Determination of saliva epigenetic age in infancy, and its association with parental socio-economic characteristics and pregnancy outcomes

Abstract Epigenetic age acceleration (AA) has been associated with adverse environmental exposures and many chronic conditions. We estimated, in the NINFEA birth cohort, infant saliva epigenetic age, and investigated whether parental socio-economic position (SEP) and pregnancy outcomes are associated with infant epigenetic AA. A total of 139 saliva samples collected at on average 10.8 (range 7–17) months were used to estimate Horvath’s DNA methylation age. Epigenetic AA was defined as the residual from a linear regression of epigenetic age on chronological age. Linear regression models were used to test the associations of parental SEP and pregnancy outcomes with saliva epigenetic AA. A moderate positive association was found between DNA methylation age and chronological age, with the median absolute difference of 6.8 months (standard deviation [SD] 3.9). The evidence of the association between the indicators of low SEP and epigenetic AA was weak; infants born to unemployed mothers or with low education had on average 1 month higher epigenetic age than infants of mothers with high education and employment (coefficient 0.78 months, 95% confidence intervals [CIs]: −0.79 to 2.34 for low/medium education; 0.96, 95% CI: −1.81 to 3.73 for unemployment). There was no evidence for association of gestational age, birthweight or caesarean section with infant epigenetic AA. Using the Horvath’s method, DNA methylation age can be fairly accurately predicted from saliva samples already in the first months of life. This study did not reveal clear associations between either pregnancy outcomes or parental socio-economic characteristics and infant saliva epigenetic AA.

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Epigenetic Age Acceleration of Stomach Adenocarcinoma Associated With Tumor Stemness Features, Immunoactivation, and Favorable Prognosis

Frontiers in Genetics ◽

10.3389/fgene.2021.563051 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chunhong Hong ◽

Shaohua Yang ◽

Qiaojin Wang ◽

Shiqiang Zhang ◽

Wenhui Wu ◽

...

Keyword(s):

Dna Methylation ◽

Correlation Analysis ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Chronological Age ◽

Favorable Prognosis ◽

Molecular Features ◽

Epigenetic Age ◽

Epigenetic Age Acceleration ◽

Stomach Adenocarcinoma

Background: Abnormal DNA methylation (DNAm) age has been assumed to be an indicator for canceration and all-cause mortality. However, associations between DNAm age and molecular features of stomach adenocarcinoma (STAD), and its prognosis have not been systematically studied.Method: We calculated the DNAm age of 591 STAD samples and 115 normal stomach samples from The Cancer Genome Atlas (TCGA) and gene expression omnibus (GEO) database using the Horvath’s clock model. Meanwhile, we utilized survival analysis to evaluate the prognostic value of DNAm age and epigenetic age acceleration shift. In addition, we performed weighted gene co-expression network analysis (WGCNA) to identify DNAm age-associated gene modules and pathways. Finally, the association between DNAm age and molecular features was performed by correlation analysis.Results: DNA methylation age was significantly correlated with chronological age in normal gastric tissues (r = 0.85, p < 0.0001), but it was not associated with chronological age in STAD samples (r = 0.060, p = 0.2369). Compared with tumor adjacent normal tissue, the DNAm age of STAD tissues was significantly decreased. Meanwhile, chronological age in STAD samples was higher than its DNAm age. Both DNAm age and epigenetic acceleration shift were associated with the prognosis of STAD patients. By using correlation analysis, we also found that DNAm age was associated with immunoactivation and stemness in STAD samples.Conclusion: In summary, epigenetic age acceleration of STAD was associated with tumor stemness, immunoactivation, and favorable prognosis.

