科研成果

2021
Schlosser P, Tin A, Matias-Garcia PR, Thio CHL, Joehanes R, Liu H, Weihs A, Yu Z, Hoppmann A, Grundner-Culemann F, et al. Meta-analyses identify DNA methylation associated with kidney function and damage. Nat CommunNat Commun. 2021;12:7174.Abstract
Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.
Matias-Garcia PR, Ward-Caviness CK, Raffield LM, Gao X, Zhang Y, Wilson R, Gao X, Nano J, Bostom A, Colicino E, et al. DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function. Clin Epigenetics [Internet]. 2021;13:121. 访问链接Abstract
{BACKGROUND: The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies. RESULTS: We identified 23 significant associations in our large trans-ethnic meta-analysis (p < 1.43E-03 and consistent direction of effect across studies). Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as Zhang's 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate). Six of these associations were independently observed in European and African American populations. MRS in particular was consistently associated with eGFR (beta = - 0.12, 95% CI = [- 0.16, - 0.08] change in log-transformed eGFR per unit increase in MRS
Liu Q, Li H, Guo L, Chen Q, Gao X, Li P-hui, Tang N, Guo X, Deng F, Wu S. Effects of Short-term Personal Exposure to Air Pollution on Platelet Mitochondrial DNA Methylation Levels and the Potential Mitigation by L-arginine Supplementation. Journal of Hazardous Materials [Internet]. 2021:125963. 访问链接Abstract
The potential effect of short-term exposure to air pollution on mitochondrial DNA (mtDNA) methylation remains to be explored. This study adopted an experimental exposure protocol nested with an intervention study on L-arginine (L-Arg) supplementation. Participants walked along a traffic road for 2h in the last day of a 14-day intervention to investigate the effects of short-term personal exposure to air pollution on platelet mtDNA methylation and the possible modifying effects of L-Arg supplementation. Results showed that short-term personal exposure to air pollutants was associated with hypomethylation in platelet mtDNA. Specifically, 2-h fine particulate matter (PM2.5) exposure during the outdoor walk was significantly associated with hypomethylation in mt12sRNA and ATP6; 24-h black carbon (BC) exposure from the start of the walk till next morning and 2-h NO2 exposure was significantly associated with hypomethylation in ATP8; and 24-h PM2.5 exposure, 2-h and 24-h BC exposure were significantly associated with hypomethylation in D-loop. Supplementation with L-Arg could mitigate the air pollution effects on methylation in ATP8 and D-loop. These findings suggest that platelet mtDNA methylation may be sensitive effect biomarker for short-term exposure to air pollution and may help deepen the understanding of the epigenetic mechanisms of adverse cardiovascular effects of air pollution.
Gao X, Koutrakis P, Coull B, Lin X, Vokonas P, Schwartz J, Baccarelli AA. Short-term exposure to PM2.5 components and renal health: Findings from the Veterans Affairs Normative Aging Study. Journal of Hazardous Materials [Internet]. 2021;420:126557. 访问链接Abstract
There is little evidence on the short-term impact of fine particulate matter (PM2.5) on renal health, and the potential interactions and various influences of PM2.5 components on renal health have not been examined. We investigated whether short-term (≤28 days) ambient PM2.5 and 15 PM2.5 components were associated with serum uric acid (SUA), blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), and odds of incident chronic kidney disease (CKD) using both mixed-effect and Bayesian kernel machine regression (BKMR) models in the Normative Aging Study. This analysis included 2466 study visits from 808 older males enrolled during 1998–2016 with available data. BKMR showed positive relationships of PM2.5 mixture with SUA and odds of CKD, and an inverse relationship with eGFR. In the 28-day exposure window, an interquartile range (IQR) increase in vanadium was associated with a 0.244-mg/dL higher SUA. IQR increases in sulfur and lead were associated with a 1.281- and 1.008-mL/min/1.73m2 decrease in eGFR, respectively. The same change in sulfur was also associated with a 39% higher odds of CKD. Our findings provide solid evidence supporting short-term adverse effects of PM2.5 on renal health and further highlight that components from oil combustion and regional pollution may be major contributors.
