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

2017 ◽  
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.

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

2020 ◽  
pp. 1-9
Author(s):  
Maja Popovic ◽  
Valentina Fiano ◽  
Elena Isaevska ◽  
Chiara Moccia ◽  
Morena Trevisan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Linear Regression ◽  
Pregnancy Outcomes ◽  
Positive Association ◽  
Absolute Difference ◽  
Chronological Age ◽  
Linear Regression Models ◽  
Epigenetic Age ◽  
Epigenetic Age Acceleration ◽  
Dna Methylation Age

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.

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

2019 ◽  
Vol 9 (1) ◽  
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.

scholarly journals Association of cardiovascular health and epigenetic age acceleration

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.

Accelerated Epigenetic Age in Normal Cognitive Aging of Korean Community-Dwelling Older Adults

2021 ◽  
pp. 109980042098389
Author(s):  
Jongmin Park ◽  
Chang Won Won ◽  
Leorey N. Saligan ◽  
Youn-Jung Kim ◽  
Yoonju Kim ◽  
...  
Keyword(s):  
Older Adults ◽  
Dna Methylation ◽  
Cognitive Function ◽  
Cognitive Aging ◽  
Community Dwelling ◽  
Test Results ◽  
Cohen’S D ◽  
Epigenetic Age ◽  
Epigenetic Age Acceleration ◽  
Community Dwelling Older Adults

Background: Epigenetic age acceleration has been studied as a promising biomarker of age-related conditions, including cognitive aging. This pilot study aims to explore potential cognitive aging-related biomarkers by investigating the relationship of epigenetic age acceleration and cognitive function and by examining the epigenetic age acceleration differences between successful cognitive aging (SCA) and normal cognitive aging (NCA) among Korean community-dwelling older adults (CDOAs). Methods: We used data and blood samples of Korean CDOAs from the Korean Frailty and Aging Cohort Study. The participants were classified into two groups, SCA (above the 50th percentile in all domains of cognitive function) and NCA. The genome-wide DNA methylation profiling array using Illumina Infinium MethylationEPIC BeadChip was used to calculate the following: the DNA methylation age, universal epigenetic age acceleration, intrinsic epigenetic age acceleration (IEAA), and extrinsic epigenetic age acceleration (EEAA). We also used Pearson correlation analysis and independent t-tests to analyze the data. Results: Universal age acceleration correlated with the Frontal Assessment Battery test results ( r = −0.42, p = 0.025); the EEAA correlated with the Word List Recognition test results ( r = −0.41, p = 0.027). There was a significant difference between SCA and NCA groups in IEAA ( p = 0.041, Cohen’s d = 0.82) and EEAA ( p = 0.042, Cohen’s d = 0.78). Conclusions: Epigenetic age acceleration can be used as a biomarker for early detection of cognitive decline in Korean community-dwelling older adults. Large longitudinal studies are warranted.

scholarly journals Epigenetic Age Acceleration and Hearing: Observations From the Baltimore Longitudinal Study of Aging

2021 ◽  
Vol 13 ◽  
Author(s):  
Pei-Lun Kuo ◽  
Ann Zenobia Moore ◽  
Frank R. Lin ◽  
Luigi Ferrucci
Keyword(s):  
Dna Methylation ◽  
Longitudinal Study ◽  
Smoking History ◽  
Future Research ◽  
Age Related ◽  
Epigenetic Age ◽  
Epigenetic Age Acceleration ◽  
Baltimore Longitudinal Study ◽  
Age Related Hearing Loss ◽  
The Relationship

Objectives: Age-related hearing loss (ARHL) is highly prevalent among older adults, but the potential mechanisms and predictive markers for ARHL are lacking. Epigenetic age acceleration has been shown to be predictive of many age-associated diseases and mortality. However, the association between epigenetic age acceleration and hearing remains unknown. Our study aims to investigate the relationship between epigenetic age acceleration and audiometric hearing in the Baltimore Longitudinal Study of Aging (BLSA).Methods: Participants with both DNA methylation and audiometric hearing measurements were included. The main independent variables are epigenetic age acceleration measures, including intrinsic epigenetic age acceleration—“IEAA,” Hannum age acceleration—“AgeAccelerationResidualHannum,” PhenoAge acceleration—“AgeAccelPheno,” GrimAge acceleration—“AgeAccelGrim,” and methylation-based pace of aging estimation—“DunedinPoAm.” The main dependent variable is speech-frequency pure tone average. Linear regression was used to assess the association between epigenetic age acceleration and hearing.Results: Among the 236 participants (52.5% female), after adjusting for age, sex, race, time difference between measurements, cardiovascular factors, and smoking history, the effect sizes were 0.11 995% CI: (–0.00, 0.23), p = 0.054] for Hannum’s clock, 0.08 [95% CI: (–0.03, 0.19), p = 0.143] for Horvath’s clock, 0.10 [95% CI: (–0.01, 0.21), p = 0.089] for PhenoAge, 0.20 [95% CI: (0.06, 0.33), p = 0.004] for GrimAge, and 0.21 [95% CI: (0.09, 0.33), p = 0.001] for DunedinPoAm.Discussion: The present study suggests that some epigenetic age acceleration measurements are associated with hearing. Future research is needed to study the potential subclinical cardiovascular causes of hearing and to investigate the longitudinal relationship between DNA methylation and hearing.