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Different epigenetic clocks reflect distinct pathophysiological features of multiple sclerosis

Epigenomics ◽

10.2217/epi-2019-0102 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1429-1439 ◽

Cited By ~ 1

Author(s):

Eleftheria Theodoropoulou ◽

Lars Alfredsson ◽

Fredrik Piehl ◽

Francesco Marabita ◽

Maja Jagodic

Keyword(s):

Multiple Sclerosis ◽

Dna Methylation ◽

Positive Association ◽

Cell Types ◽

Gene Expression Omnibus ◽

Methylation Data ◽

Accession Number ◽

Age Related ◽

Epigenetic Age ◽

Epigenetic Age Acceleration

Aim: Accumulating evidence links epigenetic age to diseases and age-related conditions, but little is known about its association with multiple sclerosis (MS). Materials & methods: We estimated epigenetic age acceleration measures using DNA methylation from blood or sorted cells of MS patients and controls. Results: In blood, sex (p = 4.39E-05) and MS (p = 2.99E-03) explained the variation in age acceleration, and isolated blood cell types showed different epigenetic age. Intrinsic epigenetic age acceleration and extrinsic epigenetic age acceleration were only associated with sex (p = 2.52E-03 and p = 1.58E-04, respectively), while PhenoAge Acceleration displayed positive association with MS (p = 3.40E-02). Conclusion: Different age acceleration measures are distinctly influenced by phenotypic factors, and they might measure separate pathophysiological aspects of MS. Data deposition: DNA methylation data can be accessed at Gene Expression Omnibus database under accession number GSE35069, GSE43976, GSE106648, GSE130029, GSE130030.

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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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GWAS of epigenetic ageing rates in blood reveals a critical role forTERT

10.1101/157776 ◽

2017 ◽

Cited By ~ 1

Author(s):

Ake T. Lu ◽

Luting Xue ◽

Elias L. Salfati ◽

Brian H. Chen ◽

Luigi Ferrucci ◽

...

Keyword(s):

Dna Methylation ◽

Molecular Mechanisms ◽

Genome Wide Association Study ◽

Human Fibroblasts ◽

Critical Role ◽

Population Doubling ◽

Gene Variants ◽

Epigenetic Age ◽

Epigenetic Age Acceleration ◽

Dna Methylation Age

AbstractDNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9,907 individuals, we found gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in 3 loci associated extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggested causal influences of menarche and menopause on IEAA and lipid levels on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) locus at 5p15.33 confer higher IEAA (P<2.7×10-11). Causal modelling indicatesTERT-specific and independent effects on LTL and IEAA. Experimental hTERT expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the DNA methylation clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.

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A comparison of blood and brain-derived ageing and inflammation-related DNA methylation signatures and their association with microglial burdens

10.1101/2020.11.30.404228 ◽

2020 ◽

Author(s):

Anna J. Stevenson ◽

Daniel L. McCartney ◽

Gemma L. Shireby ◽

Robert F. Hillary ◽

Declan King ◽

...

Keyword(s):

Dna Methylation ◽

Positive Association ◽

Brain Regions ◽

Preliminary Evidence ◽

Epigenetic Clock ◽

Significant Positive Association ◽

Epigenetic Age ◽

Lothian Birth Cohort ◽

Epigenetic Age Acceleration ◽

The Brain

AbstractInflammation and ageing-related DNA methylation patterns in the blood have been linked to a variety of morbidities, including cognitive decline and neurodegenerative disease. However, it is unclear how these blood-based patterns relate to patterns within the brain, and how each associates with central cellular profiles. In this study, we profiled DNA methylation in both the blood and in five post-mortem brain regions (BA17, BA20/21, BA24, BA46 and hippocampus) in 14 individuals from the Lothian Birth Cohort 1936. Microglial burdens were additionally quantified in the same brain regions. DNA methylation signatures of five epigenetic ageing biomarkers (‘epigenetic clocks’), and two inflammatory biomarkers (DNA methylation proxies for C-reactive protein and interleukin-6) were compared across tissues and regions. Divergent correlations between the inflammation and ageing signatures in the blood and brain were identified, depending on region assessed. Four out of the five assessed epigenetic age acceleration measures were found to be highest in the hippocampus (β range=0.83-1.14, p≤0.02). The inflammation-related DNA methylation signatures showed no clear variation across brain regions. Reactive microglial burdens were found to be highest in the hippocampus (β=1.32, p=5×10-4); however, the only association identified between the blood- and brain-based methylation signatures and microglia was a significant positive association with acceleration of one epigenetic clock (termed DNAm PhenoAge) averaged over all five brain regions (β=0.40, p=0.002). This work highlights a potential vulnerability of the hippocampus to epigenetic ageing and provides preliminary evidence of a relationship between DNA methylation signatures in the brain and differences in microglial burdens.

