Accelerated DNA methylation aging and increased resilience in veterans: the biological cost for soldiering on

AbstractAccelerated epigenetic aging, the difference between the DNA methylation-predicted age (DNAm age) and the chronological age, is associated with a myriad of diseases. This study investigates the relationship between epigenetic aging and risk and protective factors of PTSD. Genome-wide DNA methylation analysis was performed in 211 individuals including combat-exposed Australian veterans (discovery cohort, n = 96 males) and trauma-exposed civilian males from the Grady Trauma Project (replication cohort, n = 115 males). Primary measures included the Clinician Administered PTSD Scale for DSM-5 and the Connor-Davidson Resilience Scale (CDRISC). DNAm age prediction was performed using the validated epigenetic clock calculator. Veterans with PTSD had increased PTSD symptom severity (P-value = 3.75 x 10-34) and lower CDRISC scores (P-value = 7.5 x 10-8) than veterans without PTSD. DNAm age was significantly correlated with the chronological age (P-value = 3.3 x 10-6), but DNAm age acceleration was not different between the PTSD and non-PTSD groups (P-value = 0.24). Evaluating potential protective factors, we found that DNAm age acceleration was significantly associated with CDRISC resilience scores in veterans with PTSD, these results remained significant after multiple testing correction (P-value = 0.023; r = 0.32). This finding was also replicated in an independent trauma-exposed civilian cohort (P-value = 0.02; r = 0.23). Post-hoc factor analyses revealed that this association was driven by “self-efficacy” items within the CDRISC (P-value = 0.015). These results suggest that among individuals already suffering from PTSD, some aspects of increased resilience might come at a biological cost.

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Pair bonding slows epigenetic aging and alters methylation in brains of prairie voles

10.1101/2020.09.25.313775 ◽

2020 ◽

Author(s):

Lindsay L. Sailer ◽

Amin Haghani ◽

Joseph A. Zoller ◽

Caesar Z. Li ◽

Alexander G. Ophir ◽

...

Keyword(s):

Dna Methylation ◽

Brain Tissue ◽

Association Studies ◽

Chronological Age ◽

Epigenetic Clock ◽

Pair Bonding ◽

Prairie Voles ◽

Relative Age ◽

Biomarkers Of Aging ◽

Epigenetic Aging

ABSTRACTThe quality of romantic relationships can be predictive of health consequences related to aging. DNA methylation-based biomarkers of aging have been developed for humans and many other mammals and could be used to assess how pair bonding impacts aging. Prairie voles (Microtus ochrogaster) have emerged as a model to study social attachment among adult pairs. Here we describe DNA methylation-based estimators of age for prairie voles based on novel DNA methylation data generated on highly conserved mammalian CpGs measured with a custom array. The multi-tissue epigenetic clock for voles was trained on 3 tissue sources (ear, liver, and samples of brain tissue from within the pair bonding circuit). A novel dual species human-vole clock accurately measured relative age defined as the ratio of chronological age to maximum age. According to the human-vole clock of relative age, sexually inexperienced voles exhibit accelerated epigenetic aging in brain tissue (p = 0.02) when compared to pair bonded animals of the same chronological age. Epigenome wide association studies identified CpGs in four genes that were strongly associated with pair bonding across the three tissue types (brain, ear, and liver): Hnrnph1, Fancl, Fam13b, and Fzd1. Further, four CpGs (near the Bmp4 exon, Eif4g2 3 prime UTR, Robo1 exon, and Nfat5 intron) exhibited a convergent methylation change between pair bonding and aging. This study describes highly accurate DNA methylation-based estimators of age in prairie voles and provides evidence that pair bonding status modulates the methylome.

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Abstract MP99: Cerebral Small Vessel Disease and the Epigenetic Clock: The Atherosclerosis Risk in Communities Study

Circulation ◽

10.1161/circ.133.suppl_1.mp99 ◽

2016 ◽

Vol 133 (suppl_1) ◽

Author(s):

Abhay Raina ◽

Xiaoping Zhao ◽

Jan Bressler ◽

Rebecca F Gottesman ◽

Megan L Grove ◽

...