Gao X, Coull B, Lin X, Vokonas P, Spiro A, Hou L, Schwartz J, Baccarelli AA. Short-term air pollution, cognitive performance and nonsteroidal anti-inflammatory drug use in the Veterans Affairs Normative Aging Study. Nature Aging [Internet]. 2021;1:430-437. 访问链接Abstract
Air pollution, especially fine particulate matter (PM2.5), may impair cognitive performance1–3, but its short-term impact is poorly understood. We investigated the short-term association of PM2.5 with the cognitive performances of 954 white males measured as global cognitive function and Mini-Mental State Examination (MMSE) scores and further explored whether taking nonsteroidal anti-inflammatory drugs (NSAIDs) could modify their relationships. Higher short-term exposure to PM2.5 demonstrated nonlinear negative associations with cognitive function. Compared with the lowest quartile of the 28-d average PM2.5 concentration, the 2nd, 3rd and 4th quartiles were associated with 0.378, 0.376 and 0.499 unit decreases in global cognitive function score, 0.484, 0.315 and 0.414 unit decreases in MMSE score and 69, 45 and 63% greater odds of low MMSE scores (≤25), respectively. Such adverse effects were attenuated in users of NSAIDs compared to nonusers. This study elucidates the short-term impacts of air pollution on cognition and warrants further investigations on the modifying effects of NSAIDs.
2020
Gao X, Coull B, Lin X, Vokonas P, Sparrow D, Hou L, DeMeo DL, Litonjua AA, Schwartz J, Baccarelli AA. Association of Neutrophil to Lymphocyte Ratio With Pulmonary Function in a 30-Year Longitudinal Study of US Veterans. JAMA Netw Open [Internet]. 2020;3:e2010350. 访问链接Abstract
Importance: Chronic obstructive pulmonary disease (COPD) is a critical public health burden. The neutrophil to lymphocyte ratio (NLR), an inflammation biomarker, has been associated with COPD morbidity and mortality; however, its associations with lung function decline and COPD development are poorly understood. Objective: To explore the associations of NLR with lung function decline and COPD risks. Design, Setting, and Participants: This longitudinal cohort study included white male veterans in the US with more than 30 years of follow-up to investigate the associations of NLR with lung function, COPD, and hypomethylation of cg05575921, the top DNA methylation marker of lung function changes in response to tobacco smoking. This study included 7466 visits from 1549 participants, each examined up to 13 times between 1982 and 2018. A subgroup of 1411 participants without COPD at baseline were selected to analyze the association of NLR with incident COPD. Data were analyzed from September 2019 to January 2020. Exposures: The primary exposure was NLR, which was estimated using automated whole blood cell counts based on a blood sample collected at each visit. The methylation level of cg05575921 was measured in blood DNA from a subgroup of 1228 visits. Main Outcomes and Measures: The outcomes of interest were lung function, measured as forced respiratory volume in the first second (FEV1) in liters, forced vital capacity (FVC) in liters, percentage of FVC exhaled in the first second (FEV1/FVC), and maximal midexpiratory flow rate (MMEF) in liters per minute and COPD status, defined as meeting the Global Initiative for Chronic Obstructive Lung Diseases stage II (or higher) criteria. Both outcomes were measured as each visit. Results: Among 1549 included men (mean [SD] age, 68.3 [9.3] years) with 7466 visits from 1982 to 2018, a 1-unit increase in NLR was associated with statistically significant mean (SE) decreases of 0.021 (0.004) L in FEV1, 0.016 (0.005) L in FVC, 0.290% (0.005) L in FVC, 0.290% (0.065%) in FEV1/FVC, and 3.65 (0.916) L/min MMEF. Changes in NLR up to approximately 10 years were associated with corresponding longitudinal changes in lung function. Furthermore, this increase in NLR was associated with 9% higher odds of COPD (odds ratio, 1.09 [95% CI, 1.03-1.15]) for all visits and 27% higher risk of incident COPD (odds ratio, 1.07 [95% CI, 1.07-1.51]) for participants without COPD at baseline. Additionally, a 1-unit increase in NLR was associated with a mean (SE) decrease of 0.0048 (0.0021 in cg05575921 hypomethylation, which may mediate the adverse association of NLR-related inflammation on lung function. Conclusions and Relevance: These findings suggest that NLR may be a clinically relevant biomarker associated with high risk of lung function impairment and COPD alone or in combination with DNA methylation profiles.
