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1.
J Emerg Med ; 57(3): 395-396, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31416652
2.
Int J Epidemiol ; 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31038702

RESUMO

BACKGROUND: A 'mortality risk score' (MS) based on ten prominent mortality-related cytosine-phosphate-guanine (CpG) sites was previously associated with all-cause mortality, but has not been verified externally. We aimed to validate the association of MS with mortality and to compare MS with three aging biomarkers: telomere length (TL), DNA methylation age (DNAmAge) and phenotypic age (DNAmPhenoAge) to explore whether MS can serve as a reliable measure of biological aging and mortality. METHODS: Among 534 males aged 55-85 years from the US Normative Aging Study, the MS, DNAmAge and DNAmPhenoAge were derived from blood DNA methylation profiles from the Illumina HumanMethylation450 BeadChip, and TL was measured by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: A total of 147 participants died during a median follow-up of 9.4 years. The MS showed strong associations with all-cause, cardiovascular disease (CVD) and cancer mortality. After controlling for all potential covariates, participants with high MS (>5 CpG sites with aberrant methylation) had almost 4-fold all-cause mortality (hazard ratio: 3.84, 95% confidence interval: 1.92-7.67) compared with participants with a low MS (0-1 CpG site with aberrant methylation). Similar patterns were observed with respect to CVD and cancer mortality. MS was associated with TL and DNAmPhenoAge acceleration but not with DNAmAge acceleration. Although the MS and DNAmPhenoAge acceleration were independently associated with all-cause mortality, the former exhibited a higher predictive accuracy of mortality than the latter. CONCLUSIONS: MS has the potential to be a prominent predictor of mortality that could enhance survival prediction in clinical settings.

4.
Environ Int ; 126: 395-405, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30826618

RESUMO

BACKGROUND: Exploring the associations of air pollution and weather variables with blood leukocyte distribution is critical to understand the impacts of environmental exposures on the human immune system. OBJECTIVES: As previous analyses have been mainly based on data from cell counters, which might not be feasible in epidemiologic studies including large populations of long-stored blood samples, we aimed to expand the understanding of this topic by employing the leukocyte distribution estimated by DNA methylation profiles. METHODS: We measured DNA methylation profiles in blood samples using Illumina HumanMethylation450 BeadChip from 1519 visits of 774 Caucasian males participating in the Normative Aging Study. Leukocyte distribution was estimated using Houseman's and Horvath's algorithms. Data on air pollution exposure, temperature, and relative humidity within 28 days before each blood draw was obtained. RESULTS: After fully adjusting for potential covariates, PM2.5, black carbon, particle number, carbon monoxide, nitrogen dioxide, sulfur dioxide, temperature, and relative humidity were associated with the proportions of at least one subtype of leukocytes. Particularly, an interquartile range-higher 28-day average exposure of PM2.5 was associated with 0.147-, 0.054- and 0.101-unit lower proportions (z-scored) of plasma cells, naïve CD8+ T cells, and natural killers, respectively, and 0.059- and 0.161-unit higher proportions (z-scored) of naïve CD4+ T cells and CD8+ T cells, respectively. CONCLUSIONS: Our study suggests that short-term air pollution exposure, temperature, and relative humidity are associated with leukocyte distribution. Our study further provides a successful attempt to use epigenetic patterns to assess the influences of environmental exposures on human immune profiles.

5.
Aging (Albany NY) ; 10(11): 3210-3228, 2018 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-30414594

RESUMO

The discrepancy of DNA methylation age (DNAmAge) with chronological age (termed as age acceleration, AA) has been identified to be associated with many aging-related health outcomes including hypertension. Since taking antihypertensive medication (AHM) could prevent aging-related diseases caused by hypertension, we hypothesized that using AHM could also reduce the AA. We examined this hypothesis among 546 males aged 55-85 years by exploring the associations of AHM use with AA and its change rate (ΔAA) in two visits with a median follow-up of 3.86 years. Horvath DNAmAge was derived from DNA methylation profiles measured by Illumina HumanMethylation450 BeadChip and information on AHM use was collected by physician interview. A general decreasing pattern of AA was observed between the two visits. After the fully adjusting for potential covariates including hypertension, any AHM use showed a cross-sectional significant association with higher AA at each visit, as well as a longitudinal association with increased ΔAA between visits. Particularly, relative to participants who never took any AHM, individuals with continuous AHM use had a higher ΔAA of 0.6 year/chronological year. This finding underlines that DNAmAge and AA may not be able to capture the preventive effects of AHMs that reduce cardiovascular risks and mortality.

