protein levels were altered with mtDNA haplogroup, race, and EV mtDNA. Our findings highlight that race is a social construct and that ancestry is crucial when examining health and biomarker differences between groups., Competing Interests: The authors declare no conflicts of interest.

Diet quality is a modifiable risk factor for frailty, but research on the association of frailty with dietary inflammatory potential is limited. The objective was to determine associations between diet quality assessed by the dietary inflammatory index (DII) with frailty status over time. Participants with both dietary and frailty data from the longitudinal Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study were used ( n = 2901, 43.5% male, 43.8% African American, 48.5 y mean baseline age, with a mean 8.7 y of follow-up). Group-based trajectory modeling identified two frailty (remaining non-frail or being pre-frail/frail over time) and three diet quality trajectory groups (high or medium pro-inflammatory and anti-inflammatory potentials). Multiple logistic regression found both medium pro-inflammatory and anti-inflammatory DII trajectory groups, compared to the high pro-inflammatory group, were positively associated with being non-frail over time for the overall sample, both sexes and races. Kaplan-Meier curves and log-rank test revealed anti-inflammatory DII scores were associated with lower risk for being pre-frail or frail. No longitudinal relationship existed between frailty status at baseline and annualized DII change, a check on reverse causality. This study contributes to our current knowledge providing longitudinal evidence of the link between anti-inflammatory DII score with lower frailty risk.

Background: Recent data indicate a decline in overall longevity in the United States. Even prior to the COVID-19 pandemic, an increase in midlife mortality rates had been reported. Life expectancy disparities have persisted in the United States for racial and ethnic groups and for individuals living at low socioeconomic status. These continued trends in mortality indicate the importance of examining biomarkers of mortality at midlife in at-risk populations. Circulating levels of cytokines and inflammatory markers reflect systemic chronic inflammation, which is a well-known driver of many age-related diseases., Methods: In this study, we examined the relationship of nine different inflammatory proteins with mortality in a middle-aged socioeconomically diverse cohort of African-American and White men and women (n = 1122; mean age = 47.8 years)., Results: We found significant differences in inflammatory-related protein serum levels between African-American and White middle-aged adults. E-selectin and fibrinogen were significantly higher in African-American adults. IFN-γ, TNF-α trimer, monocyte chemoattractant protein-1 (MCP-1), soluble receptor for advanced glycation end-products (sRAGE) and P-selectin were significantly higher in White participants compared to African-American participants. Higher levels of E-selectin, MCP-1 and P-selectin were associated with a higher mortality risk. Furthermore, there was a significant interaction between sex and IL-6 with mortality. IL-6 levels were associated with an increased risk of mortality, an association that was significantly greater in women than men. In addition, White participants with high levels of sRAGE had significantly higher survival probability than White participants with low levels of sRAGE, while African-American participants had similar survival probabilities across sRAGE levels., Conclusions: These results suggest that circulating inflammatory markers can be utilized as indicators of midlife mortality risk in a socioeconomically diverse cohort of African-American and White individuals., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Frailty is an age-related syndrome characterized by reduced recovery from stressors and increased risks of morbidity and mortality. Although frailty is usually studied in those over 65 years, our previous work showed that frailty is both present and a risk factor for premature mortality in midlife. We identified altered gene expression patterns and biological pathways associated with inflammation in frailty. Evidence suggests DNA oxidation damage related to inflammation accumulates with age, and that DNA repair capacity (DRC) declines with age and age-related conditions. We hypothesized that inter-individual differences in DNA oxidation damage and DRC are associated with frailty status and poverty level. Using the CometChip assay, we assessed baseline single-strand breaks and hydrogen peroxide (H 2 O 2 )-induced DNA oxidation damage and DRC in non-frail and frail middle-aged African American and White individuals with household incomes above and below poverty. Analysis of baseline single-strand breaks showed no associations with frailty, poverty, race, or sex. However, we identified an interaction between frailty and poverty in H 2 O 2 -induced DNA oxidation damage. We also identified interactions between sex and frailty as well as sex and poverty status with DRC. The social determinant of health, poverty, associates with DRC in men. Baseline DNA damage, H 2 O 2 -induced DNA damage as well as DRC were associated with serum cytokine levels. IL-10 levels were inversely associated with baseline DNA damage as well as H 2 O 2 -induced DNA damage, DRC was altered by IL-4 levels and sex, and by TNF-α levels in the context of sex and poverty status. This is the first evidence that DRC may be influenced by poverty status at midlife. Our data show that social determinants of health should be considered in examining biological pathways through which disparate age-related health outcomes become manifest., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Published by Elsevier B.V.)

Limited investigation has been done on diet quality trajectories over adulthood. The main study objectives were to determine the diet quality group trajectories (GTs) over time and to detect changes in a socio-economically and racially diverse middle-aged cohort. Data from three waves of the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study were used to determine diet quality with group-based trajectory modeling (GBTM). Three quality indices-the Healthy Eating Index (HEI), the Dietary Inflammatory Index (DII), and the Mean Adequacy Ratio (MAR)-were explored. The rate of change in quality over time was determined by mixed-effects regression analysis. Three diet quality GTs, low, middle, and high quality, were identified for each index and confirmed with spaghetti plots. Within each GT, only small changes in diet quality scores were observed, with improvements for the HEI and DII indices and a slight decline in MAR scores. Weighted kappa values revealed that the DII had better agreement with the HEI-2010 and MAR indices compared with the agreement between the HEI-2010 and MAR. Bayesian estimates revealed that the annualized rate of change in diet quality per person across the GTs was similar. There was minimal change in diet quality over time, regardless of the diet quality index used.