Wang C, Koutrakis P, Gao X, Baccarelli A, Schwartz J. Associations of annual ambient PM2.5 components with DNAm PhenoAge acceleration in elderly men: The Normative Aging Study. Environ Pollut [Internet]. 2020;258:113690. 访问链接Abstract
Current studies indicate that long-term exposure to ambient fine particulate matter (PM2.5) is related with global mortality, yet no studies have explored relationships of PM2.5 and its species with DNAm PhenoAge acceleration (DNAmPhenoAccel), a new epigenetic biomarker of phenotypic age. We identified which PM2.5 species had association with DNAmPhenoAccel in a one-year exposure window in a longitudinal cohort. We collected whole blood samples from 683 elderly men in the Normative Aging Study between 1999 and 2013 (n = 1254 visits). DNAm PhenoAge was calculated using 513 CpGs retrieved from the Illumina Infinium HumanMethylation450 BeadChip. Daily concentrations of PM2.5 species were measured at a fixed air-quality monitoring site and one-year moving averages were computed. Linear mixed-effect (LME) regression and Bayesian kernel machine (BKM) regression were used to estimate the associations. The covariates included chronological age, body mass index (BMI), cigarette pack years, smoking status, estimated cell types, batch effects etc. Benjamini-Hochberg false discovery rate at a 5% false positive threshold was used to adjust for multiple comparison. During the study period, the mean DNAm PhenoAge and chronological age in our subjects were 68 and 73 years old, respectively. Using LME model, only lead and calcium were significantly associated with DNAmPhenoAccel. For example, an interquartile range (IQR, 0.0011 mug/m(3)) increase in lead was associated with a 1.29-year [95% confidence interval (CI): 0.47, 2.11] increase in DNAmPhenoAccel. Using BKM model, we selected PM2.5, lead, and silicon to be predictors for DNAmPhenoAccel. A subsequent LME model showed that only lead had significant effect on DNAmPhenoAccel: 1.45-year (95% CI: 0.46, 2.46) increase in DNAmPhenoAccel following an IQR increase in one-year lead. This is the first study that investigates long-term effects of PM2.5 components on DNAmPhenoAccel. The results demonstrate that lead and calcium contained in PM2.5 was robustly associated with DNAmPhenoAccel.
Nwanaji-Enwerem JC, Colicino E, Gao X, Wang C, Vokonas P, Boyer EW, Baccarelli AA, Schwartz J. Associations of Plasma Folate and Vitamin B6 with Blood DNA Methylation Age: An Analysis of One-Carbon Metabolites in the VA Normative Aging Study. J Gerontol A Biol Sci Med Sci [Internet]. 2020. 访问链接Abstract
One-carbon metabolism is an important contributor to aging-related diseases; nevertheless, relationships of one-carbon metabolites with novel DNA methylation-based measures of biological aging remain poorly characterized. We examined relationships of one-carbon metabolites with three DNA methylation-based measures of biological aging: DNAmAge, GrimAge, and PhenoAge. We measured plasma levels of four common one-carbon metabolites (vitamin B6, vitamin B12, folate, and homocysteine) in 715 VA Normative Aging Study participants with at least one visit between 1999 and 2008 (observations = 1153). DNA methylation age metrics were calculated using the HumanMethylation450 BeadChip. We utilized Bayesian Kernel Machine Regression (BKMR) models adjusted for chronological age, lifestyle factors, age-related diseases, and study visits to determine metabolites important to the aging outcomes. BKMR models allowed for the estimation of the relationships of single metabolites and the cumulative metabolite mixture with methylation age. Log vitamin B6 was selected as important to PhenoAge (beta = -1.62-years, 95%CI: -2.28, -0.96). Log folate was selected as important to GrimAge (beta = 0.75-years, 95%CI: 0.41, 1.09) and PhenoAge (beta = 1.62-years, 95%CI: 0.95, 2.29). Compared to a model where each metabolite in the mixture is set to its 50 th percentile, the log cumulative mixture with each metabolite at its 30 th (beta = -0.13-years, 95%CI: -0.26, -0.005) and 40 th percentile (beta = -0.06-years, 95%CI: -0.11, -0.005) was associated with decreased GrimAge. Our results provide novel characterizations of the relationships between one-carbon metabolites and DNA methylation age in a human population study. Further research is required to confirm these findings and establish their generalizability.