Keyword(s):

Risk Factors ◽

Dna Methylation ◽

Small Vessel Disease ◽

Chronological Age ◽

Epigenetic Clock ◽

Atherosclerosis Risk In Communities ◽

Vessel Disease ◽

Epigenetic Aging ◽

Atherosclerosis Risk ◽

Aric Study

Cerebral small vessel disease (SVD) is one of the most common degenerative vessel disorders of the aging brain. White matter hyperintensities (WMH) on magnetic resonance imaging (MRI) are viewed as typical markers of SVD and are associated with an increased risk of stroke, dementia, and death. Advancing age is the strongest predictor of WMH prevalence and severity. Recent studies have developed a novel biomarker of aging, termed “epigenetic clock”, based on DNA methylation levels at specific sites across the genome, which are strongly correlated with chronological age. The deviation of the DNA methylation (DNAm)-predicted age from the chronological age, defined as “age acceleration”, is used as an index of an individual’s rate of aging. Here, we estimated blood DNAm age in African-Americans from the Atherosclerosis Risk in Communities (ARIC) study using two methodologies, and examined the cross-sectional association between WMH on MRI and measures of accelerated epigenetic aging. We hypothesized that DNAm age acceleration, defined as the residual value from the regression of the predicted DNAm age onto chronological age, is associated with greater WMH burden independently of chronological age and other known risk factors, including sex, body mass index, systolic blood pressure, hypertension, diabetes, and current smoking. DNA methylation was measured using the Illumina HM450 array on genomic DNA extracted from blood samples of African-American participants of the ARIC study. We estimated DNAm age using two published algorithms in 713 individuals aged 51-73 with both DNAm and brain MRI data. Linear regression models were used to estimate the association of the natural log-transformed WMH burden with each measure of age acceleration adjusting for covariates. Age acceleration was significantly associated with WMH burden and results were similar for both estimates of DNAm age. Each unit increase in WMH burden (on the log scale) was associated with a 1.2 and 1.3 year increase in DNAm age after accounting for chronological age and other known risk factors (P=0.01 and 0.004). Further adjustment for blood cell composition did not meaningfully change these results. In this population-based study of middle-aged to older African-American adults, we report evidence of an association between accelerated epigenetic aging of blood and increased WMH burden, independent of known risk factors, including chronologic age. Additional studies are ongoing to clarify whether DNAm age is simply a marker of the rate of aging or reflects biological mechanisms implicated in the aging of the cerebral white matter.

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Dysfunctional epigenetic aging of the normal colon and colorectal cancer risk

Clinical Epigenetics ◽

10.1186/s13148-019-0801-3 ◽

2020 ◽

Vol 12 (1) ◽

Cited By ~ 11

Author(s):

Ting Wang ◽

Sean K. Maden ◽

Georg E. Luebeck ◽

Christopher I. Li ◽

Polly A. Newcomb ◽

...

Keyword(s):

Dna Methylation ◽

Risk Group ◽

Risk Groups ◽

Biological Age ◽

Chronological Age ◽

Epigenetic Clock ◽

Normal Colon ◽

Epigenetic Aging ◽

Epigenetic Age ◽

Epigenetic Age Acceleration

Abstract Background Chronological age is a prominent risk factor for many types of cancers including colorectal cancer (CRC). Yet, the risk of CRC varies substantially between individuals, even within the same age group, which may reflect heterogeneity in biological tissue aging between people. Epigenetic clocks based on DNA methylation are a useful measure of the biological aging process with the potential to serve as a biomarker of an individual’s susceptibility to age-related diseases such as CRC. Methods We conducted a genome-wide DNA methylation study on samples of normal colon mucosa (N = 334). Subjects were assigned to three cancer risk groups (low, medium, and high) based on their personal adenoma or cancer history. Using previously established epigenetic clocks (Hannum, Horvath, PhenoAge, and EpiTOC), we estimated the biological age of each sample and assessed for epigenetic age acceleration in the samples by regressing the estimated biological age on the individual’s chronological age. We compared the epigenetic age acceleration between different risk groups using a multivariate linear regression model with the adjustment for gender and cell-type fractions for each epigenetic clock. An epigenome-wide association study (EWAS) was performed to identify differential methylation changes associated with CRC risk. Results Each epigenetic clock was significantly correlated with the chronological age of the subjects, and the Horvath clock exhibited the strongest correlation in all risk groups (r > 0.8, p < 1 × 10−30). The PhenoAge clock (p = 0.0012) revealed epigenetic age deceleration in the high-risk group compared to the low-risk group. Conclusions Among the four DNA methylation-based measures of biological age, the Horvath clock is the most accurate for estimating the chronological age of individuals. Individuals with a high risk for CRC have epigenetic age deceleration in their normal colons measured by the PhenoAge clock, which may reflect a dysfunctional epigenetic aging process.