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Acceleration in the DNA methylation age in breast cancer tumours from very young women

Scientific Reports ◽

10.1038/s41598-019-51457-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Sara S. Oltra ◽

Maria Peña-Chilet ◽

Kirsty Flower ◽

María Teresa Martinez ◽

Elisa Alonso ◽

...

Keyword(s):

Breast Cancer ◽

Dna Methylation ◽

Older Women ◽

Young Women ◽

Cell Communication ◽

Neuronal System ◽

Open Sea ◽

Epigenetic Age ◽

Epigenetic Age Acceleration ◽

Dna Methylation Age

Abstract Breast cancer in very young women (≤35 years; BCVY) presents more aggressive and complex biological features than their older counterparts (BCO). Our aim was to evaluate methylation differences between BCVY and BCO and their DNA epigenetic age. EPIC and 450k Illumina methylation arrays were used in 67 breast cancer tumours, including 32 from BCVY, for methylation study and additionally we analysed their epigenetic age. We identified 2 219 CpG sites differently-methylated in BCVY vs. BCO (FDR < 0.05; β-value difference ± 0.1). The signature showed a general hypomethylation profile with a selective small hypermethylation profile located in open-sea regions in BCVY against BCO and normal tissue. Strikingly, BCVY presented a significant increased epigenetic age-acceleration compared with older women. The affected genes were enriched for pathways in neuronal-system pathways, cell communication, and matrix organisation. Validation in an independent sample highlighted consistent higher expression of HOXD9, and PCDH10 genes in BCVY. Regions implicated in the hypermethylation profile were involved in Notch signalling pathways, the immune system or DNA repair. We further validated HDAC5 expression in BCVY. We have identified a DNA methylation signature that is specific to BCVY and have shown that epigenetic age-acceleration is increased in BCVY.

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Shift work, DNA methylation and epigenetic age

International Journal of Epidemiology ◽

10.1093/ije/dyz027 ◽

2019 ◽

Vol 48 (5) ◽

pp. 1536-1544 ◽

Cited By ~ 9

Author(s):

Alexandra J White ◽

Jacob K Kresovich ◽

Zongli Xu ◽

Dale P Sandler ◽

Jack A Taylor

Keyword(s):

Dna Methylation ◽

Linear Regression ◽

Association Study ◽

Shift Work ◽

Night Shift ◽

Night Shift Work ◽

Age Related ◽

Epigenetic Age ◽

Increased Risk ◽

Epigenetic Age Acceleration

Abstract Background Shift work has been associated with increased risk of age-related morbidity and mortality. Biological age, estimated using DNA methylation (DNAm), may quantify the biological consequences of shift work on the risk of age-related disease. We examined whether prior employment in shift-working occupations was associated with epigenetic age acceleration. Methods In a sample of non-Hispanic White women aged 35–74 (n = 2574), we measured DNAm using the Illumina Infinium Human450 BeadChip and calculated DNAm age using three established epigenetic clocks. Age-acceleration metrics were derived by regressing DNAm age on chronological age and predicting the residuals. Using linear regression, we estimated associations between shift work history and age acceleration. We also conducted an epigenome-wide association study using robust linear-regression models corrected with false discovery rate (FDR) q-values. Results Approximately 7% of women reported any shift work. Higher age acceleration was observed for a 1-year increase in overall [β = 0.11, 95% confidence interval (CI): 0.02–0.21] and night-specific shift work (β = 0.12, 95% CI: 0.03–0.21). The association was strongest for ≥10 years of night shift work (β = 3.16, 95% CI: 1.17–5.15). From the epigenome-wide association study, years of overall and night shift work were associated with DNAm at 66 and 85 CpG sites (FDR < 0.05), respectively. Years of night shift work was associated with lower methylation of a CpG in the gene body of ZFHX3 (cg04994202, q = 0.04), a gene related to circadian rhythm. Conclusions Shift work was associated with differential CpG site methylation and with differential DNAm patterns, measured by epigenetic age acceleration, consistent with long-term negative health effects.