Wang C, Ni W, Yao Y, Just A, Heiss J, Wei Y, Gao X, Coull BA, Kosheleva A, Baccarelli AA, et al. DNA methylation-based biomarkers of age acceleration and all-cause death, myocardial infarction, stroke, and cancer in two cohorts: The NAS, and KORA F4. EBioMedicine [Internet]. 2020;63:103151. 访问链接Abstract
BACKGROUND: DNA methylation (DNAm) may play a role in age-related outcomes. It is not yet known which DNAm-based biomarkers of age acceleration (BoAA) has the strongest association with age-related endpoints. METHODS: We collected the blood samples from two independent cohorts: the Normative Ageing Study, and the Cooperative Health Research in the Region of Augsburg cohort. We measured epigenome-wide DNAm level, and generated five DNAm BoAA at baseline. We used Cox proportional hazards model to analyze the relationships between BoAA and all-cause death. We applied the Fine and Gray competing risk model to estimate the risk of BoAA on myocardial infarction (MI), stroke, and cancer, accounting for death of other reasons as the competing risks. We used random-effects meta-analyses to pool the individual results, with adjustment for multiple testing. FINDINGS: The mean chronological ages in the two cohorts were 74, and 61, respectively. Baseline GrimAgeAccel, and DNAm-related mortality risk score (DNAmRS) both had strong associations with all-cause death, MI, and stroke, independent from chronological age. For example, a one standard deviation (SD) increment in GrimAgeAccel was significantly associated with increased risk of all-cause death [hazard ratio (HR): 2.01; 95% confidence interval (CI), 1.15, 3.50], higher risk of MI (HR: 1.44; 95% CI, 1.16, 1.79), and elevated risk of stroke (HR: 1.42; 95% CI, 1.06, 1.91). There were no associations between any BoAA and cancer. INTERPRETATION: From the public health perspective, GrimAgeAccel is the most useful tool for identifying at-risk elderly, and evaluating the efficacy of anti-aging interventions. FUNDING: National Institute of Environmental Health Sciences of U.S., Harvard Chan-NIEHS Center for Environmental Health, German Federal Ministry of Education and Research, and the State of Bavaria in Germany.