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The aging DNA methylome reveals environment-by-aging interactions in a model teleost

10.1101/2021.03.01.433371 ◽

2021 ◽

Author(s):

Emily M Bertucci ◽

Marilyn W Mason ◽

Olin E Rhodes ◽

Benjamin B Parrott

Keyword(s):

Dna Methylation ◽

Environmental Factors ◽

Environmental Drivers ◽

Chronological Age ◽

Epigenetic Clock ◽

Ongoing Research ◽

Dna Methylome ◽

Age Related ◽

Epigenetic Aging ◽

Epigenetic Age

The rate at which individuals age underlies variation in life history and attendant health and disease trajectories. Age specific patterning of the DNA methylome (epigenetic aging) is strongly correlated with chronological age in humans and can be modeled to produce epigenetic age predictors. However, epigenetic age estimates vary among individuals of the same age, and this mismatch is correlated to the onset of age-related disease and all-cause mortality. Yet, the origins of epigenetic-to-chronological age discordance are not resolved. In an effort to develop a tractable model in which environmental drivers of epigenetic aging can be assessed, we investigate the relationship between aging and DNA methylation in a small teleost, medaka (Oryzias latipes). We find that age-associated DNA methylation patterning occurs broadly across the genome, with the majority of age-related changes occurring during early life. By modeling the stereotypical nature of age-associated DNA methylation dynamics, we built an epigenetic clock, which predicts chronological age with a mean error of 29.1 days (~4% of average lifespan). Characterization of clock loci suggests that aspects of epigenetic aging are functionally similar across vertebrates. To understand how environmental factors interact with epigenetic aging, we exposed medaka to four doses of ionizing radiation for seven weeks, hypothesizing that exposure to such an environmental stressor would accelerate epigenetic aging. While the epigenetic clock was not significantly affected, radiation exposure accelerated and decelerated patterns of normal epigenetic aging, with radiation-induced epigenetic alterations enriched at loci that become hypermethylated with age. Together, our findings advance ongoing research attempting to elucidate the functional role of DNA methylation in integrating environmental factors into the rate of biological aging.

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Abstract P012: The Effect of Vitamin D Supplementation on Epigenetic Aging: A Randomized Placebo-Controlled Clinical Trial

Circulation ◽

10.1161/circ.137.suppl_1.p012 ◽

2018 ◽

Vol 137 (suppl_1) ◽

Author(s):

Li Chen ◽

Yanbin Dong ◽

Jigar Bhagatwala ◽

Anas Raed ◽

Ying Huang ◽

...

Keyword(s):