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Associations Between Blood Pressure and Accelerated DNA Methylation Aging

Journal of the American Heart Association ◽

10.1161/jaha.121.022257 ◽

2022 ◽

Author(s):

Lili Xiao ◽

Gaohui Zan ◽

Chaoqun Liu ◽

Xia Xu ◽

Longman Li ◽

...

Keyword(s):

Blood Pressure ◽

Dna Methylation ◽

Systolic Blood Pressure ◽

Pulse Pressure ◽

Chronological Age ◽

Cross Sectional ◽

High Systolic Blood Pressure ◽

Aging Rate ◽

Epigenetic Age ◽

Epigenetic Age Acceleration

Background Individuals of the same chronological age may exhibit diverse susceptibilities to death. However, few studies have investigated the associations between blood pressure and the accelerated aging. Methods and Results A cross‐sectional study was conducted in 288 adults aged ≥50 years. We assessed the DNA methylation‐based measures of biological age using CpG sites on the Illumina HumanMethylationEPIC BeadChip. Epigenetic age acceleration metrics were derived by regressing residuals (ΔAge) and ratios (aging rate) of DNA methylation age on chronological age. Dose‐response relationships between blood pressure and epigenetic age acceleration were quantified using multiple linear regression and restricted cubic regression models. We found that each 10–mm Hg increase in systolic blood pressure was associated with 0.608 (95% CI, 0.231–0.984) years increase in ΔAge and 0.007 (95% CI, 0.002–0.012) increase in aging rate; meanwhile, for pulse pressure, the increase was 1.12 (95% CI, 0.625–1.61) years for ΔAge and 0.013 (95% CI, 0.007–0.020) for aging rate. Subgroup analysis showed that the significant associations of systolic blood pressure and pulse pressure with epigenetic age acceleration appeared to be limited to women, although interactions between blood pressure and sex were not significant ( P values for interaction >0.05). The combination of women and hypertension was associated with a much higher increase in ΔAge (β [95% CI], 4.05 [1.07–7.02]) and aging rate (β [95% CI], 0.047 [0.008–0.087]), compared with male participants without hypertension. Conclusions Our findings suggested that high systolic blood pressure and pulse pressure were associated with the epigenetic age acceleration, providing important clues for relationships between blood pressure and epigenetic aging.

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Abstract P106: Epigenetic Age Acceleration and Postprandial Lipemia in the Genetics of Lipid Lowering Drugs and Diet Network Study

Circulation ◽

10.1161/circ.135.suppl_1.p106 ◽

2017 ◽

Vol 135 (suppl_1) ◽

Author(s):

Marguerite R Irvin ◽

Bertha Hidalgo ◽

Degui Zhi ◽

Stella Aslibekyan ◽

Hemant K Tiwari ◽

...