Ochoa-Rosales C, Portilla-Fernandez E, Nano J, Wilson R, Lehne B, Mishra PP, Gao X, Ghanbari M, Rueda-Ochoa OL, Juvinao-Quintero D, et al. Epigenetic Link Between Statin Therapy and Type 2 Diabetes. Diabetes Care [Internet]. 2020;43:875-884. 访问链接Abstract
OBJECTIVE: To investigate the role of epigenetics in statins' diabetogenic effect comparing DNA methylation (DNAm) between statin users and nonusers in an epigenome-wide association study in blood. RESEARCH DESIGN AND METHODS: Five cohort studies' participants (n = 8,270) were classified as statin users when they were on statin therapy at the time of DNAm assessment with Illumina 450K or EPIC array or noncurrent users otherwise. Associations of DNAm with various outcomes like incident type 2 diabetes, plasma glucose, insulin, and insulin resistance (HOMA of insulin resistance [HOMA-IR]) as well as with gene expression were investigated. RESULTS: Discovery (n = 6,820) and replication (n = 1,450) phases associated five DNAm sites with statin use: cg17901584 (1.12 x 10(-25) [DHCR24]), cg10177197 (3.94 x 10(-08) [DHCR24]), cg06500161 (2.67 x 10(-23) [ABCG1]), cg27243685 (6.01 x 10(-09) [ABCG1]), and cg05119988 (7.26 x 10(-12) [SC4MOL]). Two sites were associated with at least one glycemic trait or type 2 diabetes. Higher cg06500161 methylation was associated with higher fasting glucose, insulin, HOMA-IR, and type 2 diabetes (odds ratio 1.34 [95% CI 1.22, 1.47]). Mediation analyses suggested that ABCG1 methylation partially mediates the effect of statins on high insulin and HOMA-IR. Gene expression analyses showed that statin exposure and ABCG1 methylation were associated with ABCG1 downregulation, suggesting epigenetic regulation of ABCG1 expression. Further, outcomes insulin and HOMA-IR were significantly associated with ABCG1 expression. CONCLUSIONS: This study sheds light on potential mechanisms linking statins with type 2 diabetes risk, providing evidence on DNAm partially mediating statins' effects on insulin traits. Further efforts shall disentangle the molecular mechanisms through which statins may induce DNAm changes, potentially leading to ABCG1 epigenetic regulation.
Nwanaji-Enwerem JC, Colicino E, Specht AJ, Gao X, Wang C, Vokonas P, Weisskopf MG, Boyer EW, Baccarelli AA, Schwartz J. Individual species and cumulative mixture relationships of 24-hour urine metal concentrations with DNA methylation age variables in older men. Environ Res [Internet]. 2020;186:109573. 访问链接Abstract
{BACKGROUND: Globally, toxic metal exposures are a well-recognized risk factor for many adverse health outcomes. DNA methylation-based measures of biological aging are predictive of disease, but have poorly understood relationships with metal exposures. OBJECTIVE: We performed a pilot study examining the relationships of 24-h urine metal concentrations with three novel DNA methylation-based measures of biological aging: DNAmAge, GrimAge, and PhenoAge. METHODS: We utilized a previously established urine panel of five common metals [arsenic (As), cadmium (Cd), lead (Pb), manganese (Mn), and mercury (Hg)] found in a subset of the elderly US Veterans Affairs Normative Aging Study cohort (N = 48). The measures of DNA methylation-based biological age were calculated using CpG sites on the Illumina HumanMethylation450 BeadChip. Bayesian Kernel Machine Regression (BKMR) was used to determine metals most important to the aging outcomes and the relationship of the cumulative metal mixture with the outcomes. Individual relationships of important metals with the biological aging outcomes were modeled using fully-adjusted linear models controlling for chronological age, renal function, and lifestyle/environmental factors. RESULTS: Mn was selected as important to PhenoAge. A 1 ng/mL increase in urine Mn was associated with a 9.93-year increase in PhenoAge (95%CI: 1.24, 18.61
Breen M, Nwanaji-Enwerem JC, Karrasch S, Flexeder C, Schulz H, Waldenberger M, Kunze S, Ollert M, Weidinger S, Colicino E, et al. Accelerated epigenetic aging as a risk factor for chronic obstructive pulmonary disease and decreased lung function in two prospective cohort studies. Aging (Albany NY) [Internet]. 2020;12. 访问链接Abstract
Chronic obstructive pulmonary disease (COPD) is a frequent diagnosis in older individuals and contributor to global morbidity and mortality. Given the link between lung disease and aging, we need to understand how molecular indicators of aging relate to lung function and disease. Using data from the population-based KORA (Cooperative Health Research in the Region of Augsburg) surveys, we associated baseline epigenetic (DNA methylation) age acceleration with incident COPD and lung function. Models were adjusted for age, sex, smoking, height, weight, and baseline lung disease as appropriate. Associations were replicated in the Normative Aging Study. Of 770 KORA participants, 131 developed incident COPD over 7 years. Baseline accelerated epigenetic aging was significantly associated with incident COPD. The change in age acceleration (follow-up - baseline) was more strongly associated with COPD than baseline aging alone. The association between the change in age acceleration between baseline and follow-up and incident COPD replicated in the Normative Aging Study. Associations with spirometric lung function parameters were weaker than those with COPD, but a meta-analysis of both cohorts provide suggestive evidence of associations. Accelerated epigenetic aging, both baseline measures and changes over time, may be a risk factor for COPD and reduced lung function.