6.
JAMA Ophthalmol ; 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30419128

RESUMO

Importance: Elevated intraocular pressure is a major risk factor for glaucoma, a leading cause of irreversible blindness worldwide. Environmental air pollution has been suggested as a potential contributor to elevated intraocular pressure; however, no studies have demonstrated such an association to date. Objective: To investigate the association of long-term ambient black carbon exposure with intraocular pressure in community-dwelling older adults. Design, Setting, and Participants: This population-based analysis, conducted from October 18, 2017, through March 22, 2018, used data from the all-male, New England-based Normative Aging Study of the US Department of Veterans Affairs. The analysis included 419 older men with a total of 911 follow-up study visits between January 1, 2000, and December 30, 2011. Intraocular pressure was measured by Goldmann applanation tonometry during the study visits. Validated spatiotemporal models were used to generate 1-year black carbon exposure levels at the addresses of the participants. Main Outcomes and Measures: An independently developed genetic score approach was used to calculate allelic risk scores for 3 pathways associated with black carbon toxicity: endothelial function, oxidative stress, and metal processing. The associations among black carbon exposure, allelic risk scores, and intraocular pressure were explored using linear mixed-effects models. Results: All 419 participants were men with a mean (SD) age of 75.3 (6.9) years. The mean (SD) 1-year black carbon exposure was 0.51 (0.18) µg/m3, and the mean (SD) intraocular pressure for the left eye was 14.1 (2.8) mm Hg and for the right eye was 14.1 (3.0) mm Hg. Of the 911 visits, 520 (57.1%) had a high endothelial function allelic risk score, 644 (70.7%) had a high metal-processing allelic risk score, and 623 (68.4%) had a high oxidative stress allelic risk score. In fully adjusted linear mixed-effects models, the association of black carbon with intraocular pressure was greater in individuals with a high oxidative stress allelic score (ß = 0.36; 95% CI, 0.003-0.73) compared with individuals with a low score (ß = -0.35; 95% CI, -0.86 to 0.15). Conclusions and Relevance: Ambient black carbon exposure may be a risk factor for increased intraocular pressure in individuals susceptible to other biological oxidative stressors. If additional studies confirm these results, monitoring ambient black carbon exposure and physiological oxidative stress may prevent the development and progression of intraocular pressure-related disease.

7.
Epigenetics ; : 1-17, 2018 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-30343628

RESUMO

DNA methylation is an epigenetic regulator of gene transcription, which has been found to be both metastable and variable within human cohort studies. Currently, few studies have been done to identify metastable DNA methylation biomarkers associated with longitudinal lung function decline in humans. The identification of such biomarkers is important for screening vulnerable populations. We hypothesized that quantifiable blood-based DNA methylation alterations would serve as metastable biomarkers of lung function decline and aging, which may help to discover new pathways and/or mechanisms related to pulmonary pathogenesis. Using linear mixed models, we performed an Epigenome Wide Association Study (EWAS) between DNA methylation at CpG dinucleotides and longitudinal lung function (FVC, FEV1, FEF25-75%) decline and aging with initial discovery in the Normative Aging Study, and replication in the Cooperative Health Research in the Region of Augsburg cohort. We identified two metastable epigenetic loci associated with either poor lung function and aging, cg05575921 (AHRR gene), or lung function independently of aging, cg06126421 (IER3 gene). These loci may inform basic mechanisms associated with pulmonary function, pathogenesis, and aging. Human epigenomic variation, may help explain features of lung function decline and related pathophysiology not attributable to DNA sequence alone, such as accelerated pulmonary decline in smokers, former smokers, and perhaps non-smokers. Our EWAS across two cohorts, therefore, will likely have implications for the human population, not just the elderly.

