DNA Methylomes and Epigenetic Age Acceleration Associations with Poor Metabolic Control in T1D.
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SUBMITTER: Perez RF
PROVIDER: S-EPMC7824441 | biostudies-literature | 2020 Dec
REPOSITORIES: biostudies-literature
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DNA Methylomes and Epigenetic Age Acceleration Associations with Poor Metabolic Control in T1D.
Pérez Raúl F RF Fernandez-Morera Juan Luis JL Romano-Garcia Judit J Menendez-Torre Edelmiro E Delgado-Alvarez Elias E Fraga Mario F MF Fernandez Agustin F AF
Biomedicines 20201224 1
Type 1 diabetes (T1D) is an autoimmune disease that leads to insulin deficiency and hyperglycemia. Little is known about how this metabolic dysfunction, which substantially alters the internal environment, forces cells to adapt through epigenetic mechanisms. Consequently, the purpose of this work was to study what changes occur in the epigenome of T1D patients after the onset of disease and in the context of poor metabolic control. We performed a genome-wide analysis of DNA methylation patterns ...[more]
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Project description:Study questionIs the use of ART, a proxy for infertility, associated with epigenetic age acceleration?Summary answerThe epigenetic age acceleration measured by Dunedin Pace of Aging methylation (DunedinPoAm) differed significantly between non-ART and ART mothers.What is known alreadyAmong mothers who used ART, epigenetic age acceleration may be associated with low oocyte yield and poor ovarian response. However, the difference in epigenetic age acceleration between non-ART and ART mothers (or even fathers) has not been examined.Study design, size, durationThe Norwegian Mother, Father and Child Cohort Study (MoBa) recruited pregnant women and their partners across Norway at around 18 gestational weeks between 1999 and 2008. Approximately 95 000 mothers, 75 000 fathers and 114 000 children were included. Peripheral blood samples were taken from mothers and fathers at ultrasound appointments or from mothers at childbirth, and umbilical cord blood samples were collected from the newborns at birth.Participants/materials, setting, methodsAmong the MoBa participants, we selected 1000 couples who conceived by coitus and 894 couples who conceived by IVF (n = 525) or ICSI (n = 369). We measured their DNA methylation (DNAm) levels using the Illumina MethylationEPIC array and calculated epigenetic age acceleration. A linear mixed model was used to examine the differences in five different epigenetic age accelerations between non-ART and ART parents.Main results and the role of chanceWe found a significant difference in the epigenetic age acceleration calculated by DunedinPoAm between IVF and non-ART mothers (0.021 years, P-value = 2.89E-06) after adjustment for potential confounders. Further, we detected elevated DunedinPoAm in mothers with tubal factor infertility (0.030 years, P-value = 1.34E-05), ovulation factor (0.023 years, P-value = 0.0018) and unexplained infertility (0.023 years, P-value = 1.39E-04) compared with non-ART mothers. No differences in epigenetic age accelerations between non-ART and ICSI fathers were found. DunedinPoAm also showed stronger associations with smoking, education and parity than the other four epigenetic age accelerations.Limitations, reasons for cautionWe were not able to determine the directionality of the causal pathway between the epigenetic age accelerations and infertility. Since parents' peripheral blood samples were collected after conception, we cannot rule out the possibility that the epigenetic profile of ART mothers was influenced by the ART treatment. Hence, the results should be interpreted with caution, and our results might not be generalizable to non-pregnant women.Wider implications of the findingsA plausible biological mechanism behind the reported association is that IVF mothers could be closer to menopause than non-ART mothers. The pace of decline of the ovarian reserve that eventually leads to menopause varies between females yet, in general, accelerates after the age of 30, and some studies show an increased risk of infertility in females with low ovarian reserve.Study funding/competing interest(s)This study was partly funded by the Research Council of Norway (Women's fertility, project no. 320656) and through its Centres of Excellence Funding Scheme (project no. 262700). M.C.M. has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement number 947684). The authors declare no conflict of interest.Trial registration numberN/A.