Colicino E, Marioni R, Ward-Caviness C, Gondalia R, Guan W, Chen B, Tsai PC, Huan T, Xu G, Golareh A, et al. Blood DNA methylation sites predict death risk in a longitudinal study of 12, 300 individuals. Aging (Albany NY) [Internet]. 2020;12. 访问链接Abstract
DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality (P < 9.3x10(-7)) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)-mapping respectively to BMPR1B, MIR1973, IFITM3, NLRC5, and two intergenic regions-were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)-mapping respectively to SERINC2, CHST12, and an intergenic region-were associated with increased mortality risk. DNA methylation at each site predicted 5%-15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes (IFITM3, IRF, NLRC5, MT1, MT2, MARCKSL1) linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.
Gao X, Coull B, Lin X, Vokonas P, Schwartz J, Baccarelli AA. Nonsteroidal Antiinflammatory Drugs Modify the Effect of Short-Term Air Pollution on Lung Function. Am J Respir Crit Care Med [Internet]. 2020;201:374-378. 访问链接
Belsky DW, Caspi A, Arseneault L, Baccarelli A, Corcoran DL, Gao X, Hannon E, Harrington HL, Rasmussen LJ, Houts R, et al. Quantification of the pace of biological aging in humans through a blood test, the DunedinPoAm DNA methylation algorithm. Elife [Internet]. 2020;9:e54870. 访问链接Abstract
Biological aging is the gradual, progressive decline in system integrity that occurs with advancing chronological age, causing morbidity and disability. Measurements of the pace of aging are needed as surrogate endpoints in trials of therapies designed to prevent disease by slowing biological aging. We report a blood-DNA-methylation measure that is sensitive to variation in pace of biological aging among individuals born the same year. We first modeled change-over-time in 18 biomarkers tracking organ-system integrity across 12 years of follow-up in n = 954 members of the Dunedin Study born in 1972-1973. Rates of change in each biomarker over ages 26-38 years were composited to form a measure of aging-related decline, termed Pace-of-Aging. Elastic-net regression was used to develop a DNA-methylation predictor of Pace-of-Aging, called DunedinPoAm for Dunedin(P)ace(o)f(A)ging(m)ethylation. Validation analysis in cohort studies and the CALERIE trial provide proof-of-principle for DunedinPoAm as a single-time-point measure of a person's pace of biological aging. People's bodies age at different rates. Age-related biological changes that increase the risk of disease and disability progress rapidly in some people. In others, these processes occur at a slower pace, allowing those individuals to live longer, healthier lives. This observation has led scientists to try to develop therapies that slow aging. The hope is that such treatments could prevent or delay diseases like heart disease or dementia, for which older age is the leading risk factor. Studies in animals have identified treatments that extend the creatures' lives and slow age-related disease. But testing these treatments in humans is challenging. Our lives are much longer than the worms, flies or mice used in the experiments. Scientists would have to follow human study participants for decades to detect delays in disease onset or an extension of their lives. An alternative approach is to try to develop a test that measures the pace of aging, or essentially "a speedometer for aging". This would allow scientists to more quickly determine if treatments slow the aging process. Now, Belsky et al. show a blood test designed to measure the pace of aging predicts which people are at increased risk of poor health, chronic disease and an earlier death. First, data about chemical changes to an individual's DNA, called DNA methylation, were analyzed from white blood cell samples collected from 954 people in a long-term health study known as "The Dunedin Study". Using the data, Belsky et al. then developed an algorithm - named "DunedinPoAm" - that identified people with an accelerated or slowed pace of aging based on a single blood test. Next, they used the algorithm on samples from participants in three other long-term studies. This verified that those people the algorithm identified as aging faster had a greater risk of poor health, developing chronic diseases or dying earlier. Similarly, those identified as aging more slowly performed better on tests of balance, strength, walking speed and mental ability, and they also looked younger to trained raters. Additionally, Belsky et al. used the test on participants in a randomized trial testing whether restricting calories had potential to extend healthy lifespan. The results suggested that the calorie restriction could counter the effects of an accelerated pace of aging. The test developed by Belsky et al. may provide an alternate way of measuring whether age-slowing treatments work. This would allow faster testing of treatments that can extend the healthy lifespan of humans. The test may also help identify individuals with accelerated aging. This might help public health officials test whether policies or programs can help people lead longer, healthier lives. eng