scholarly journals Epigenetic Clocks and Allostatic Load Reveal Potential Sex-Specific Drivers of Biological Aging

2019 ◽  
Author(s):  
Cathal McCrory ◽  
Giovanni Fiorito ◽  
Sinead McLoughlin ◽  
Silvia Polidoro ◽  
Cliona Ni Cheallaigh ◽  
...  
Keyword(s):  
Allostatic Load ◽  
Accelerated Aging ◽  
Community Dwelling ◽  
Biological Aging ◽  
Cross Sectional ◽  
Metabolic Dysregulation ◽  
Age Related ◽  
Epigenetic Age ◽  
Epigenetic Age Acceleration ◽  
Dna Methylation Age

Abstract Allostatic load (AL) and epigenetic clocks both attempt to characterize the accelerated aging of biological systems, but at present it is unclear whether these measures are complementary or distinct. This study examines the cross-sectional association of AL with epigenetic age acceleration (EAA) in a subsample of 490 community-dwelling older adults participating in The Irish Longitudinal study on Aging (TILDA). A battery of 14 biomarkers representing the activity of four different physiological systems: immunological, cardiovascular, metabolic, renal, was used to construct the AL score. DNA methylation age was computed according to the algorithms described by Horvath, Hannum, and Levine allowing for estimation of whether an individual is experiencing accelerated or decelerated aging. Horvath, Hannum, and Levine EAA correlated 0.05, 0.03, and 0.21 with AL, respectively. Disaggregation by sex revealed that AL was more strongly associated with EAA in men compared with women as assessed using Horvath’s clock. Metabolic dysregulation was a strong driver of EAA in men as assessed using Horvath and Levine’s clock, while metabolic and cardiovascular dysregulation were associated with EAA in women using Levine’s clock. Results indicate that AL and the epigenetic clocks are measuring different age-related variance and implicate sex-specific drivers of biological aging.

scholarly journals Intrinsic and extrinsic epigenetic age acceleration are associated with hypertensive target organ damage in older African Americans

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Jennifer A. Smith ◽  
Jeremy Raisky ◽  
Scott M. Ratliff ◽  
Jiaxuan Liu ◽  
Sharon L. R. Kardia ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Dna Methylation ◽  
African Americans ◽  
Target Organ Damage ◽  
Organ Damage ◽  
Left Ventricular ◽  
Effect Modification ◽  
Target Organ ◽  
Epigenetic Age ◽  
Epigenetic Age Acceleration

Abstract Background Epigenetic age acceleration, a measure of biological aging based on DNA methylation, is associated with cardiovascular mortality. However, little is known about its relationship with hypertensive target organ damage to the heart, kidneys, brain, and peripheral arteries. Methods We investigated associations between intrinsic (IEAA) or extrinsic (EEAA) epigenetic age acceleration, blood pressure, and six types of organ damage in a primarily hypertensive cohort of 1390 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. DNA methylation from peripheral blood leukocytes was collected at baseline (1996–2000), and measures of target organ damage were assessed in a follow-up visit (2000–2004). Linear regression with generalized estimating equations was used to test for associations between epigenetic age acceleration and target organ damage, as well as effect modification of epigenetic age by blood pressure or sex. Sequential Oligogenic Linkage Analysis Routines (SOLAR) was used to test for evidence of shared genetic and/or environmental effects between epigenetic age acceleration and organ damage pairs that were significantly associated. Results After adjustment for sex, chronological age, and time between methylation and organ damage measures, higher IEAA was associated with higher urine albumin to creatinine ratio (UACR, p = 0.004), relative wall thickness (RWT, p = 0.022), and left ventricular mass index (LVMI, p = 0.007), and with lower ankle-brachial index (ABI, p = 0.014). EEAA was associated with higher LVMI (p = 0.005). Target organ damage associations for all but IEAA with LVMI remained significant after further adjustment for blood pressure and antihypertensive use (p < 0.05). Further adjustment for diabetes attenuated the IEAA associations with UACR and RWT, and adjustment for smoking attenuated the IEAA association with ABI. No effect modification by age or sex was observed. Conclusions Measures of epigenetic age acceleration may help to better characterize the functional mechanisms underlying organ damage from cellular aging and/or hypertension. These measures may act as subclinical biomarkers for damage to the kidney, heart, and peripheral vasculature; however more research is needed to determine whether these relationships remain independent of lifestyle factors and comorbidities.