| S-EPMC9433848 | biostudies-literature
Project description:DNA methylation-derived epigenetic clocks offer the opportunity to examine aspects of age acceleration (ie, the difference between an individual's biological age and chronological age), which vary among individuals and may better account for age-related changes in cognitive function than chronological age. Leveraging existing ambulatory cognitive assessments in daily life from a genetically diverse sample of 142 adults in midlife, we examined associations between 5 measures of epigenetic age acceleration and performance on tasks of processing speed and working memory. Covarying for chronological age, we used multilevel models to examine associations of epigenetic age acceleration (Horvath 1, Horvath 2, Hannum, PhenoAge, and GrimAge clocks) with both average level and variability of cognitive performance. Positive age acceleration (ie, epigenetic age greater than chronological age) was associated with poorer mean processing speed (Horvath 1 and 2) and working memory (GrimAge). Higher chronological age was also associated with poorer mean processing speed and working memory performance. Further, positive age acceleration was generally associated with greater intraindividual variability in working memory and processing speed tasks, whereas being chronologically older was associated with less intraindividual variability. Although further work is needed, our results indicate age acceleration effects have comparable or greater size as those for chronological age differences, suggesting that epigenetic age acceleration may account for additional risk and interindividual variation in cognitive performance above chronological age.
| S-EPMC10733172 | biostudies-literature
Project description:IntroductionPrior studies have shown inconsistent findings of an association between depression and epigenetic aging. DNA methylation (DNAm) age acceleration can measure biological aging. We adopted a robust co-twin control study design to examine whether depression is associated with DNAm age acceleration after accounting for the potential confounding influences of genetics and family environment.MethodsWe analyzed data on a sub-cohort of the Vietnam Era Twin Registry. A total of 291 twins participated at baseline and 177 at follow-up visit after a mean of 11.7 years, with 111 participants having DNA samples for both time points. Depression was measured using the Beck Depression Inventory II (BDI-II). Six measures of DNAm age acceleration were computed at each time point, including Horvath's DNAm age acceleration (HorvathAA), intrinsic epigenetic age acceleration (IEAA), Hannum's DNAm age acceleration (HannumAA), extrinsic epigenetic age acceleration (EEAA), GrimAge acceleration (GrimAA), and PhenoAge acceleration (PhenoAA). Mixed-effects modeling was used to assess the within-pair association between depression and DNAm age acceleration.ResultsAt baseline, a 10-unit higher BDI-II total score was associated with HannumAA (0.73 years, 95% confidence interval [CI] 0.13-1.33, p = .019) and EEAA (0.94 years, 95% CI 0.22-1.66, p = .012). At follow-up, 10-unit higher BDI-II score was associated with PhenoAA (1.32 years, 95% CI 0.18-2.47, p = .027).ConclusionWe identified that depression is associated with higher levels of DNAm age acceleration. Further investigation is warranted to better understand the underlying mechanisms for the potential causal relationship between depression and accelerated aging.
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Project description:Early life is seen as a particularly sensitive period for environmental exposures. Natural space exposure during pregnancy has been associated with offspring health. Epigenetic gestational age acceleration, a discrepancy between clinical and DNA methylation-based gestational age, may underlie these associations. In 1359 mother-newborn pairs from the population-based Generation R Study, we examined the associations of natural space exposure, defined as surrounding greenness, distance to major green and blue (water) space, and size of the blue space during pregnancy with offspring epigenetic gestational age acceleration. Natural space exposure was based on participants' geocoded addresses, and epigenetic gestational age acceleration was calculated from cord blood DNA methylation using Bohlin's and Knight's epigenetic clocks. Sensitivity analyses were conducted in a subgroup of newborns with optimal pregnancy dating, based on last menstrual period. Surrounding greenness, measured in normalized difference vegetation index values, was intermediate (median 0.4, IQR 0.2), and 84% and 56% of the participants had a major green or blue space near their home address, respectively. We did not observe associations of natural space availability during pregnancy with offspring epigenetic gestational age acceleration. This could imply that epigenetic gestational age acceleration in cord blood does not underlie the effects of residential natural space availability in pregnancy on offspring health. Future studies could investigate whether residential natural space availability during pregnancy is associated with offspring differential DNA methylation at other CpGs than those included in the epigenetic gestational clocks.