Importance: The Dunedin Pace of Aging Calculated From the Epigenome (DunedinPACE) measure is a newly constructed DNA methylation (DNAm) biomarker associated with morbidity, mortality, and adverse childhood experiences in several cohorts with European ancestry. However, there are few studies of the DunedinPACE measure among socioeconomically and racially diverse cohorts with longitudinal assessments., Objective: To investigate the association of race and poverty status with DunedinPACE scores in a socioeconomically diverse middle-aged cohort of African American and White participants., Design, Setting, and Participants: This longitudinal cohort study used data from the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) study. HANDLS is a population-based study of socioeconomically diverse African American and White adults aged 30 to 64 years at baseline in Baltimore, Maryland, with follow-up approximately every 5 years. The current study was restricted to 470 participants with blood samples at 2 time points: August 14, 2004, to June 22, 2009 (visit 1), and June 23, 2009, to September 12, 2017 (visit 2). Genome-wide DNAm was assessed at visit 1 (chronological age, 30-64 years) and visit 2. Data were analyzed from March 18, 2022, to February 9, 2023., Main Outcomes and Measures: DunedinPACE scores were estimated for each participant at 2 visits. DunedinPACE scores are values scaled to a mean of 1, interpretable with reference to a rate of 1 year of biological aging per 1 year of chronological aging. Linear mixed-model regression analysis was used to examine the trajectories of DunedinPACE scores by chronological age, race, sex, and poverty status., Results: Among 470 participants, the mean (SD) chronological age at visit 1 was 48.7 (8.7) years. Participants were balanced by sex (238 [50.6%] were men and 232 [49.4%] were women), race (237 [50.4%] African American and 233 [49.6%] White), and poverty status (236 [50.2%] living below poverty level and 234 [49.8%] living above poverty level). The mean (SD) time between visits was 5.1 (1.5) years. Overall, the mean (SD) DunedinPACE score was 1.07 (0.14), representing a 7% faster pace of biological aging than chronological aging. Linear mixed-effects regression analysis revealed an association between the 2-way interaction between race and poverty status (White race and household income below poverty level: β = 0.0665; 95% CI, 0.0298-0.1031; P < .001) and significantly higher DunedinPACE scores and an association between quadratic age (age squared: β = -0.0113; 95% CI, -0.0212 to -0.0013; P = .03) and significantly higher DunedinPACE scores., Conclusions and Relevance: In this cohort study, household income below poverty level and African American race were associated with higher DunedinPACE scores. These findings suggest that the DunedinPACE biomarker varies with race and poverty status as adverse social determinants of health. Consequently, measures of accelerated aging should be based on representative samples.