8.
Artigo em Inglês | MEDLINE | ID: mdl-30200602

RESUMO

The implications of environmental contamination on human health in the Niger Delta region of Nigeria remain a topic of growing international public health interest. To better understand ongoing air pollution and initiate remediation efforts, the United Nations Environmental Programme (UNEP) report recommended the monitoring of volatile organic compounds (VOCs) across different media (water, soil, and air) in Ogoniland, an at-risk population in the Niger Delta region of Nigeria. In this pilot study, we measured indoor VOC concentrations in the indoor air of 20 households in Ogale, an Ogoniland community whose groundwater system is contaminated with benzene at levels 900 times the World Health Organization guidelines and evaluated self-reported health conditions and predicted cancer risks and hazards from inhalation exposure to VOCs. We detected higher concentrations of benzene (mean = 25.7 µg/m³, SD = 23.2 µg/m³) and naphthalene (mean = 7.6 µg/m³, SD = 13.8 µg/m³) than has been reported in other regions. Although study participants reported health symptoms consistent with VOC exposure, we were underpowered to detect a significant association between select indoor VOCs and these self-reported health symptoms using univariate logistic regression models. These findings suggest that that the health symptoms reported by participants may be poor proxies for the underlying disease processes associated with adverse health outcomes due to VOC exposure in this community and that the burden of adverse health effects due to VOC exposure may stem from the contaminated groundwater system. We estimated a non-cancer hazard quotient of 3 from exposure to naphthalene and lifetime excess cancer risks from exposure to naphthalene, benzene, p-dichlorobenzene, carbon tetrachloride, and ethylbenzene of 3 × 10-4, 2 × 10-4, 6 × 10-5, 6 × 10-6, and 1 × 10-5, respectively. These results exceed common risk benchmarks in the United States, suggesting a need for further studies to characterize VOC exposures, sources, and associated health risks in the Niger Delta.

9.
Curr Environ Health Rep ; 5(3): 317-327, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30047075

RESUMO

PURPOSE OF REVIEW: DNA methylation-based aging biomarkers are valuable tools for evaluating the aging process from a molecular perspective. These epigenetic aging biomarkers can be evaluated across the lifespan and are tissue specific. This review examines the literature relating environmental exposures to DNA methylation-based aging biomarkers and also the literature evaluating these biomarkers as predictors of health outcomes. RECENT FINDINGS: Multiple studies evaluated the association between air pollution and DNA methylation age and consistently observed that higher exposures are associated with elevated DNA methylation age. Psychosocial exposures, e.g., traumas and adolescent adversity, and infections are also associated with epigenetic aging. DNA methylation age has been repeatedly associated with mortality, cancer, and cognitive impairment. DNA methylation age is responsive to the environment and predictive of health outcomes. Studies are still needed to evaluate whether DNA methylation age acts as a mediator or modifier of environmental health effects and to understand the impact of factors such as race, gender, and genetics.

10.
Nicotine Tob Res ; 2018 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-30053132

RESUMO

Introduction: Currently, there is no widely-accepted, non-self-report measure that simultaneously reflects smoking behaviors and is molecularly informative of general disease processes. Recently, researchers developed a smoking index (SI) using nucleated blood cells and a multi-tissue DNA methylation-based predictor of chronological age and disease (DNAm-age). To better understand the utility of this novel SI in readily accessible cell types, we used buccal cell DNA methylation to examine SI relationships with long-term tobacco smoking and moist snuff consumption. Methods: We used a publicly available dataset comprised of buccal cell DNA methylation values from 120 middle-aged men (40 long-term smokers, 40 moist snuff consumers, and 40 non-smokers). DNAm-age (353-CpGs) and SI (66-CpGs) were calculated using CpG sites measured using the Illumina HumanMethylation450 BeadChip. We estimated associations of tobacco consumption habits with both SI and DNAm-age using linear regression models adjusted for chronological age, race, and methylation technical covariates. Results: In fully-adjusted models with non-smokers as the reference, smoking (ß=1.08, 95%CI: 0.82, 1.33, P<0.0001) but not snuff consumption (ß=0.06, 95%CI: -0.19, 0.32, P=0.63) was significantly associated with SI. SI was an excellent predictor of smoking versus non-smoking (AUC=0.92, 95%CI: 0.85, 0.98). Four DNAm-age CpGs were differentially methylated between smokers and non-smokers including cg14992253[EIF3I], which has been previously shown to be differentially methylated with exposure to long-term fine particle air pollution (PM2.5). Conclusions: The 66-CpG SI appears to be a useful tool for measuring smoking-specific behaviors in buccal cells. Still, further research is needed to broadly confirm our findings and SI relationships with DNAm-age. Implications: Our findings demonstrate that this 66-CpG blood-derived SI can reflect long-term tobacco smoking, but not long-term snuff consumption, in buccal cells. This evidence will be useful as the field works to identify an accurate non-self-report smoking biomarker that can be measured in an easily accessible tissue. Future research efforts should focus on: (1) optimizing the relationship of the SI with DNAm-age so that the metric can maximize its utility as a tool for understanding general disease processes, and (2) determining normal values for the SI CpGs so that the measure is not as study sample specific.

