Nasal DNA Methylation Architecture of the {ACE2} gene and Epigenetic Aging

Abstract Background Circulating folate, vitamin B12 and homocysteine concentrations during fetal development have been associated with health outcomes in childhood. Changes in fetal DNA methylation may be an underlying mechanism. This may be reflected in altered epigenetic aging of the fetus, as compared to chronological aging. The difference between gestational age derived in clinical practice and gestational age predicted from neonatal DNA methylation data is referred to as gestational age acceleration. Differences in circulating folate, vitamin B12 and homocysteine concentrations during fetal development may be associated with gestational age acceleration. Results Up to 1346 newborns participating in the Generation R Study, a population-based prospective cohort study, had both cord blood DNA methylation data available and information on plasma folate, serum total and active B12 and plasma homocysteine concentrations, measured in early pregnancy and/or in cord blood. A subgroup of 380 newborns had mothers with optimal pregnancy dating based on a regular menstrual cycle and a known date of last menstrual period. For comparison, gestational age acceleration was calculated based the method of both Bohlin and Knight. In the total study population, which was more similar to Bohlin’s training population, one standard deviation score (SDS) higher maternal plasma homocysteine concentrations was nominally associated with positive gestational age acceleration [0.07 weeks, 95% confidence interval (CI) 0.02, 0.13] by Bohlin’s method. In the subgroup with pregnancy dating based on last menstrual period, the method that was also used in Knight’s training population, one SDS higher cord serum total and active B12 concentrations were nominally associated with negative gestational age acceleration [(− 0.16 weeks, 95% CI − 0.30, − 0.02) and (− 0.15 weeks, 95% CI − 0.29, − 0.01), respectively] by Knight’s method. Conclusions We found some evidence to support associations of higher maternal plasma homocysteine concentrations with positive gestational age acceleration, suggesting faster epigenetic than clinical gestational aging. Cord serum vitamin B12 concentrations may be associated with negative gestational age acceleration, indicating slower epigenetic than clinical gestational aging. Future studies could examine whether altered fetal epigenetic aging underlies the associations of circulating homocysteine and vitamin B12 blood concentrations during fetal development with long-term health outcomes.

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Multi-species and multi-tissue methylation clocks for age estimation in toothed whales and dolphins

Communications Biology ◽

10.1038/s42003-021-02179-x ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Todd R. Robeck ◽

Zhe Fei ◽

Ake T. Lu ◽

Amin Haghani ◽

Eve Jourdain ◽

...

Keyword(s):

Dna Methylation ◽

Age Estimation ◽

Species Conservation ◽

Genome Wide ◽

Epigenetic Aging ◽

Highly Correlated ◽

Methylation Patterns ◽

Cg Dinucleotides ◽

Free Ranging ◽

Unique Species

AbstractThe development of a precise blood or skin tissue DNA Epigenetic Aging Clock for Odontocete (OEAC) would solve current age estimation inaccuracies for wild odontocetes. Therefore, we determined genome-wide DNA methylation profiles using a custom array (HorvathMammalMethyl40) across skin and blood samples (n = 446) from known age animals representing nine odontocete species within 4 phylogenetic families to identify age associated CG dinucleotides (CpGs). The top CpGs were used to create a cross-validated OEAC clock which was highly correlated for individuals (r = 0.94) and for unique species (median r = 0.93). Finally, we applied the OEAC for estimating the age and sex of 22 wild Norwegian killer whales. DNA methylation patterns of age associated CpGs are highly conserved across odontocetes. These similarities allowed us to develop an odontocete epigenetic aging clock (OEAC) which can be used for species conservation efforts by provide a mechanism for estimating the age of free ranging odontocetes from either blood or skin samples.

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Racial Disparities in Epigenetic Aging of the Right vs Left Colon

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djaa206 ◽

2020 ◽

Author(s):

Matthew Devall ◽

Xiangqing Sun ◽

Fangcheng Yuan ◽

Gregory S Cooper ◽

Joseph Willis ◽

...

Keyword(s):

Dna Methylation ◽

African Americans ◽

Racial Differences ◽

Age Of Onset ◽

Left Colon ◽

Right Colon ◽

Normal Colon ◽

Epigenetic Aging ◽

Epigenetic Age Acceleration ◽

The Right

Abstract There are well-documented racial differences in age-of-onset and laterality of colorectal cancer. Epigenetic age acceleration is postulated to be an underlying factor. However, comparative studies of side-specific colonic tissue epigenetic aging are lacking. Here, we performed DNA methylation analysis of matched right and left biopsies of normal colon from 128 individuals. Among African Americans (n = 88), the right colon showed accelerated epigenetic aging as compared to individual-matched left colon (1.51 years; 95% CI = 0.62 to 2.40 years; two-sided P = .001). In contrast, among European Americans (n = 40), the right colon shows remarkable age deceleration (1.93 years; 95% CI = 0.65 to 3.21 years; two-sided P = .004). Further, epigenome-wide analysis of DNA methylation identifies a unique pattern of hypermethylation in African American right colon. Our study is the first to report such race and side-specific differences in epigenetic aging of normal colon, providing novel insight into the observed younger age-of-onset and relative preponderance of right-side colon neoplasia in African Americans.

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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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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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Human Aging DNA Methylation Signatures are Conserved but Accelerated in Cultured Fibroblasts

10.1101/605295 ◽

2019 ◽

Author(s):

Gabriel Sturm ◽

Andres Cardenas ◽

Marie-Abèle Bind ◽

Steve Horvath ◽

Shuang Wang ◽

...