Background: The growing epidemic of the inflammation-related metabolic disease, type 2 diabetes mellitus, presents a challenge to improve our understanding of potential mechanisms or biomarkers to prevent or better control this age-associated disease. A gelsolin isoform is secreted into the plasma as part of the extracellular actin scavenger system which serves a protective role by digesting and removing actin filaments released from damaged cells. Recent data indicate a role for decreased plasma gelsolin (pGSN) levels as a biomarker of inflammatory conditions. Extracellular vesicles (EVs), a heterogeneous group of cell-derived membranous structures involved in intercellular signaling, have been implicated in metabolic and inflammatory diseases including type 2 diabetes mellitus. We examined whether pGSN levels were associated with EV concentration and inflammatory plasma proteins in individuals with or without diabetes., Methods: We quantified pGSN longitudinally (n = 104) in a socioeconomically diverse cohort of middle-aged African American and White study participants with and without diabetes mellitus. Plasma gelsolin levels were assayed by ELISA. EV concentration (sub-cohort n = 40) was measured using nanoparticle tracking analysis. Inflammatory plasma proteins were assayed on the SomaScan® v4 proteomic platform., Results: pGSN levels were lower in men than women. White individuals with diabetes had significantly lower levels of pGSN compared to White individuals without diabetes and to African American individuals either with or without diabetes. For adults living below poverty, those with diabetes had lower pGSN levels than those without diabetes. Adults living above poverty had similar pGSN levels regardless of diabetes status. No correlation between EV concentrations and pGSN levels was identified (r = - 0.03; p = 0.85). Large-scale exploratory plasma protein proteomics revealed 47 proteins that significantly differed by diabetes status, 19 of which significantly correlated with pGSN levels, including adiponectin., Conclusions: In this cohort of racially diverse individuals with and without diabetes, we found differences in pGSN levels with diabetes status, sex, race, and poverty. We also report significant associations of pGSN with the adipokine, adiponectin, and other inflammation- and diabetes-related proteins. These data provide mechanistic insights into the relationship of pGSN and diabetes., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Frailty, a clinical syndrome commencing at midlife, is a risk for morbidity and mortality. Little is known about the factors that contribute to the chronic inflammatory state associated with frailty. Extracellular vesicles (EVs) are small, membrane-bound vesicles that are released into the circulation and are mediators of intercellular communication. We examined whether mitochondrial DNA (mtDNA) and inflammatory proteins in EVs may act as damage-associated molecular pattern (DAMP) molecules in frailty., Results: To address whether EVs and their associated mtDNA and inflammatory protein cargo are altered with frailty, EVs were isolated from non-frail (n = 90) and frail (n = 87) middle-aged (45-55 years) participants from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. EV concentration was highest in frail White participants. EV mtDNA levels were significantly higher in frail individuals compared to non-frail individuals. The presence of six inflammatory proteins in EVs (FGF-21, HGF, IL-12B, PD-L1, PRDX3, and STAMBP) were significantly associated with frailty. EV inflammatory proteins were significantly altered by frailty status, race, sex, and poverty status. Notably, frail White participants had higher levels of EV-associated CD5, CD8A, CD244, CXCL1, CXCL6, CXCL11, LAP-TGF-beta-1 and MCP-4 compared to frail and non-frail African American participants. Frail White participants living below poverty had higher levels of EV-associated uPA. EV-associated CCL28 levels were highest in non-frail women and CXCL1 were highest in non-frail men. Men living below poverty had higher levels of CD5, CD8A, CXCL1, LAP-TGF-beta-1, and uPA. CXCL6 levels were significantly higher in individuals living above poverty. There was a significant correlation between EV mtDNA levels and the presence of inflammatory proteins., Conclusions: These data suggest that mtDNA within EVs may act as a DAMP molecule in frailty. Its association with chemokines and other inflammatory EV cargo proteins, may contribute to the frailty phenotype. In addition, the social determinant of health, poverty, influences the inflammatory cargo of EVs in midlife., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Even before the COVID-19 pandemic declines in life expectancy in the United States were attributed to increased mortality rates in midlife adults across racial and ethnic groups, indicating a need for markers to identify individuals at risk for early mortality. Extracellular vesicles (EVs) are small, lipid-bound vesicles capable of shuttling functional proteins, nucleic acids, and lipids. Given their role as intercellular communicators and potential biomarkers of disease, we explored whether circulating EVs may be markers of mortality in a prospective, racially, and socioeconomically diverse middle-aged cohort. We isolated plasma EVs from 76 individuals (mean age = 59.6 years) who died within a 5 year period and 76 surviving individuals matched by age, race, and poverty status. There were no significant differences in EV concentration, size, or EV-associated mitochondrial DNA levels associated with mortality. We found that several EV-associated inflammatory proteins including CCL23, CSF-1, CXCL9, GDNF, MCP-1, STAMBP, and 4E-BP1 were significantly associated with mortality. IL-10RB and CDCP1 were more likely to be present in plasma EVs from deceased individuals than in their alive counterparts. We also report differences in EV-associated inflammatory proteins with poverty status, race, and sex. Our results suggest that plasma EV-associated inflammatory proteins are promising potential clinical biomarkers of mortality., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Frailty is a clinical syndrome described as reduced physiological reserve and increased vulnerability. Typically examined in older adults, recent work shows frailty occurs in middle-aged individuals and is associated with increased mortality. Previous investigation of global transcriptome changes in a middle-aged cohort from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study demonstrated inflammatory genes and pathways were significantly altered by frailty status and race. Transcriptome differences in frailty by sex remain unclear. We sought to discover novel genes and pathways associated with sex and frailty in a diverse middle-aged cohort using RNA-Sequencing., Methods: Differential gene expression and pathway analyses were performed in peripheral blood mononuclear cells for 1) frail females (FRAF, n = 4) vs non-frail females (NORF, n = 4), 2) frail males (FRAM, n = 4) vs non-frail males (NORM, n = 4), 3) FRAM vs FRAF, and 4) NORM vs NORF. We evaluated exclusive significant genes and pathways, as well as overlaps, between the comparison groups., Results: Over 80% of the significant genes exclusive to FRAF vs NORF, FRAM vs NORM, and FRAM vs FRAF, respectively, were novel and associated with various biological functions. Pathways exclusive to FRAF vs NORF were associated with reduced inflammation, while FRAM vs NORM exclusive pathways were related to aberrant musculoskeletal physiology. Pathways exclusive to FRAM vs FRAF were associated with reduced cell cycle regulation and activated catabolism and Coronavirus pathogenesis., Conclusions: Our results indicate sex-specific transcriptional changes occur in middle-aged frailty, enhancing knowledge on frailty progression and potential therapeutic targets to prevent frailty., (© 2022. The Author(s).)

Apolipoprotein (APOE) ε4 allele is a strong risk factor for Alzheimer's disease (AD) and cognitive decline. Epigenetic modifications such as DNA methylation (DNAm) play a central role in cognition. This study sought to identify DNAm sites in the APOE genomic region associated with cognitive performance in a racially diverse middle-aged cohort (n = 411). Cognitive performance was measured by 11 standard neuropsychological tests. Two CpG sites were associated with the Card Rotation and Benton Visual Retention cognitive tests. The methylation level of the CpG site cg00397545 was associated with Card Rotation Test score (p = 0.000177) and a novel CpG site cg10178308 was associated with Benton Visual Retention Test score (p = 0.000084). Significant associations were observed among the dietary inflammatory index, which reflects the inflammatory potential of the diet, cognitive performance and the methylation level of several CpG sites. Our results indicate that DNAm in the APOE genomic area is correlated with cognitive performance and may presage cognitive decline., (Published by Elsevier Inc.)

Over time, adherence to healthy behaviors may improve physical and mental strength which is essential for successful aging. A plausible mechanism is the reduction of inflammation. Research on the association of risky health behaviors on change in strength with age is limited. This study examined changes in the inflammatory potential of the diet, smoking, illicit drug use with changes in strength in a racially and socioeconomically diverse adult sample from the Healthy Aging in Neighborhoods of Diversity Across the Life Span study. The dietary inflammatory index (DII) was calculated from 35 food components derived from multiple 24-h dietary recalls. Strength was evaluated by handgrip strength (HGS), SF-12 PCS and SF-12 MCS (physical and mental component scores). Repeated measures analyses were used to examine associations. At baseline, mean age was 48.4 ± 0.25 years, 56% of the sample were women, and 58% African American. Significant 4-way interactions were found between age, race, socioeconomic status, and DII for women, on change in HGS ( p < 0.05) and in SF-12 PCS ( p < 0.05) and for men, in change in SF-12 PCS ( p < 0.05). Improvements in SF-12 MCS were associated with all three health behaviors as main effects. This study provided evidence that changes towards improving healthy behaviors, diet with anti-inflammatory potential, not smoking cigarettes and not using illicit drugs, were associated with improved strength. Health professionals, especially registered dietitians and health coaches, should create lifestyle interventions to reduce inflammation targeting change in more than one risky health behavior.