Keyword(s):

Dna Methylation ◽

T Cell ◽

Density Lipoprotein ◽

Lipid Lowering ◽

Chronological Age ◽

Lipid Levels ◽

Lipid Lowering Drugs ◽

Epigenetic Aging ◽

Epigenetic Age ◽

Epigenetic Age Acceleration

Background: Calculated ‘epigenetic age,’ a novel biomarker based on DNA methylation levels of 353 CpGs, has been demonstrated to accurately predict chronological age across a broad spectrum of tissues and cell types. Recently epigenetic age acceleration or older epigenetic age in comparison to chronological age has been robustly associated with all-cause mortality independent of chronological age in multiple human cohorts. However, accelerated epigenetic aging has not been associated with lipids levels, including postprandial lipid levels which are linked to prothrombotic and proinflammatory processes that may precipitate aging. In the current study we aimed to evaluate the association between epigenetic age acceleration and lipid levels. Methods: We used the Horvath DNA methylation age calculator to estimate epigenetic age in 988 Caucasian participants from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) using Illumina Infinium HumanMethylation450 BeadChip array data derived from CD4+ T-cell DNA. GOLDN participants did not take lipid lowering drugs for at least four weeks prior to enrollment and underwent a standardized high fat meal challenge after fasting for at least 8 hours followed by timed blood draws at 3.5 and 6 hours following the meal. Epigenetic age acceleration was calculated as the residual from regressing methylation age on chronological age. We used linear mixed models to examine the association of age acceleration quartiles with fasting and postrandial (3.5 and 6 hour time points) low density lipoprotein (LDL), high density lipoprotein (HDL) and triglyceride (TG) levels after adjusting for age, study site, sex, fasting lipid level (if applicable), deconvolution estimated T-cell type percentages and a random effect of family relationship. Results: The correlation between calculated methylation age and chronological age was 0.91. The difference between methylation age and chronological age (methylation age - chronological age) was on average -5.8 (5.9), -0.5 (4.7), 2.9 (4.3), and 7.8 (5.0) years for the first through fourth quartiles of age acceleration, respectively. After adjustment for covariates neither fasting nor postprandial lipids were associated with age acceleration quartile. Conclusions: Evidence from the current study suggests lipid levels in the fasting and postprandial state are not related to accelerated epigenetic aging, however given the association between epigenetic age acceleration and mortality observed in previous studies the relationship of other metabolic parameters with age acceleration may be worthy of investigation.

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Association of cardiovascular health and epigenetic age acceleration

Clinical Epigenetics ◽

10.1186/s13148-021-01028-2 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Tess D. Pottinger ◽

Sadiya S. Khan ◽

Yinan Zheng ◽

Wei Zhang ◽

Hilary A. Tindle ◽

...

Keyword(s):

Dna Methylation ◽

Cardiovascular Health ◽

Heart Association ◽

The United States ◽

Cross Sectional ◽

Epigenetic Age ◽

Younger Age ◽

Cardiovascular Morbidity And Mortality ◽

Epigenetic Age Acceleration ◽

Linear Regression Modeling

Abstract Background Cardiovascular health (CVH) has been defined by the American Heart Association (AHA) as the presence of the “Life’s Simple 7” ideal lifestyle and clinical factors. CVH is known to predict longevity and freedom from cardiovascular disease, the leading cause of death for women in the United States. DNA methylation markers of aging have been aggregated into a composite epigenetic age score, which is associated with cardiovascular morbidity and mortality. However, it is unknown whether poor CVH is associated with acceleration of aging as measured by DNA methylation markers in epigenetic age. Methods and results We performed a cross-sectional analysis of racially/ethnically diverse post-menopausal women enrolled in the Women’s Health Initiative cohort recruited between 1993 and 1998. Epigenetic age acceleration (EAA) was calculated using DNA methylation data on a subset of participants and the published Horvath and Hannum methods for intrinsic and extrinsic EAA. CVH was calculated using the AHA measures of CVH contributing to a 7-point score. We examined the association between CVH score and EAA using linear regression modeling adjusting for self-reported race/ethnicity and education. Among the 2,170 participants analyzed, 50% were white and mean age was 64 (7 SD) years. Higher or more favorable CVH scores were associated with lower extrinsic EAA (~ 6 months younger age per 1 point higher CVH score, p < 0.0001), and lower intrinsic EAA (3 months younger age per 1 point higher CVH score, p < 0.028). Conclusions These cross-sectional observations suggest a possible mechanism by which ideal CVH is associated with greater longevity.

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