11.
Ageing Res Rev ; 45: 15-23, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29698722

RESUMO

The multi-tissue DNA methylation estimator of chronological age (DNAm-age) has been associated with a wide range of exposures and health outcomes. Still, it is unclear how DNAm-age can have such broad relationships and how it can be best utilized as a biomarker. Understanding DNAm-age's molecular relationships is a promising approach to address this critical knowledge gap. In this review, we discuss the existing literature regarding DNAm-age's molecular relationships in six major categories: animal model systems, cancer processes, cellular aging processes, immune system processes, metabolic processes, and nucleic acid processes. We also present perspectives regarding the future of DNAm-age research, including the need to translate a greater number of ongoing research efforts to experimental and animal model systems.

12.
Epigenomics ; 9(12): 1529-1542, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29106301

RESUMO

AIM: We tested whether genetic variation in miRNA processing genes modified the association of PM2.5 with DNA methylation (DNAm) age. PATIENTS & METHODS: We conducted a repeated measures study based on 552 participants from the Normative Aging Study with multiple visits between 2000 and 2011 (n = 940 visits). Address-level 1-year PM2.5 exposures were estimated using the GEOS-chem model. DNAm-age and a panel of 14 SNPs in miRNA processing genes were measured from participant blood samples. RESULTS & CONCLUSION: In fully adjusted linear mixed-effects models, having at least one copy of the minor rs4961280 [AGO2] allele was associated with a lower DNAm-age (ß = -1.13; 95% CI: -2.26 to -0.002). However, the association of PM2.5 with DNAm-age was significantly (Pinteraction  = 0.01) weaker in homozygous carriers of the major rs4961280 [AGO2] allele (ß = 0.38; 95% CI: -0.20 to 0.96) when compared with all other participants (ß = 1.58; 95% CI: 0.76 to 2.39). Our results suggest that miRNA processing impacts DNAm-age relationships. Graphical abstract: miRNA processing AGO2 polymorphism (rs4961280) modifies the association of long-term ambient fine particle exposure with blood DNA methylation age [Formula: see text] The graph depicts lines from a fully adjusted linear regression model with fine particle exposure levels ranging from the tenth to the ninetieth percentile, all other continuous variables held constant at their means, and all other categorical variables held at their most frequent level.


Assuntos
Metilação de DNA , MicroRNAs/genética , Material Particulado/efeitos adversos , Polimorfismo de Nucleotídeo Único , Idoso , Humanos , Masculino , MicroRNAs/metabolismo
13.
Environ Sci Technol ; 51(14): 8185-8195, 2017 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-28636816

RESUMO

The mitochondrial genome has long been implicated in age-related disease, but no studies have examined its role in the relationship of long-term fine particle (PM2.5) exposure and DNA methylation age (DNAm-age)-a novel measure of biological age. In this analysis based on 940 observations between 2000 and 2011 from 552 Normative Aging Study participants, we determined the roles of mitochondrial DNA haplogroup variation and mitochondrial genome abundance in the relationship of PM2.5 with DNAm-age. We used the GEOS-chem transport model to estimate address-specific, one-year PM2.5 levels for each participant. DNAm-age and mitochondrial DNA markers were measured from participant blood samples. Nine haplogroups (H, I, J, K, T, U, V, W, and X) were present in the population. In fully adjusted linear mixed-effects models, the association of PM2.5 with DNAm-age (in years) was significantly diminished in carriers of haplogroup V (Pinteraction = 0.01; ß = 0.18, 95%CI: -0.41, 0.78) compared to noncarriers (ß = 1.25, 95%CI: 0.58, 1.93). Mediation analysis estimated that decreases in mitochondrial DNA copy number, a measure of mitochondrial genome abundance, mediated 12% of the association of PM2.5 with DNAm-age. Our data suggests that the mitochondrial genome plays a role in DNAm-age relationships particularly in the context of long-term PM2.5 exposure.