Gao X, Baccarelli A. Reply to Alexis: Controlled Chamber Studies Showed Protective Effect of Nonsteroidal Antiinflammatory Drugs against Ozone Exposure: The Stage Was Set for Broader Epidemiologic Investigation. Am J Respir Crit Care Med [Internet]. 2020;201:1583-1584. 访问链接
2019
Schottker B, Hagen L, Zhang Y, Gao X, Holleczek B, Gao X, Brenner H. Serum 25-Hydroxyvitamin D Levels as an Aging Marker: Strong Associations With Age and All-Cause Mortality Independent From Telomere Length, Epigenetic Age Acceleration, and 8-Isoprostane Levels. J Gerontol A Biol Sci Med Sci [Internet]. 2019;74:121-128. 访问链接Abstract
Background: A strong association of serum 25-hydroxyvitamin-D levels (25(OH)D) with all-cause mortality has been shown previously and 25(OH)D could be a useful aging marker. Methods: The analysis was performed in a population-based, cohort study from Germany with 9,940 participants, aged 50-74 years at baseline. A general linear model was used to assess associations of 25(OH)D levels with chronological age and the aging markers leukocyte telomere length (LTL), epigenetic age acceleration, and 8-isoprostane levels. A multivariate Cox regression model was applied to explore the independent and combined associations of these biomarkers with all-cause mortality (2,204 deaths occurred during a median follow-up of 14.3 years). Results: On average, study participants lost 2.9 nmol/L 25(OH)D each 10 years of age. Increasing 25(OH)D levels were significantly associated with decreasing levels of 8-isoprostane levels but neither with LTL nor epigenetic age acceleration. The association of 25(OH)D quartiles with mortality was almost unchanged after adjusting for all aging markers (1.6-fold increased mortality in bottom quartile compared with top quartile). All aging markers were independent mortality predictors and subjects with unfavorable values for 4, 3, 2, and 1 aging marker(s) had 4.3-, 2.9-, 2.2, and 1.4-fold increased mortality, respectively. Conclusions: The 25(OH)D level can be regarded as an aging marker because it is linearly associated with age and an independent mortality predictor. Mechanisms linking vitamin D to healthy aging are unique and can neither be fully explained by aging of the epigenome, loss of telomeres, or antioxidative effects of vitamin D metabolites.
Yang Y, Gao X, Just AC, Colicino E, Wang C, Coull BA, Hou L, Zheng Y, Vokonas P, Schwartz J, et al. Smoking-Related DNA Methylation is Associated with DNA Methylation Phenotypic Age Acceleration: The Veterans Affairs Normative Aging Study. Int J Environ Res Public Health [Internet]. 2019;16:2356. 访问链接Abstract
DNA methylation may play a critical role in aging and age-related diseases. DNA methylation phenotypic age (DNAmPhenoAge) is a new aging biomarker and predictor of chronic disease risk. While smoking is a strong risk factor for chronic diseases and influences methylation, its influence on DNAmPhenoAge is unknown. We investigated associations of self-reported and epigenetic smoking indicators with DNAmPhenoAge acceleration in a longitudinal aging study in eastern Massachusetts. DNA methylation was measured in whole blood samples from multiple visits for 692 male participants in the Veterans Affairs Normative Aging Study during 1999-2013. Acceleration was defined using residuals from linear regression of the DNAmPhenoAge on the chronological age. Cumulative smoking (pack-years) was significantly associated with DNAmPhenoAge acceleration, whereas self-reported smoking status was not. We observed significant validated associations between smoking-related loci and DNAmPhenoAge acceleration for 52 CpG sites, where 18 were hypomethylated and 34 were hypermethylated, mapped to 16 genes. The AHRR gene had the most loci (N = 8) among the 16 genes. We generated a smoking aging index based on these 52 loci, which showed positive significant associations with DNAmPhenoAge acceleration. These epigenetic biomarkers may help to predict age-related risks driven by smoking.