Clinical Trial ◽

Dna Methylation ◽

Vitamin D ◽

African Americans ◽

Vitamin D Supplementation ◽

Chronological Age ◽

Controlled Clinical Trial ◽

P Value ◽

Epigenetic Aging ◽

Dna Methylation Age

Background: Vitamin D deficiency is associated with age-related diseases, such as cardiovascular disease, diabetes and cancer. We have previously shown that vitamin D plays a role in regulating human epigenome. Moreover, we have demonstrated that vitamin D supplementation increases telomerase activity, suggesting an anti-aging property. Epigenetic age acceleration, an emerging marker of biological aging, predicts cardiovascular mortality, morbidity and cancer. In this study, we tested the hypothesis that vitamin D supplementation would decelerate epigenetic aging. Methods: We have previously completed a 16 week randomized placebo-controlled clinical trial of vitamin D3 supplementation in overweight/obese African-Americans (NCT01583621). The participants were randomly assigned into four groups of placebo, 600 IU/day, 2000 IU/day, and 4000 IU/day of vitamin D supplements. A genome-wide methylation scan was performed using the Illumina Human Methylation 480K Bead Chip on peripheral blood mononuclear cell DNA. DNA methylation age of 52 participants was determined based on 353 CpG sites using the statistical pipeline developed by Horvath. Epigenetic aging, methylation-based age acceleration index (Δage) was defined as the difference between DNA methylation age and chronological age in years. Mixed-effects models were used to evaluate the treatment effects. Results: DNAm age was significantly correlated with chronological age (r=0.9082, p-value < 0.001). The correlation was higher at baseline (r=0.9281, p-value < 0.001) than at 16 weeks (r=0.8887, p-value < 0.001), which implies that the 16 week treatment may drive the DNAm age deviated from the chronological age. Compared with placebo, vitamin D supplementation was also associated with decreased Δage after adjustment for sex, BMI, lymphocyte percentage, month and baseline 25(OH)D concentration (600 IU/day: β = 0.90, p-value = 0.325; 2000 IU/day: β= -1.21, p-value = 0.118; 4000 IU/day: β= -1.70, p-value = 0.035), but only the treatment effect of 4000 IU/day supplementation was significant. Conclusion: Our results suggest that vitamin D supplementation might decelerate epigenetic aging, further supporting the anti-aging effect of vitamin D supplementation in overweight/obese African Americans. Larger studies are needed to replicate the findings.

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Epigenetic clock and DNA methylation studies of roe deer in the wild

10.1101/2020.09.21.306613 ◽

2020 ◽

Author(s):

Jean-François Lemaître ◽

Benjamin Rey ◽

Jean-Michel Gaillard ◽

Corinne Régis ◽

Emmanuelle Gilot ◽

...

Keyword(s):

Dna Methylation ◽

Evolutionary Biology ◽

Roe Deer ◽

Chronological Age ◽

Epigenetic Clock ◽

Aging Effects ◽

Methylation Array ◽

Biomarkers Of Aging ◽

Epigenetic Age ◽

The Relationship

AbstractDNA methylation-based biomarkers of aging (epigenetic clocks) promise to lead to new insights in the evolutionary biology of ageing. Relatively little is known about how the natural environment affects epigenetic aging effects in wild species. In this study, we took advantage of a unique long-term (>40 years) longitudinal monitoring of individual roe deer (Capreolus capreolus) living in two wild populations (Chizé and Trois Fontaines, France) facing different ecological contexts to investigate the relationship between chronological age and levels of DNA methylation (DNAm). We generated novel DNA methylation data from n=90 blood samples using a custom methylation array (HorvathMammalMethylChip40). We present three DNA methylation-based estimators of age (DNAm or epigenetic age), which were trained in males, females, and both sexes combined. We investigated how sex differences influenced the relationship between DNAm age and chronological age through the use of sex-specific epigenetic clocks. Our results highlight that both populations and sex influence the epigenetic age, with the bias toward a stronger male average age acceleration (i.e. differences between epigenetic age and chronological ages) particularly pronounced in the population facing harsh environmental conditions. Further, we identify the main sites of epigenetic alteration that have distinct aging patterns across the two sexes. These findings open the door to promising avenues of research at the crossroad of evolutionary biology and biogerontology.

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Effects of Vitamin D3 Supplementation on Epigenetic Aging in Overweight and Obese African Americans With Suboptimal Vitamin D Status: A Randomized Clinical Trial

The Journals of Gerontology Series A ◽

10.1093/gerona/gly223 ◽

2018 ◽

Vol 74 (1) ◽

pp. 91-98 ◽

Cited By ~ 17

Author(s):

Li Chen ◽

Yanbin Dong ◽

Jigar Bhagatwala ◽

Anas Raed ◽

Ying Huang ◽

...