Assuntos
Poluentes Atmosféricos/toxicidade , Metilação de DNA , Genoma Mitocondrial , Material Particulado/toxicidade , Fatores Etários , Idoso , Envelhecimento , Feminino , Humanos , Masculino
14.
Toxicol Sci ; 158(1): 116-126, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28486674

RESUMO

Recent studies have reported robust associations of long-term PM2.5 exposure with DNA methylation-based measures of aging; yet, the molecular implications of these relationships remain poorly understood. We evaluated if genetic variation in 3 biological pathways implicated in PM2.5-related disease-oxidative stress, endothelial function, and metal processing-could modify the effect of PM2.5 on DNAm-age, one prominent DNA methylation-based measure of biological age. This analysis was based on 552 individuals from the Normative Aging Study with at least one visit between 2000 and 2011 (n = 940 visits). A genetic-score approach was used to calculate aging-risk variant scores for endothelial function, oxidative stress, and metal processing pathways. One-year PM2.5 and PM2.5 component (sulfate and ammonium) levels at participants' addresses were estimated using the GEOS-chem transport model. Blood DNAm-age was calculated using CpG sites on the Illumina HumanMethylation450 BeadChip. In fully-adjusted linear mixed-effects models, the effects of sulfate on DNAm-age (in years) were greater in individuals with high aging-risk endothelial function variant scores when compared with individuals with low aging-risk endothelial function variant scores (Pinteraction = 0.0007; ßHigh = 1.09, 95% CIHigh: 0.70, 1.48; ßLow = 0.40, 95% CILow: 0.14, 0.67). Similar trends were observed in fully adjusted models of ammonium and total PM2.5 alone. No effect modification was observed by oxidative stress and metal processing variant scores. Secondary analyses revealed significant associations of serum endothelial markers, intercellular adhesion molecule-1 (ß = 0.01, 95% CI: 0.002, 0.012) and vascular cell adhesion molecule-1 (ß = 0.002, 95% CI: 0.0005, 0.0026), with DNAm-age. Our results add novel evidence that endothelial physiology may be important to DNAm-age relationships, but further research is required to establish their generalizability.


Assuntos
Envelhecimento/fisiologia , Metilação de DNA , Endotélio Vascular/efeitos dos fármacos , Exposição Ambiental , Variação Genética , Material Particulado/toxicidade , Idoso , Idoso de 80 Anos ou mais , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiologia , Grupo com Ancestrais do Continente Europeu , Humanos , Masculino , Estresse Oxidativo , Estados Unidos , United States Department of Veterans Affairs
15.
Environ Int ; 102: 57-65, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28284819

RESUMO

BACKGROUND: Long-term PM2.5 exposure and aging have been implicated in multiple shared diseases; studying their relationship is a promising strategy to further understand the adverse impact of PM2.5 on human health. OBJECTIVE: We assessed the relationship of major PM2.5 component species (ammonium, elemental carbon, organic carbon, nitrate, and sulfate) with Horvath and Hannum DNA methylation (DNAm) age, two DNA methylation-based predictors of chronological age. METHODS: This analysis included 552 participants from the Normative Aging Study with multiple visits between 2000 and 2011 (n=940 visits). We estimated 1-year PM2.5 species levels at participants' addresses using the GEOS-chem transport model. Blood DNAm-age was calculated using CpG sites on the Illumina HumanMethylation450 BeadChip. We fit linear mixed-effects models, controlling for PM2.5 mass and lifestyle/environmental factors as fixed effects, with the adaptive LASSO penalty to identify PM2.5 species associated with DNAm-age. RESULTS: Sulfate and ammonium were selected by the LASSO in the Horvath DNAm-age models. In a fully-adjusted multiple-species model, interquartile range increases in both 1-year sulfate (95%CI: 0.28, 0.74, P<0.0001) and ammonium (95%CI: 0.02, 0.70, P=0.04) levels were associated with at least a 0.36-year increase in Horvath DNAm-age. No PM2.5 species were selected by the LASSO in the Hannum DNAm-age models. Our findings persisted in sensitivity analyses including only visits with 1-year PM2.5 levels within US EPA national ambient air quality standards. CONCLUSION: Our results demonstrate that sulfate and ammonium were most associated with Horvath DNAm-age and suggest that DNAm-age measures differ in their sensitivity to ambient particle exposures and potentially disease.