Gao X, Gao X, Zhang Y, Holleczek B, Schottker B, Brenner H. Oxidative stress and epigenetic mortality risk score: associations with all-cause mortality among elderly people. Eur J Epidemiol [Internet]. 2019;34:451-462. 访问链接Abstract
Oxidative stress (OS) has been found to be related to accelerated aging and many aging-related health outcomes. Recently, an epigenetic "mortality risk score" (MS) based on whole blood DNA methylation at 10 mortality-related CpG sites has been demonstrated to be associated with all-cause mortality. This study aimed to address the association between OS and MS, and to assess and compare their performance in the prediction of all-cause mortality. For 1448 participants aged 50-75 of the German ESTHER cohort study, the MS was derived from the DNA methylation profiles measured by Illumina HumanMethylation450K Beadchip and the levels of two urinary OS markers, 8-isoprostane (8-iso) and oxidized guanine/guanosine [including 8-hydroxy-2'-deoxyguanosine (8-oxo)], were measured by ELISA kits. Associations between OS markers and the MS were evaluated by linear and ordinal logistic regression models, and their associations with all-cause mortality were examined by Cox regression models. Both OS markers were associated with the MS at baseline. The 8-iso levels and MS, but not 8-oxo levels, were associated with all-cause mortality during a median follow-up of 15.1 years. Fully-adjusted hazard ratios (95% CI) were 1.56 (1.13-2.16) for the 4th quartile of 8-iso levels compared with the 1st, 1.71 (1.27-2.29) and 2.92 (2.03-4.18) for the moderate and high MS defined by 2-5 and > 5 CpG sites with aberrant methylation compared with a MS of 0-1, respectively. After controlling for 8-iso levels, the hazard ratios of MS remained essentially unchanged while the association of 8-iso levels with mortality was attenuated. This study demonstrates that OS is highly associated with the epigenetic MS, and the latter at the same time has a higher predictive value for all-cause mortality.
Gao X, Koutrakis P, Blomberg AJ, Coull B, Vokonas P, Schwartz J, Baccarelli AA. Short-term ambient particle radioactivity level and renal function in older men: Insight from the Normative Aging Study. Environ Int [Internet]. 2019;131:105018. 访问链接Abstract
{BACKGROUND: Whole-body and thoracic ionizing radiation exposure are both associated with the development of renal dysfunction. However, whether low-level environmental radiation from air pollution affects renal function remains unknown. OBJECTIVES: We investigated the association of particle radioactivity (PR) with renal function defined by the estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD) in the Normative Aging Study. METHODS: This longitudinal analysis included 2491 medical visits from 809 white males enrolled between 1999 and 2013. The eGFR was calculated using the CKD-EPI and MDRD equations, and CKD cases were identified as those with an eGFR <60mL/min/1.73m(2). Gross beta activity measured by five monitors of the U.S. Environmental Protection Agency's RadNet monitoring network was utilized to represent PR. RESULTS: Ambient PR levels from 1 to 28days prior to clinical visit demonstrated robust negative associations with both forms of eGFR, but not with the increased odds of CKD. An interquartile range higher 28-day average ambient PR level was significantly associated with 0.83-mL/min/1.73m(2) lower eGFR estimated by the CKD-EPI equation (95% confidence interval: -1.46, -0.20

Pages