| S-EPMC9980449 | biostudies-literature
Project description:BackgroundDNA methylation may play a role in the progression from normative to problematic drinking and underlie adverse health outcomes associated with alcohol misuse. We examined the association between alcohol consumption and DNA methylation patterns using 3 approaches: a conventional epigenome-wide association study (EWAS); a co-twin comparison design, which controls for genetic and environmental influences that twins share; and a regression of age acceleration, defined as a discrepancy between chronological age and DNA methylation age, on alcohol consumption.MethodsParticipants came from the Finnish Twin Cohorts (FinnTwin12/FinnTwin16; N = 1,004; 55% female; average age = 23 years). Individuals reported the number of alcoholic beverages consumed in the past week, and epigenome-wide DNA methylation was assessed in whole blood using the Infinium HumanMethylation450 BeadChip.ResultsIn the EWAS, alcohol consumption was significantly related to methylation at 24 CpG sites. When evaluating whether differences between twin siblings (185 monozygotic pairs) in alcohol consumption predicted differences in DNA methylation, co-twin comparisons replicated 4 CpG sites from the EWAS and identified 23 additional sites. However, when we examined qualitative differences in drinking patterns between twins (heavy drinker vs. light drinker/abstainer or moderate drinker vs. abstainer; 44 pairs), methylation patterns did not significantly differ within twin pairs. Finally, individuals who reported higher alcohol consumption also exhibited greater age acceleration, though results were no longer significant after controlling for genetic and environmental influences shared by co-twins.ConclusionsOur analyses offer insight into the associations between epigenetic variation and levels of alcohol consumption in young adulthood.
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Project description:Epigenetic clocks use DNA methylation to estimate biological age. Whether body composition and physical activity are associated with these clocks is not well understood. Using blood samples collected at enrollment (2003-2009) from 2,758 women in the US nationwide Sister Study, we calculated 6 epigenetic age acceleration metrics using 4 epigenetic clocks (Hannum, Horvath, PhenoAge, GrimAge). Recreational physical activity was self-reported, and adiposity measures were assessed by trained medical examiners (body mass index (BMI), waist-to-hip ratio (WtH), waist circumference). In cross-sectional analyses, all adiposity measures were associated with epigenetic age acceleration. The strongest association was for BMI and PhenoAge, a measure of biological age that correlates with chronic disease (BMI of ≥35.0 vs. 18.5-24.9, β = 3.15 years, 95% confidence interval (CI): 2.41, 3.90; P for trend < 0.001). In a mutual-adjustment model, both were associated with PhenoAge age acceleration (BMI of ≥35.0 vs. 18.5-24.9, β = 2.69 years, 95% CI: 1.90, 3.48; P for trend < 0.001; quartile 4 vs.1 WtH, β = 1.00 years, 95% CI: 0.34, 1.65; P for trend < 0.008). After adjustment, physical activity was associated only with GrimAge (quartile 4 vs. 1, β = -0.42 years, 95% CI: -0.70, -0.14; P for trend = 0.001). Physical activity attenuated the waist circumference associations with PhenoAge and GrimAge. Excess adiposity was associated with epigenetic age acceleration; physical activity might attenuate associations with waist circumference.