Assuntos
Envelhecimento/sangue , Poluentes Atmosféricos/análise , Metilação de DNA/efeitos dos fármacos , DNA/sangue , Monitoramento Ambiental/métodos , Material Particulado/análise , Idoso , Envelhecimento/genética , Poluentes Atmosféricos/toxicidade , Feminino , Humanos , Exposição por Inalação/análise , Masculino , Tamanho da Partícula , Material Particulado/toxicidade , Estados Unidos , United States Environmental Protection Agency
16.
Oncotarget ; 7(46): 74510-74525, 2016 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-27793020

RESUMO

Long-term exposure to air pollution is associated with age-related diseases. We explored the association between accelerated biological aging and air pollution, a potential mechanism linking air pollution and health. We estimated long-term exposure to PM10, PM2.5, PM2.5 absorbance/black carbon (BC), and NOx via land-use regression models in individuals from the KORA F4 cohort. Accelerated biological aging was assessed using telomere length (TeloAA) and three epigenetic measures: DNA methylation age acceleration (DNAmAA), extrinsic epigenetic age acceleration (correlated with immune cell counts, EEAA), and intrinsic epigenetic age acceleration (independent of immune cell counts, IEAA). We also investigated sex-specific associations between air pollution and biological aging, given the published association between sex and aging measures. In KORA an interquartile range (0.97 µg/m3) increase in PM2.5 was associated with a 0.33 y increase in EEAA (CI = 0.01, 0.64; P = 0.04). BC and NOx (indicators or traffic exposure) were associated with DNAmAA and IEAA in women, while TeloAA was inversely associated with BC in men. We replicated this inverse BC-TeloAA association in the Normative Aging Study, a male cohort based in the USA. A multiple phenotype analysis in KORA F4 combining all aging measures showed that BC and PM10 were broadly associated with biological aging in men. Thus, we conclude that long-term exposure to air pollution is associated with biological aging measures, potentially in a sex-specific manner. However, many of the associations were relatively weak and further replication of overall and sex-specific associations is warranted.


Assuntos
Envelhecimento , Poluentes Atmosféricos/efeitos adversos , Poluição do Ar/efeitos adversos , Exposição Ambiental/efeitos adversos , Idoso , Envelhecimento/genética , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Material Particulado , Risco , Fatores de Tempo
17.
Environ Epigenet ; 2(2)2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27453791

RESUMO

BACKGROUND: Ambient particles have been shown to exacerbate measures of biological aging; yet, no studies have examined their relationships with DNA methylation age (DNAm-age), an epigenome-wide DNA methylation based predictor of chronological age. OBJECTIVE: We examined the relationship of DNAm-age with fine particulate matter (PM2.5), a measure of total inhalable particle mass, and black carbon (BC), a measure of particles from vehicular traffic. METHODS: We used validated spatiotemporal models to generate 1-year PM2.5 and BC exposure levels at the addresses of 589 older men participating in the VA Normative Aging Study with 1-3 visits between 2000 and 2011 (n = 1032 observations). Blood DNAm-age was calculated using 353 CpG sites from the Illumina HumanMethylation450 BeadChip. We estimated associations of PM2.5 and BC with DNAm-age using linear mixed effects models adjusted for age, lifestyle/environmental factors, and aging-related diseases. RESULTS: After adjusting for covariates, a 1-µg/m3 increase in PM2.5 (95% CI: 0.30, 0.75, P<0.0001) was significantly associated with a 0.52-year increase in DNAm-age. Adjusted BC models showed similar patterns of association (ß = 3.02, 95% CI: 0.48, 5.57, P = 0.02). Only PM2.5 (ß = 0.54, 95% CI: 0.24, 0.84, P = 0.0004) remained significantly associated with DNAm-age in two-particle models. Methylation levels from 20 of the 353 CpGs contributing to DNAm-age were significantly associated with PM2.5 levels in our two-particle models. Several of these CpGs mapped to genes implicated in lung pathologies including LZTFL1, PDLIM5, and ATPAF1. CONCLUSION: Our results support an association of long-termambient particle levels with DNAm-age and suggest that DNAm-age is a biomarker of particle-related physiological processes.

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