Stochastic epigenetic mutations (DNA methylation) increase exponentially in human aging and correlate with X chromosome inactivation skewing in females

Gentilini, Davide; Garagnani, Paolo; Pisoni, Serena; Bacalini, Maria Giulia; Calzari, Luciano; Mari, Daniela; Vitale, Giovanni; Franceschi, Claudio; Blasio, Anna Maria Di

doi:10.18632/aging.100792

Cited by 55 publications

(91 citation statements)

References 40 publications

(37 reference statements)

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“…cis-methylation quantitative loci (cis-meQTLs). In the remaining 370,234 CpGs, the number of epigenetic mutations ranged from 58 to 26,291 in each sample, using the definition in Gentilini et al [7]. Across samples, the number of epigenetic mutations had a right-skewed distribution, which was close to normal distribution after log10-transformation (Figure S1).…”

Section: Resultsmentioning

confidence: 91%

Comprehensive longitudinal study of epigenetic mutations in aging

Wang

Karlsson

Jylhävä

et al. 2019

Preprint

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BackgroundThe role of DNA methylation in aging has been widely studied. However, epigenetic mutations, here defined as aberrant methylation levels compared to the distribution in a population, are less understood. Hence, we investigated longitudinal accumulation of epigenetic mutations, using 994 blood samples collected at up to five time points from 375 individuals in old ages.ResultsWe verified earlier cross-sectional evidence on the increase of epigenetic mutations with age, and identified important contributing factors including sex, CD19+ B cells, genetic background, cancer diagnosis and technical artifacts. We further classified epigenetic mutations into High/Low Methylation Outliers (HMO/LMO) according to their changes in methylation, and specifically studied methylation sites (CpGs) that were prone to mutate (frequently mutated CpGs). We validated four epigenetically mutated CpGs using pyrosequencing in 93 samples. Furthermore, by using twins, we concluded that the age-related accumulation of epigenetic mutations was not related to genetic factors, hence driven by stochastic or environmental effects.ConclusionsHere we conducted a comprehensive study of epigenetic mutation and highlighted its important role in aging process and cancer development.

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Section: Resultsmentioning

confidence: 91%

Comprehensive longitudinal study of epigenetic mutations in aging

Wang

Karlsson

Jylhävä

et al. 2019

Preprint

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“…In addition, we found mixed evidence regarding the association of DNA methylation outlier burden and lifestyle variables. DNA methylation outlier burden has previously been linked to smoking [19] but not to BMI [12,19]. In Generation Scotland, higher DNA methylation outlier burden was found to be significantly positively associated with smoking pack-years and significantly negatively associated with BMI.…”

Section: Dna Methylation Outlier Burden Health and Survivalmentioning

confidence: 86%

“…Here, we provide a comprehensive characterisation of DNA methylation outlier burden in three large independent cohorts. The sample size of the Generation Scotland cohort is an order of magnitude greater than previous studies [12][13][14]. In addition, this is the first study to systematically relate DNA methylation outlier burden to a range of diseases and to survival.…”

Section: Strengths and Limitationsmentioning

confidence: 98%

“…In Generation Scotland, DNA methylation outliers were defined as per Gentilini and colleagues [12], that is, as sites with methylation levels greater than three times the interquartile range (IQR) from the upper or lower quartile. Outliers were calculated within each set separately.…”

Section: Dna Methylation Outlier Burdenmentioning

confidence: 99%

“…Indeed, Gentilini and colleagues [12] found an exponential association between age and DNA methylation outlier burden in 170 individuals aged between 3 and 106 years (r log (outlier burden)age = 0.63). The authors defined outliers as methylation levels of greater than 3 times the inter-quartile range (IQR) from the 25th and 75th percentiles compared to the rest of the population.…”

Section: Introductionmentioning

confidence: 99%

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DNA methylation outlier burden, health, and ageing in Generation Scotland and the Lothian Birth Cohorts of 1921 and 1936

et al. 2020

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Background: DNA methylation outlier burden has been suggested as a potential marker of biological age. An outlier is typically defined as DNA methylation levels at any one CpG site that are three times beyond the interquartile range from the 25th or 75th percentiles compared to the rest of the population. DNA methylation outlier burden (the number of such outlier sites per individual) increases exponentially with age. However, these findings have been observed in small samples. Results: Here, we showed an association between age and log 10 -transformed DNA methylation outlier burden in a large cross-sectional cohort, the Generation Scotland Family Health Study (N = 7010, β = 0.0091, p < 2 × 10 −16 ), and in two longitudinal cohort studies, the Lothian Birth Cohorts of 1921 (N = 430, β = 0.033, p = 7.9 × 10 −4 ) and 1936 (N = 898, β = 0.0079, p = 0.074). Significant confounders of both cross-sectional and longitudinal associations between outlier burden and age included white blood cell proportions, body mass index (BMI), smoking, and batch effects. In Generation Scotland, the increase in epigenetic outlier burden with age was not purely an artefact of an increase in DNA methylation level variability with age (epigenetic drift). Log 10 -transformed DNA methylation outlier burden in Generation Scotland was not related to self-reported, or family history of, age-related diseases, and it was not heritable (SNP-based heritability of 4.4%, p = 0.18). Finally, DNA methylation outlier burden was not significantly related to survival in either of the Lothian Birth Cohorts individually or in the meta-analysis after correction for multiple testing (HR meta = 1.12; 95% CI meta = [1.02; 1.21]; p meta = 0.021).Conclusions: These findings suggest that, while it does not associate with ageing-related health outcomes, DNA methylation outlier burden does track chronological ageing and may also relate to survival. DNA methylation outlier burden may thus be useful as a marker of biological ageing.

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Stochastic epigenetic mutations (DNA methylation) increase exponentially in human aging and correlate with X chromosome inactivation skewing in females

Cited by 55 publications

References 40 publications

Comprehensive longitudinal study of epigenetic mutations in aging

Comprehensive longitudinal study of epigenetic mutations in aging

DNA methylation outlier burden, health, and ageing in Generation Scotland and the Lothian Birth Cohorts of 1921 and 1936

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