scholarly journals Reproductive history and blood cell DNA methylation later in life: the Young Finns Study

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Emily W. Harville ◽  
Pashupati P. Mishra ◽  
Mika Kähönen ◽  
Emma Raitoharju ◽  
Saara Marttila ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Reproductive History ◽  
Hypertensive Disorders Of Pregnancy ◽  
Birth Registry ◽  
Hypertensive Disorders ◽  
Epigenetic Age ◽  
Epigenetic Age Acceleration ◽  
Epigenetic Methylation ◽  
History Of ◽  
Young Finns Study

Abstract Background Women with a history of complications of pregnancy, including hypertensive disorders, gestational diabetes or an infant fetal growth restriction or preterm birth, are at higher risk for cardiovascular disease later in life. We aimed to examine differences in maternal DNA methylation following pregnancy complications. Methods Data on women participating in the Young Finns study (n = 836) were linked to the national birth registry. DNA methylation in whole blood was assessed using the Infinium Methylation EPIC BeadChip. Epigenome-wide analysis was conducted on differential CpG methylation at 850 K sites. Reproductive history was also modeled as a predictor of four epigenetic age indices. Results Fourteen significant differentially methylated sites were found associated with both history of pre-eclampsia and overall hypertensive disorders of pregnancy. No associations were found between reproductive history and any epigenetic age acceleration measure. Conclusions Differences in epigenetic methylation profiles could represent pre-existing risk factors, or changes that occurred as a result of experiencing these complications.

scholarly journals Alcohol consumption and methylation-based measures of biological age

2021 ◽  
Author(s):  
Jacob K Kresovich ◽  
Alexandra M Martinez Lopez ◽  
Emma L Garval ◽  
Zongli Xu ◽  
Alexandra J White ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Alcohol Consumption ◽  
Biological Age ◽  
Average Lifetime ◽  
Epigenetic Clock ◽  
Genome Wide ◽  
Epigenetic Age ◽  
Epigenetic Age Acceleration ◽  
The Mean ◽  
Average Consumption

Abstract Epigenetic age acceleration is considered a measure of biological aging based on genome-wide patterns of DNA methylation. Although age acceleration has been associated with incidence of diseases and death, less is known about how it is related to lifestyle behaviors. Among 2,316 women, we evaluate associations between self-reported alcohol consumption and various metrics of epigenetic age acceleration. Recent average alcohol consumption was defined as the mean number of drinks consumed per week within the past year; lifetime average consumption was estimated as the mean number of drinks per year drinking. Whole blood genome-wide DNA methylation was measured with HumanMethylation450 BeadChips and used to assess four epigenetic clocks (Hannum, Horvath, PhenoAge, GrimAge) and their corresponding metrics of epigenetic age acceleration (Hannum AgeAccel, Horvath AgeAccel, PhenoAgeAccel, GrimAgeAccel). Although alcohol consumption showed little association with most age acceleration metrics, both lifetime and recent average consumption measures were positively associated with GrimAgeAccel (lifetime, per additional 135 drinks/year: β=0.30 years, 95% CI: 0.11, 0.48, p=0.002; recent, per additional 5 drinks/week: β=0.19 years, 95% CI: 0.01, 0.37, p=0.04). In a mutually adjusted model, only average lifetime alcohol consumption remained associated with GrimAgeAccel (lifetime, per additional 135 drinks/year: β=0.27 years, 95% CI: 0.04, 0.50, p=0.02; recent, per 5 additional drinks/week: β=0.05 years, 95% CI: -0.16, 0.26, p=0.64). Although alcohol use does not appear to be strongly associated with biological age measured by most epigenetic clocks, lifetime average consumption is associated with higher biological age assessed by the GrimAge epigenetic clock.

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