The mitochondrial free radical theory of aging suggests that accumulating oxidative damage to mitochondria and mitochondrial DNA (mtDNA) plays a central role in aging. Circulating cell-free mtDNA (ccf-mtDNA) isolated from blood may be a biomarker of disease. Extracellular vesicles (EVs) are small (30-400 nm), lipid-bound vesicles capable of shuttling proteins, nucleic acids, and lipids as part of intercellular communication systems. Here, we report that a portion of ccf-mtDNA in plasma is encapsulated in EVs. To address whether EV mtDNA levels change with human age, we analyzed mtDNA in EVs from individuals aged 30-64 years cross-sectionally and longitudinally. EV mtDNA levels decreased with age. Furthermore, the maximal mitochondrial respiration of cultured cells was differentially affected by EVs from old and young donors. Our results suggest that plasma mtDNA is present in EVs, that the level of EV-derived mtDNA is associated with age, and that EVs affect mitochondrial energetics in an EV age-dependent manner., (Published 2020. This article is a US Government work and is in the public domain in the USA.)

Mortality disparities are influenced by race and poverty. There is limited information about whether poverty influences biologic markers of mortality risk. Emerging data suggests that growth differentiation factor 15 (GDF15) is associated with mortality; however, the interplay between GDF15, sociodemographic factors and mortality is not known. We sought to evaluate the interactions between GDF15 and sex, race and poverty status on mortality. Serum GDF15 was measured in 1036 African American and white middle-aged men and women above and below 125% of the Federal poverty status from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. Multivariable adjusted Cox regression models were used to assess the association between log-transformed GDF15 (logGDF15) and 12-year mortality outcomes (all-cause, cardiovascular- and cancer-specific outcomes) and interactions with sex, race and poverty status. Likelihood ratio tests were used to assess significance of the interaction terms. Median GDF15 was 655.2 pg/mL (IQR = 575.1). During 12.2 years of follow-up, 331 died of which 94 cardiovascular- and 87 were cancer-specific deaths. One unit of increase in logGDF15 was associated with a hazard ratio for all-cause mortality, cardiovascular- and cancer-specific mortality of 2.26 (95% confidence interval [CI], 1.94-2.64), 2.74 (95%CI, 2.06-3.63) and 1.41 (95%CI, 1.00-2.00), respectively. There was an interaction between logGDF15 and poverty status on all-cause mortality (p<0.05). The GDF15×poverty status interaction term improved model calibration for all-cause mortality. Our study provides the first evidence that the effect of elevated GDF15 on all-cause mortality is modified by poverty status., Competing Interests: The authors have declared that no competing interests exist.

Background: Inflammation-related atherosclerotic peripheral vascular disease is a major end organ complication of diabetes mellitus that results in devastating morbidity and mortality. Extracellular vesicles (EVs) are nano-sized particles that contain molecular cargo and circulate in the blood. Here, we examined EV protein cargo from diabetic individuals and whether these EVs cause functional changes in endothelial cells., Methods: We quantified inflammatory protein levels in plasma-derived EVs from a longitudinal cohort of euglycemic and diabetic individuals and used in vitro endothelial cell biological assays to assess the functional effects of these EVs with samples from a cross-sectional cohort., Results: We found several significant associations between EV inflammatory protein levels and diabetes status. The angiogenic factor, vascular endothelial growth factor A (VEGF-A), was associated with diabetes status in our longitudinal cohort. Those with diabetes mellitus had higher EV VEGF-A levels compared to euglycemic individuals. Additionally, EV levels of VEGF-A were significantly associated with homeostatic model assessment of insulin resistance (HOMA-IR) and β-cell function (HOMA-B). To test whether EVs with different inflammatory cargo can demonstrate different effects on endothelial cells, we performed cell migration and immunofluorescence assays. We observed that EVs from diabetic individuals increased cell lamellipodia formation and migration when compared to EVs from euglycemic individuals., Conclusions: Higher levels of inflammatory proteins were found in EVs from diabetic individuals. Our data implicate EVs as playing important roles in peripheral vascular disease that occur in individuals with diabetes mellitus and suggest that EVs may serve as an informative diagnostic tool for the disease.

Metabolic syndrome (MetS) is a cluster of cardiometabolic risk factors for all-cause mortality, cardiovascular disease, and cancer. Identifying epigenetic alterations associated with MetS in African Americans (AAs) and Whites may provide insight into genes that influence its differential health outcomes. We examined DNA methylation (DNAm) and performed an epigenome-wide association study (EWAS) of MetS among AAs and Whites with and without MetS. We assessed age, race and poverty status associated DNAm among AAs (n = 225) and White (n = 233) adults using NCEP-ATP III guidelines. Genome-wide DNAm measurement was assessed using Illumina Infinium Methylation EPIC BeadChip. Differentially methylated positions (DMPs) and differentially methylated regions (DMRs) were identified using dmpFinder and bumphunter . EWAS was performed using CpGassoc. We found significant DMPs associated with age, poverty status and MetS in each race. GSTT1 (Glutathione S-Transferase Theta 1) was one of the top-hypermethylated genes and MIPEP (Mitochondrial Intermediate Peptidase) was one of the most hypomethylated genes when comparing AAs with and without MetS. PPP1R13L (Protein Phosphatase 1 Regulatory Subunit 13 Like) was the top hypermethylated and SCD (stearoyl-CoA desaturase-1) was one of the most hypomethylated genes for Whites with and without MetS. EWAS results showed that DNAm differences might contribute to MetS risk among Whites and AAs since different genes were identified in AAs and Whites. We replicated previously identified MetS associated genes and found that Thioredoxin-interacting protein ( TXN1P ) was statistically significantly differentially expressed only in Whites. Our results may be useful in further studies of genes underlying differences in MetS among AAs and Whites.