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Project description:Recent studies have identified biomarkers of chronological age based on DNA methylation levels. Since active smoking contributes to a wide spectrum of aging-related diseases in adults, this study intended to examine whether active smoking exposure could accelerate the DNA methylation age in forms of age acceleration (AA, residuals of the DNA methylation age estimate regressed on chronological age). We obtained the DNA methylation profiles in whole blood samples by Illumina Infinium Human Methylation450 Beadchip array in two independent subsamples of the ESTHER study and calculated their DNA methylation ages by two recently proposed algorithms. None of the self-reported smoking indicators (smoking status, cumulative exposure and smoking cessation time) or serum cotinine levels was significantly associated with AA. On the contrary, we successfully confirmed that 66 out of 150 smoking-related CpG sites were associated with AA, even after correction for multiple testing (FDR <0.05). We further built a smoking index (SI) based on these loci and demonstrated a monotonic dose-response relationship of this index with AA. In conclusion, DNA methylation-based biological indicators for current and past smoking exposure, but not self-reported smoking information or serum cotinine levels, were found to be related to DNA methylation defined AA. Further research should address potential mechanisms underlying the observed patterns, such as potential reflections of susceptibility to environmental hazards in both smoking related methylation changes and methylation defined AA.
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Project description:Schizophrenia is a serious neuropsychiatric disorder with abnormal age-related neurodevelopmental (or neurodegenerative) trajectories. Although an accelerated aging hypothesis of schizophrenia has been proposed, the quantitative study of the disruption of the physiological trajectory caused by schizophrenia is inconclusive. In this study, we employed 3 "epigenetic clock" methods to quantify the epigenetic age of a large sample size of whole blood (1069 samples from patients with schizophrenia vs 1264 samples from unaffected controls) and brain tissues (500 samples from patients with schizophrenia vs 711 samples from unaffected controls). We observed significant positive correlations between epigenetic age and chronological age in both blood and brain tissues from unaffected controls and patients with schizophrenia, as estimated by 3 methods. Furthermore, we observed that epigenetic age acceleration was significantly delayed in schizophrenia from the whole blood samples (aged 20-90 years) and brain frontal cortex tissues (aged 20-39 years). Intriguingly, the genes regulated by the epigenetic clock also contained schizophrenia-associated genes, displaying differential expression and methylation in patients with schizophrenia and involving in the regulation of cell activation and development. These findings were further supported by the dysregulated leukocyte composition in patients with schizophrenia. Our study presents quantitative evidence for a neurodevelopmental model of schizophrenia from the perspective of a skewed "epigenetic clock." Moreover, landmark changes in an easily accessible biological sample, blood, reveal the value of these epigenetic clock genes as peripheral biomarkers for schizophrenia.
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Project description:DNA methylation (DNAm) age estimators are widely used to study aging-related conditions. It is not yet known whether DNAm age is associated with the accumulation of stochastic epigenetic mutations (SEMs), which reflect dysfunctions of the epigenetic maintenance system. Here, we defined epigenetic mutation load (EML) as the total number of SEMs per individual. We assessed associations between EML and DNAm age acceleration estimators using biweight midcorrelations in four population-based studies (total n = 6,388). EML was not only positively associated with chronological age (meta r = 0.171), but also with four measures of epigenetic age acceleration: the Horvath pan tissue clock, intrinsic epigenetic age acceleration, the Hannum clock, and the GrimAge clock (meta-analysis correlation ranging from r = 0.109 to 0.179). We further conducted pathway enrichment analyses for each participant's SEMs. The enrichment result demonstrated the stochasticity of epigenetic mutations, meanwhile implicated several pathways: signaling, neurogenesis, neurotransmitter, glucocorticoid, and circadian rhythm pathways may contribute to faster DNAm age acceleration. Finally, investigating genomic-region specific EML, we found that EMLs located within regions of transcriptional repression (TSS1500, TSS200, and 1stExon) were associated with faster age acceleration. Overall, our findings suggest a role for the accumulation of epigenetic mutations in the aging process.
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