Keyword(s):

Dna Methylation ◽

Replicative Senescence ◽

Human Fibroblasts ◽

High Temporal Resolution ◽

Global Changes ◽

Mrna Levels ◽

Cultured Fibroblasts ◽

Age Related ◽

Epigenetic Aging

SummaryAging is associated with progressive and site-specific changes in DNA methylation (DNAm). These global changes are captured by DNAm clocks that accurately predict chronological age in humans but relatively little is known about how clocks perform in vitro. Here we culture primary human fibroblasts across the cellular lifespan (∼6 months) and use four different DNAm clocks to show that age-related DNAm signatures are conserved and accelerated in vitro. The Skin & Blood clock shows the best linear correlation with chronological time (r=0.90), including during replicative senescence. Although similar in nature, the rate of epigenetic aging is approximately 62x times faster in cultured cells than in the human body. Consistent with in vivo data, cells aged under hyperglycemic conditions exhibit an approximately three years elevation in baseline DNAm age. Moreover, candidate gene-based analyses further corroborate the conserved but accelerated biological aging process in cultured fibroblasts. Fibroblasts mirror the established DNAm topology of the age-related ELOVL2 gene in human blood and the rapid hypermethylation of its promoter cg16867657, which correlates with a linear decrease in ELOVL2 mRNA levels across the lifespan. Using generalized additive modeling on twelve timepoints across the lifespan, we also show how single CpGs exhibit loci-specific, linear and nonlinear trajectories that reach rates up to −47% (hypomethylation) to +23% (hypermethylation) per month. Together, these high temporal resolution global, gene-specific, and single CpG data highlight the conserved and accelerated nature of epigenetic aging in cultured fibroblasts, which may constitute a system to evaluate age-modifying interventions across the lifespan.Graphical Abstract

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Epigenetic aging of human hematopoietic cells is not accelerated upon transplantation into mice

10.1101/271817 ◽

2018 ◽

Author(s):

Joana Frobel ◽

Susann Rahmig ◽

Julia Franzen ◽

Claudia Waskow ◽

Wolfgang Wagner

Keyword(s):

Dna Methylation ◽

Epigenetic Clock ◽

Epigenetic Changes ◽

Hematopoietic Stem ◽

Hematopoietic Development ◽

Immunodeficient Mice ◽

Epigenetic Aging ◽

Normal Human ◽

Methylation Patterns

AbstractTransplantation of human hematopoietic stem cells into immunodeficient mice provides a powerful in vivo model system to gain functional insights into hematopoietic differentiation. So far, it remains unclear if epigenetic changes of normal human hematopoiesis are recapitulated upon engraftment into such “humanized mice”. Mice have a much shorter life expectancy than men, and therefore we hypothesized that the xenogeneic environment might greatly accelerate the epigenetic clock. We demonstrate that genome-wide DNA methylation patterns of normal human hematopoietic development are indeed recapitulated upon engraftment in mice – particularly those of normal early B cell progenitor cells. Furthermore, we tested three epigenetic aging signatures and none of them indicated that the murine environment accelerated age-associated DNA methylation changes. These results demonstrate that the murine transplantation model overall recapitulates epigenetic changes of human hematopoietic development, whereas epigenetic aging seems to occur cell intrinsically.

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The combined effect of obesity and aging on human sperm DNA methylation signatures: inclusion of BMI in the paternal germ line age prediction model

Scientific Reports ◽

10.1038/s41598-020-71979-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Albert Salas-Huetos ◽

Emma R. James ◽

Dallin S. Broberg ◽

Kenneth I. Aston ◽

Douglas T. Carrell ◽

...

Keyword(s):

Dna Methylation ◽

Germ Line ◽

Age Groups ◽

Human Sperm ◽

Absolute Error ◽

Epigenetic Aging ◽

Epigenetic Age ◽

Sperm Dna ◽

Epigenetic Age Acceleration ◽

The Impact

Abstract Male aging and obesity have both been shown to contribute to declines in fertility in men. Recent work in aging has shown consistent epigenetic changes to sperm as a man ages. In fact, our lab has built a tool that utilizes DNA methylation signatures from sperm to effectively predict an individual’s age. Herein, we performed this preliminary cohort study to determine if increased BMI accelerates the epigenetic aging in sperm. A total of 96 participants were divided into four age groups (22–24, 30, 40–41, and > 48 years of age) and additionally parsed into two BMI sub-categories (normal and high/obese). We found no statistically significant epigenetic age acceleration. However, it is important to note that within each age category, high BMI individuals were predicted to be older on average than their actual age (~ 1.4 years), which was not observed in the normal BMI group. To further investigate this, we re-trained a model using only the present data with and without BMI as a feature. We found a modest but non-significant improvement in prediction with BMI [r2 = 0.8814, mean absolute error (MAE) = 3.2913] compared to prediction without BMI (r2 = 0.8739, MAE = 3.3567). Future studies with higher numbers of age-matched individuals are needed to definitively understand the impact of BMI on epigenetic aging in sperm.

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Huntington's disease accelerates epigenetic aging of human brain and disrupts DNA methylation levels

Aging ◽

10.18632/aging.101005 ◽

2016 ◽

Vol 8 (7) ◽

pp. 1485-1512 ◽

Cited By ~ 93

Author(s):

Steve Horvath ◽

Peter Langfelder ◽

Seung Kwak ◽

Jeff Aaronson ◽

Jim Rosinski ◽

...

Keyword(s):

Dna Methylation ◽

Human Brain ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Epigenetic Aging

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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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