Differential mortality rates remain a significant health disparity in the United States, suggesting the need to investigate novel potential molecular markers associated with mortality. Extracellular vesicles (EVs), including exosomes, microvesicles and apoptotic bodies, are lipid-bound vesicles secreted by cells into the circulation. EVs mediate intercellular communication by shuttling functional signaling molecules as cargo. EV characteristics by race in the context of mortality risk factors have not been described. We isolated plasma EVs from a cross-sectional cohort of African Americans (AA) and whites and found no significant differences in EV size, distribution or concentration between race or by sex. However, EV cargo showed increased levels of phospho-p53, total p53, cleaved caspase 3, ERK1/2 and phospho-AKT in white individuals compared to AAs. phospho-IGF-1R levels were significantly higher in females compared to males. EV concentration was significantly associated with several clinical mortality risk factors: high-sensitivity C-reactive protein (hsCRP), homeostatic model assessment of insulin resistance (HOMA-IR), alkaline phosphatase, body mass index, waist circumference and pulse pressure. The association of EV proteins with mortality markers were dependent on race. These data suggest that EV cargo can differ by race and sex and is associated with mortality risk factors.

Background: Little is known about the role of perceived neighborhood environment as a determinant of physical activity (PA) and sedentary time (ST) in understanding obesity-related health behaviors. We focus on a biracial, socioeconomically diverse population using objectively measured ST, which is under-represented in the literature. Methods: We examined the association between self-reported neighborhood perception (Likert-scale questions), PA using the Baecke questionnaire, and both non-sedentary time and ST using accelerometry from wave 4 of the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study ( n = 2,167). After applying exclusion criteria, the sample size was n = 1,359 for analyses of self-reported PA and n = 404 for analyses of accelerometry data. Factor analysis identified key neighborhood characteristics to develop a total neighborhood perception score (NPS). Higher NPS indicated less favorable neighborhood perception. Linear regression was used to determine the relationship between NPS, PA, non-sedentary time, and ST. Results: Complete data were available for n = 1,359 [age 56.6(9.0) years, 59.5% female, 62.2% African American] for whom we identified four neighborhood perception factors: (1) concern about crime, (2) physical environment, (3) location of violent crime, and (4) social environment. Worsening perception of the overall neighborhood [β = -0.13 (SE = 0.03); p = 0.001], the physical environment [-0.11 (0.05); p = 0.03], and the social environment [-0.46 (0.07); p < 0.0001] were associated with decreased PA. Worsening perception of the overall neighborhood [1.14 (0.49); p = 0.02] and neighborhood social environment [3.59 (1.18); p = 0.003] were associated with increased ST over the day. There were no interactions for race, sex, poverty status, or economic index. Conclusion: Poor overall neighborhood perception, perceived social environment, and perceived neighborhood physical environment are associated with PA and ST in a multi-racial, socioeconomically diverse cohort of urban adults. Clinical Trial Registration: The HANDLS study is registered at ClinicalTrials.gov as NCT01323322., (Copyright © 2019 Claudel, Shiroma, Harris, Mode, Ahuja, Zonderman, Evans and Powell-Wiley.)

Background: African Americans (AAs) experience premature chronic health outcomes and longevity disparities consistent with an accelerated aging phenotype. DNA methylation (DNAm) levels at specific CpG positions are hallmarks of aging evidenced by the presence of age-associated differentially methylated CpG positions (aDMPs) that are the basis for the epigenetic clock for measuring biological age acceleration. Since DNAm has not been widely studied among non-European populations, we examined the association between DNAm and chronological age in AAs and whites, and the association between race, poverty, sex, and epigenetic age acceleration., Results: We measured genome-wide DNA methylation (866,836 CpGs) using the Illumina MethylationEPIC BeadChip in blood DNA extracted from 487 middle-aged AA (N = 244) and white (N = 243), men (N = 248), and women (N = 239). The mean (sd) age was 48.4 (8.8) in AA and 49.0 (8.7) in whites (p = 0.48). We identified 4930 significantly associated aDMPs in AAs and 469 in whites. Of these, 75.6% and 53.1% were novel, largely driven by the increased number of measured CpGs in the EPIC array, in AA and whites, respectively. AAs had more age-associated DNAm changes than whites in genes implicated in age-related diseases and cellular pathways involved in growth and development. We assessed three epigenetic age acceleration measures (universal, intrinsic, and extrinsic). AAs had a significantly slower extrinsic aging compared to whites. Furthermore, compared to AA women, both AA and white men had faster aging in the universal age acceleration measure (+ 2.04 and + 1.24 years, respectively, p < 0.05)., Conclusions: AAs have more wide-spread methylation changes than whites. Race and sex interact to underlie biological age acceleration suggesting altered DNA methylation patterns may be important in age-associated health disparities.

Frailty is an aging-associated syndrome resulting from diminished capacity to respond to stressors and is a significant risk factor for disability and mortality. Although frailty is usually studied in old age, it is present in mid-life. Given the increases in mortality statistics among middle-aged Americans, understanding molecular drivers of frailty in a younger, diverse cohort may facilitate identifying pathways for early intervention. We analyzed frailty-associated, genome-wide transcriptional changes in middle-aged blacks and whites. Next generation RNA sequencing was completed using total RNA from peripheral blood mononuclear cells (n = 16). We analyzed differential gene expression patterns and completed a parametric analysis of gene set enrichment (PAGE). Differential gene expression was validated using RT-qPCR (n = 52). We identified 5,082 genes differentially expressed with frailty. Frailty altered gene expression patterns and biological pathways differently in blacks and whites, including pathways related to inflammation and immunity. The validation study showed a significant two-way interaction between frailty, race, and expression of the cytokine IL1B and the transcription factor EGR1. The glucose transporter, SLC2A6 , the neutrophil receptor, FCGR3B, and the accessory protein, C17orf56, were decreased with frailty. These results suggest that there may be demographic dependent, divergent biological pathways underlying frailty in middle-aged adults.