Keyword(s):

Clinical Trial ◽

Dna Methylation ◽

Vitamin D ◽

African Americans ◽

Randomized Clinical Trial ◽

Vitamin D3 ◽

Vitamin D Supplementation ◽

P Value ◽

Epigenetic Aging ◽

Vitamin D3 Supplementation

Abstract Background We have previously shown that vitamin D supplementation increases telomerase activity, suggesting an anti-aging effect. In this study, we aim to test the hypothesis that vitamin D supplementation would slow down epigenetic aging, a new marker of biological aging. Methods A randomized clinical trial was previously conducted among 70 overweight/obese African Americans with serum 25-hydroxyvitamin D [25(OH)D] < 50 nmol/L, who were randomly assigned into four groups of 600 IU/d, 2,000 IU/d, 4,000 IU/d of vitamin D3 supplements or placebo followed by 16-week interventions. Whole genome-wide DNA methylation analysis was conducted in 51 participants. DNA methylation ages were calculated according to the Horvath and the Hannum methods. Methylation-based age acceleration index (∆Age) is defined as the difference between DNA methylation age and chronological age in years. Mixed-effects models were used to evaluate the treatment effects. Results Fifty-one participants (aged 26.1 ± 9.3 years, 16% are male) were included in the study. After the adjustment of multi-covariates, vitamin D3 supplementation of 4,000 IU/d was associated with 1.85 years decrease in Horvath epigenetic aging compared with placebo (p value = .046), and 2,000 IU/d was associated with 1.90 years decrease in Hannum epigenetic aging (p value = .044). Serum 25(OH)D concentrations were significantly associated with decreased Horvath ∆Age only (p values = .002), regardless of treatments. Conclusions Our results suggest that vitamin D supplementation may slow down Horvath epigenetic aging. But the effect on Hannum epigenetic aging is not conclusive. Large-scale and longer duration clinical trials are needed to replicate the findings.

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Longitudinal Changes of One-Carbon Metabolites and Amino Acid Concentrations during Pregnancy in the Women First Maternal Nutrition Trial

Current Developments in Nutrition ◽

10.1093/cdn/nzz132 ◽

2019 ◽

Vol 4 (1) ◽

Author(s):

Stephanie P Gilley ◽

Nicholas E Weaver ◽

Evan L Sticca ◽

Purevsuren Jambal ◽

Alexandra Palacios ◽

...

Keyword(s):

Dna Methylation ◽

Amino Acid ◽

Multiple Testing ◽

Maternal Nutrition ◽

Longitudinal Research ◽

Maternal Blood ◽

Replication Cohort ◽

Multiple Testing Correction ◽

Group A ◽

Study Sites

ABSTRACT Background Maternal dietary restriction and supplementation of one-carbon (1C) metabolites can impact offspring growth and DNA methylation. However, longitudinal research of 1C metabolite and amino acid (AA) concentrations over the reproductive cycle of human pregnancy is limited. Objective To investigate longitudinal 1C metabolite and AA concentrations prior to and during pregnancy and the effects of a small-quantity lipid-based nutrition supplement (LNS) containing >20 micronutrients and prepregnancy BMI (ppBMI). Methods This study was an ancillary study of the Women First Trial (NCT01883193, clinicaltrials.gov) focused on a subset of Guatemalan women (n = 134), 49% of whom entered pregnancy with a BMI ≥25 kg/m2. Ninety-five women received LNS during pregnancy (+LNS group), while the remainder did not (−LNS group). A subset of women from the Pakistan study site (n = 179) were used as a replication cohort, 124 of whom received LNS. Maternal blood was longitudinally collected on dried blood spot (DBS) cards at preconception, and at 12 and 34 wk gestation. A targeted metabolomics assay was performed on DBS samples at each time point using LC-MS/MS. Longitudinal analyses were performed using linear mixed modeling to investigate the influence of time, LNS, and ppBMI. Results Concentrations of 23 of 27 metabolites, including betaine, choline, and serine, changed from preconception across gestation after application of a Bonferroni multiple testing correction (P < 0.00185). Sixteen of those metabolites showed similar changes in the replication cohort. Asymmetric and symmetric dimethylarginine were decreased by LNS in the participants from Guatemala. Only tyrosine was statistically associated with ppBMI at both study sites. Conclusions Time influenced most 1C metabolite and AA concentrations with a high degree of similarity between the 2 diverse study populations. These patterns were not significantly altered by LNS consumption or ppBMI. Future investigations will focus on 1C metabolite changes associated with infant outcomes, including DNA methylation. This trial was registered at clinicaltrials.gov as NCT01883193.