Type 2 diabetes is a chronic age-associated degenerative metabolic disease that reflects relative insulin deficiency and resistance. Extracellular vesicles (EVs) (exosomes, microvesicles, and apoptotic bodies) are small (30-400 nm) lipid-bound vesicles capable of shuttling functional proteins, nucleic acids, and lipids as part of intercellular communication systems. Recent studies in mouse models and in cell culture suggest that EVs may modulate insulin signaling. Here, we designed cross-sectional and longitudinal cohorts of euglycemic participants and participants with prediabetes or diabetes. Individuals with diabetes had significantly higher levels of EVs in their circulation than euglycemic control participants. Using a cell-specific EV assay, we identified that levels of erythrocyte-derived EVs are higher with diabetes. We found that insulin resistance increases EV secretion. Furthermore, the levels of insulin signaling proteins were altered in EVs from individuals with high levels of insulin resistance and β-cell dysfunction. Moreover, EVs from individuals with diabetes were preferentially internalized by circulating leukocytes. Cytokine levels in the media and in EVs were higher from monocytes incubated with diabetic EVs. Microarray of these leukocytes revealed altered gene expression pathways related to cell survival, oxidative stress, and immune function. Collectively, these results suggest that insulin resistance increases the secretion of EVs, which are preferentially internalized by leukocytes, and alters leukocyte function., (© 2018 by the American Diabetes Association.)

Frailty is a risk factor for disability and mortality, and is more prevalent among African American (AA) elderly than whites. We examine frailty in middle-aged racially and economically diverse adults, and investigate how race, poverty and frailty are associated with mortality. Data were from 2541 participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span study in Baltimore, Maryland; 35-64 years old at initial assessment (56% women; 58% AA). Frailty was assessed using a modified FRAIL scale of fatigue, resistance, ambulation, illness and weight loss, and compared with difficulties in physical functioning and daily activities. Frailty prevalence was calculated across race and age groups, and associations with survival were assessed by Cox Regression. 278 participants were frail (11%); 924 pre-frail (36%); 1339 not frail (53%). For those aged 45-54, a higher proportion of whites (13%) than AAs (8%) were frail; while the proportions were similar for those 55-64 (14%,16%). Frailty was associated with overall survival with an average follow-up of 6.6 years, independent of race, sex and poverty status (HR = 2.30; 95%CI 1.67-3.18). In this sample of economically and racially diverse older adults, the known association of frailty prevalence and age differed across race with whites having higher prevalence at younger ages. Frailty was associated with survival beyond the risk factors of race and poverty status in this middle-aged group. Early recognition of frailty at these younger ages may provide an effective method for preventing or delaying disabilities.

Cells release lipid-bound extracellular vesicles (EVs; exosomes, microvesicles and apoptotic bodies) containing proteins, lipids and RNAs into the circulation. Vesicles mediate intercellular communication between both neighboring and distant cells. There is substantial interest in using EVs as biomarkers for age-related diseases including cancer, and neurodegenerative, metabolic and cardiovascular diseases. The majority of research focuses on identifying differences in EVs when comparing disease states and matched controls. Here, we analyzed circulating plasma EVs in a cross-sectional and longitudinal study in order to address age-related changes in community-dwelling individuals. We found that EV concentration decreases with advancing age. Furthermore, EVs from older individuals were more readily internalized by B cells and increased MHC-II expression on monocytes compared with EVs from younger individuals, indicating that the decreased concentration of EVs with age may be due in part to increased internalization. EVs activated both monocytes and B cells, and activation of B cells by LPS enhanced EV internalization. We also report a relative stability of EV concentration and protein amount in individual subjects over time. Our data provide important information towards establishing a profile of EVs with human age, which will further aid in the development of EV-based diagnostics for aging and age-related diseases.

Mortality rates in the United States vary based on race, individual economic status and neighborhood. Correlations among these variables in most urban areas have limited what conclusions can be drawn from existing research. Our study employs a unique factorial design of race, sex, age and individual poverty status, measuring time to death as an objective measure of health, and including both neighborhood economic status and income inequality for a sample of middle-aged urban-dwelling adults (N = 3675). At enrollment, African American and White participants lived in 46 unique census tracts in Baltimore, Maryland, which varied in neighborhood economic status and degree of income inequality. A Cox regression model for 9-year mortality identified a three-way interaction among sex, race and individual poverty status (p = 0.03), with African American men living below poverty having the highest mortality. Neighborhood economic status, whether measured by a composite index or simply median household income, was negatively associated with overall mortality (p<0.001). Neighborhood income inequality was associated with mortality through an interaction with individual poverty status (p = 0.04). While racial and economic disparities in mortality are well known, this study suggests that several social conditions associated with health may unequally affect African American men in poverty in the United States. Beyond these individual factors are the influences of neighborhood economic status and income inequality, which may be affected by a history of residential segregation. The significant association of neighborhood economic status and income inequality with mortality beyond the synergistic combination of sex, race and individual poverty status suggests the long-term importance of small area influence on overall mortality.

Two hypotheses have been proposed to explain the abundance-occupancy relationship (AOR) in parasites. The niche breadth hypothesis suggests that host generalists are more abundant and efficient at colonizing different host communities than specialists. The trade-off hypothesis argues that host specialists achieve high density across their hosts' ranges, whereas generalists incur the high cost of adaptation to diverse immuno-defence systems. We tested these hypotheses using 386 haemosporidian cytochrome-b lineages (1894 sequences) recovered from 2318 birds of 103 species sampled in NW Africa, NW Iberia, W Greater Caucasus and Transcaucasia. The number of regions occupied by lineages was associated with their frequency suggesting the presence of AOR in avian Haemosporidia. However, neither hypothesis provided a better explanation for the AOR. Although the host generalist Plasmodium SGS1 was over three times more abundant than other widespread lineages, both host specialists and generalists were successful in colonizing all study regions and achieved high overall prevalence., (© 2014 John Wiley & Sons Ltd.)

Introduction: Alaska had the highest work-related fatality rate of any state during 1980-1989. The National Institute for Occupational Safety and Health established the Alaska Field Station (AFS) to address this problem., Methods: AFS established surveillance systems to provide scientific assessments of occupational hazards. Interventions were developed in collaboration with partners and evaluated., Results: During 2000-2009, Alaska experienced a 42.5% decline in work-related fatalities over the previous decade of 1990-1999. In 2009, the workplace fatality rate for Alaska was 5.6/100,000 workers. Commercial pilot deaths were reduced by 50% and Bering Sea crab fishing death rates were reduced by 60%. Building on this success, AFS established national programs to improve safety in the commercial fishing and oil and gas extraction industries., Impact on Industry: A focused, epidemiological approach to reducing fatalities in high-risk occupations is effective. Ongoing commitment to this type of approach will assist in continued success in Alaska and elsewhere., (Published by Elsevier Ltd.)

In this study, we take advantage of a natural experiment--a 2004 mass die-off of the Common Murre in Alaska to determine whether closely related mtDNA haplotypes differ in their probability of being eliminated during such a short term but a marked event removing hundreds of thousands of individuals. We sequenced complete mtDNA ND2 gene (1041 bp) for 168 Common Murres sampled from seven breeding colonies across Alaska before the 2004 die-off and 127 dead murres washed ashore during the die-off. We found little mtDNA variation and lack of geographical structuring among the seven Common Murre breeding colonies in Alaska. A comparison of the single-dominant mtDNA haplotype's frequency between live murres sampled on breeding colonies before the die-off (73.2%; 95% confidence interval 66.3-79.9%) and dead murres sampled during the die-off (59.1%; 95% confidence interval 50.4-67.4%; Fisher's exact P=0.01) showed that carriers of the dominant haplotype were significantly less likely to die than carriers of other haplotypes. At the same time, the ratio of non-synonymous to synonymous substitutions did not differ between live (10:35) and dead birds (18:34; Fisher's exact P=0.26), indicating that non-synonymous substitutions were as likely to be eliminated as synonymous substitutions. These results are consistent with the possibility of positive selection on the dominant mtDNA haplotype during the die-off.

Background: During the 1990s, Alaskan pilots had one of the most hazardous occupations in the US. In 2000, a multifaceted public health initiative was launched, focusing on Alaskan air taxi/commuter (AT) operations, including risk factor identification, improved weather information, and the formation of an industry-led safety organization., Methods: Effectiveness was assessed by comparing rates of crashes using Poisson regression, comparing trends in annual numbers of crashes, and assessing changes in the number and type of controlled flight into terrain (CFIT) events., Results: The greatest improvements were seen in Alaska fatal AT crashes with a 57% decrease in rates between time periods. While the number of AT crashes in the rest of the US steadily declined during 1990-2009, Alaska only showed significant declines after 2000. CFIT crashes declined but remained more deadly than other crashes., Conclusions: This coordinated effort was successful in reducing crashes in the Alaskan AT industry., (Copyright © 2011 Wiley Periodicals, Inc.)

DNA sequence data often appear to contradict low-level avian taxonomy, which is usually based on patterns of external phenotypic similarity. We examined such an apparent contradiction in the Nearctic rosy-finches. On the basis of several phenotypic characters the finches were divided into three species congeneric with three Asian species. When Nearctic taxa were analyzed in a principal components analysis, 66.9% of phenotypic variation was explained by differences between the Bering Sea and continental populations, sexual dimorphism and a latitudinal cline. Our phylogenetic analysis of mitochondrial ND2 sequences revealed four clades among six species of rosy-finches. Three clades corresponded to three Asian species. The fourth clade included all three Nearctic species. Their haplotypes were not reciprocally monophyletic and the combined genetic variability of all Nearctic taxa was lower than in two of their Asian congeners. A Z-specific intron (ACO1I9) and an autosomal coding locus (MC1R) provided little additional phylogenetic information, most likely because of the longer coalescence times relative to ND2. Phylogeographic analyses of ND2 data revealed significant gene flow among neighboring localities regardless of their taxonomic assignment. Our analyses showed that DNA and phenotypic data are not in conflict, but rather complement each other, and together help clarify species limits. Our data are consistent with a single species in North America, not three.

We use standardized independent contrasts (SICs) to elucidate the effect of ecology and mating systems on morphological radiation in grouse. The analysis of SICs for 38 skeletal measurements from 20 taxa, showed that changes in mating system had a significant effect on body size of both sexes. Sexual size dimorphism in grouse is consistent with Rensch's rule; the slope of the regression of male vs. female size SICs was 1.4, significantly >1. Changes in habitat were associated with accelerated rates of evolution of body proportions. SICs for male and female scores of size independent factors were directly proportional to each other (slope = 1), indicating extreme similarities between male and female ecology. Females, however, were better adapted to longer, more energy efficient flight than males. Size independent morphological differences among grouse are adaptive and are related to the differences in habitat and foraging behaviour among the species.