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Derivation of Poly-Methylomic Profile Scores for Schizophrenia

10.1101/607309 ◽

2019 ◽

Cited By ~ 1

Author(s):

Oliver J. Watkeys ◽

Sarah Cohen-Woods ◽

Yann Quidé ◽

Murray J. Cairns ◽

Bronwyn Overs ◽

...

Keyword(s):

Dna Methylation ◽

Multiple Testing ◽

P Value ◽

Summary Statistics ◽

Illumina 450K ◽

Profile Score ◽

Methylation Patterns ◽

Control Association ◽

Schizophrenia Case ◽

450K Methylation

AbstractSchizophrenia (SZ) and bipolar disorder (BD) share numerous clinical and biological features as well as environmental risk factors that may be associated with altered DNA methylation. In this study we sought to construct a Poly-Methylomic Profile Score (PMPS) for SZ, representing the degree of epigenome-wide methylation according to previously published findings; we then examined its association with SZ and BD in an independent sample. DNA methylation for 57 SZ, 59 BD cases and 55 healthy controls (HCs) was quantified using the Illumina 450K methylation beadchip. We constructed five PMPSs for different p-value thresholds using summary statistics reported in a large epigenome-wide schizophrenia case-control association study, weighted by individual CpG effect sizes. All SZ PMPSs were significantly elevated in SZ cases relative to HCs, with the score calculated at the most stringent threshold accounting for the greatest amount of variance in SZ (compared to other PMPSs derived at more inclusivep-value thresholds). However, none of the PMPSs were associated with BD, or a combined cohort of BD and SZ cases relative to HCs. Results demonstrating elevated PMPSs in SZ relative to BD did not survive correction for multiple testing. PMPSs were also not associated with positive or negative symptom severity. That this SZ-derived PMPSs was elevated among SZ, but not BD participants, suggests that epigenome-wide methylation patterns associated with schizophrenia may represent distinct pathophysiology that is yet to be elucidated. Whether this PMPS may be associated with neuroanatomical or other biological endophenotypes relevant to SZ and/or BD remains to be determined.

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Epigenome-Wide Study of Brain DNA Methylation Among Opioid Users and Controls

10.1101/2020.11.10.377069 ◽

2020 ◽

Author(s):

Chang Shu ◽

David W. Sosnowski ◽

Ran Tao ◽

Amy Deep-Soboslay ◽

Joel E. Kleinman ◽

...

Keyword(s):

Dna Methylation ◽

Multiple Testing ◽

The United States ◽

Opioid Abuse ◽

Current Evidence ◽

Opioid Use ◽

Multiple Testing Correction ◽

Potential Biomarker ◽

Opioid Intoxication ◽

Opioid Users

AbstractOpioid abuse poses significant risk to individuals in the United States and epigenetic changes are a leading potential biomarker of abuse. Current evidence, however, is mostly limited to candidate gene analysis in whole blood. To clarify the association between opioid abuse and DNA methylation, we conducted an epigenome-wide analysis (EWAS) of DNA methylation in brains of individuals who died from opioid intoxication and controls. Tissue samples were extracted from the dorsolateral prefrontal cortex of 160 deceased individuals (Mage = 35.15, SD = 9.42 years; 62% male; 78% White). The samples included 73 individuals who died of opioid intoxication, 59 group-matched psychiatric controls, and 28 group-matched normal controls. EWAS was implemented using the Illumina Infinium MethylationEPIC BeadChip; analyses adjusted for sociodemographic characteristics, negative control and ancestry principal components, cellular composition, and surrogate variables. Epigenetic age was calculated using the Horvath and Levine clocks, and gene ontology (GO) analyses were performed. No CpG sites were epigenome-wide significant after multiple testing correction, but 13 sites reached nominal significance (p < 1.0 x 10-5). There was a significant association between opioid use and Levine phenotypic age (b = 2.24, se = 1.11, p = .045). Opioid users were approximately two years phenotypically older compared to controls. GO analyses revealed enriched pathways related to cell function and neuron differentiation, but no terms survived multiple testing correction. Results inform our understanding of the neurobiology of opioid use, and future research with larger samples across stages of opioid use will elucidate the complex genomics of opioid abuse.

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