Objective: During 1992-2000, an average of 40 fatal occupational injuries and 12,400 nonfatal occupational injuries and illnesses related to animals were recorded each year in the United States, most involving domestic farm animals. Although Alaska has a relatively small farming industry, it supports several industries that require workers to regularly be in contact with animals. This study examines the pattern and characteristics of animal-related occupational injuries in Alaska., Methods: Two data sources were accessed: the Alaska Trauma Registry for nonfatal injuries requiring hospitalization and the Alaska Occupational Injury Surveillance System for fatal injuries. The case definition included events in which the source of the injury was an animal or animal product (Occupational Injury and Illness Classification Manual source code 51)., Results: In Alaska during 1991-2000, there were 43 animal-related occupational injuries requiring hospitalization and 25 animal-related fatalities. There were only 2 fatal events: 1 bird-strike aircraft accident killing 24 military personnel and 1 bear attack. The majority of the nonfatal injury events were related to marine wildlife (n = 20), with the rest related to either domesticated (n = 11) or nondomesticated (n = 12) mammals. Of events reporting a hospital charge (23 of 43), the average cost was over dollar 9700 per person., Conclusions: The catastrophic aircraft crash increased bird-control efforts near airports around the state. The nonfatal animal-related injuries have received less notice, although they result in thousands of dollars in hospital costs and lost workdays. Fishing-industry workers in particular should be made aware of potential injuries and educated on how to treat them when away from definitive medical care.

Background: Construction industry workers are exposed to many hazards leading to fatal and nonfatal injuries. Information for nonfatal work-related injury surveillance may be vague and come from a variety of sources., Methods: The Alaska Trauma Registry (ATR) is used as an injury surveillance tool to focus on hospitalized nonfatal injuries in the Alaskan construction industry., Results: During 1991-1999, 717 workers in the Alaskan construction industry were hospitalized due to occupational injuries, with an average annual injury rate of 0.39 injuries/100 workers. Leading causes of injury included falls (48%) and machinery (15%). Thirty-four percent of the falls were from a building or structure, followed by falls from a ladder (24%). A fractured bone was the most common type of injury (57%)., Conclusions: Information on hospitalized patients from the ATR focuses on the more severe and debilitating injuries, and provides valuable information for prioritizing injury prevention efforts in Alaska., ((c) 2005 Wiley-Liss, Inc.)

Introduction: Aircraft operations are a vital component of the transportation system in Alaska. Between 1990-2002, a total of 481 people died in Alaska in aviation accidents. The purpose of this study was to examine the practices and attitudes of Alaska commuter and air taxi operators and their pilots as they relate to company fatal accident rates., Methods: A case-control analysis based on accident statistics was performed, grouping operators and their pilots into cases and controls, based on operator fatal accident rates, during January 1990 to June 2001. Responses from two aviation safety surveys-one of air carrier operators and one of active commercial pilots-were compared between cases and controls., Results: The average case pilot had less career flight experience than control pilots and worked 13 h x d(-1) and 81 h x wk(-10; that is, 1 h x d(-1) and 10 h wk-1 more than controls. Case operators were less likely to consider pilot fatigue a problem when scheduling flights (p = 0.05) and more likely to depend financially on timely delivery of bypass mail (p = 0.04). Case pilots were three times as likely as controls to fly daily into unknown weather conditions. Nearly 90% of case pilots reported that they never flew when so fatigued that they wanted to decline the flight, compared with 64% of control pilots (p = 0.01)., Conclusions: Pilots of high-risk operators differed from those working for the other operators, both in experience and working conditions. The combination of pilot inexperience and longer work hours and workweeks may contribute to Alaska's high aviation crash rate.

Introduction: Aviation crashes are a leading cause of occupational fatalities in Alaska, with Alaskan pilots having nearly 100 times the fatality rate of U.S. workers overall. A survey was designed to study pilot and company practices and attitudes in order to develop intervention strategies that would reduce aviation fatalities., Methods: Two surveys were administered: one of air carrier operators and one of active commercial pilots. Surveys from 153 air taxi and public-use operators were received at a 79% response rate., Results: There are almost 2000 pilots employed in Alaska during peak season by air taxi operators and public agencies. Surveyed operators and pilots generally agreed that improved weather information and regional hazards training would be effective ways to prevent crashes. Operators were more in favor of operator financial incentives (p < 0.05) and better pre-employment hiring checks on pilots (p < 0.05) compared with pilots' survey responses. There were 48% of pilots of large operators and 73% of pilots of small operators who considered their jobs to be at least as safe as other jobs., Conclusions: The results of operator-pilot comparisons suggest that financial pressures on operators may influence their views on what measures would be effective in preventing crashes, and that Alaskan pilots underestimate their occupational fatality risk.

Objectives: Between 1990-2002, 797 Alaskans died while working. After a scientific survey team member drowned, we examined the hazards of traumatic death to scientific and professional workers in Alaska., Study Design: Surveillance and analysis methods for acute traumatic occupational injuries: The Alaska Occupational Injury Surveillance System (AOISS) uses direct investigation, jurisdictional agency reports, and death certificates to gather data for active surveillance on occupational injury deaths in Alaska. We searched AOISS for deaths which occurred while engaged in scientific or professional work. Commercial pilots, fishermen, loggers, taxi drivers and miners were excluded, as these have been previously studied., Results: During 1990-2002, 85 scientific/professional worker deaths (including 2 suicides) occurred. Fish, game, and mountaineering guides accounted for 28 (33%) of the worker deaths, followed by biologists, who accounted for 11 (13%). Aircraft crashes accounted for 42 (49%) of all these deaths, followed by drownings, 12 (14%), and falls, 9 (11%). A seismologist was fatally mauled by a bear. Of the 14 hunting guide fatalities, 11 were the result of aircraft crashes, one was a suicide, one was a drowning, and one resulted from a motor vehicle crash. Of the 11 hunting guide fatalities, eight died in aircraft crashes, one drowned, one walked into an aircraft prop, and one sustained a fatal head injury in a fall., Conclusions: Scientific and professional workers in Alaska experienced a substantial number of fatalities from traumatic injury. Nearly half of these deaths occurred in aircraft crashes.