Publications by authors named "Steve Horvath"

301 Publications

Epigenetic clock and methylation studies in elephants.

Aging Cell 2021 Jun 12:e13414. Epub 2021 Jun 12.

Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, CA, USA.

Age-associated DNA-methylation profiles have been used successfully to develop highly accurate biomarkers of age ("epigenetic clocks") in humans, mice, dogs, and other species. Here we present epigenetic clocks for African and Asian elephants. These clocks were developed using novel DNA methylation profiles of 140 elephant blood samples of known age, at loci that are highly conserved between mammalian species, using a custom Infinium array (HorvathMammalMethylChip40). We present epigenetic clocks for Asian elephants (Elephas maximus), African elephants (Loxodonta africana), and both elephant species combined. Two additional human-elephant clocks were constructed by combining human and elephant samples. Epigenome-wide association studies identified elephant age-related CpGs and their proximal genes. The products of these genes play important roles in cellular differentiation, organismal development, metabolism, and circadian rhythms. Intracellular events observed to change with age included the methylation of bivalent chromatin domains, and targets of polycomb repressive complexes. These readily available epigenetic clocks can be used for elephant conservation efforts where accurate estimates of age are needed to predict demographic trends.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/acel.13414DOI Listing
June 2021

DNA-methylation-based telomere length estimator: comparisons with measurements from flow FISH and qPCR.

Aging (Albany NY) 2021 Jun 3;13. Epub 2021 Jun 3.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD 20850, USA.

Telomere length (TL) is a marker of biological aging associated with several health outcomes. High throughput reproducible TL measurements are needed for large epidemiological studies. We compared the novel DNA methylation-based estimator (DNAmTL) with the high-throughput quantitative PCR (qPCR) and the highly accurate flow cytometry with fluorescent hybridization (flow FISH) methods using blood samples from healthy adults. We used Pearson's correlation coefficient, Bland Altman plots and linear regression models for statistical analysis. Shorter DNAmTL was associated with older age, male sex, white race, and cytomegalovirus seropositivity (p<0.01 for all). DNAmTL was moderately correlated with qPCR TL (N=635, r=0.41, < 0.0001) and flow FISH total lymphocyte TL (N=144, r=0.56, < 0.0001). The agreements between flow FISH TL and DNAmTL or qPCR were acceptable but with wide limits of agreement. DNAmTL correctly classified >70% of TL categorized above or below the median, but the accuracy dropped with increasing TL categories. The ability of DNAmTL to detect associations with age and other TL-related factors in the absence of strong correlation with measured TL may indicate its capture of aspects of telomere maintenance mechanisms and not necessarily TL. The inaccuracy of DNAmTL prediction should be considered during data interpretation and across-study comparisons.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.203126DOI Listing
June 2021

DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function.

Clin Epigenetics 2021 Jun 2;13(1):121. Epub 2021 Jun 2.

Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Background: The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies.

Results: We identified 23 significant associations in our large trans-ethnic meta-analysis (p < 1.43E-03 and consistent direction of effect across studies). Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as Zhang's 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate). Six of these associations were independently observed in European and African American populations. MRS in particular was consistently associated with eGFR (β =  - 0.12, 95% CI = [- 0.16, - 0.08] change in log-transformed eGFR per unit increase in MRS, p = 4.39E-08), prevalent CKD (odds ratio (OR) = 1.78 [1.47, 2.16], p = 2.71E-09) and higher serum urate levels (β = 0.12 [0.07, 0.16], p = 2.08E-06). The "first-generation" clocks (Hannum, Horvath) and GrimAge showed different patterns of association with the kidney traits. Three of the DNAm-estimated components of GrimAge, namely adrenomedullin, plasminogen-activation inhibition 1 and pack years, were positively associated with higher uACR, serum urate and microalbuminuria.

Conclusion: DNAmAge acceleration and DNAm mortality predictors estimated in whole blood were associated with multiple kidney traits, including eGFR and CKD, in this multi-ethnic study. Epigenetic biomarkers which reflect the systemic effects of age-related mechanisms such as immunosenescence, inflammaging and oxidative stress may have important mechanistic or prognostic roles in kidney disease. Our study highlights new findings linking kidney disease to biological aging, and opportunities warranting future investigation into DNA methylation biomarkers for prognostic or risk stratification in kidney disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-021-01082-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170969PMC
June 2021

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

Commun Biol 2021 May 31;4(1):642. Epub 2021 May 31.

Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA.

The 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42003-021-02179-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167141PMC
May 2021

Clonal hematopoiesis associated with epigenetic aging and clinical outcomes.

Aging Cell 2021 May 29:e13366. Epub 2021 May 29.

Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.

Clonal hematopoiesis of indeterminate potential (CHIP) is a common precursor state for blood cancers that most frequently occurs due to mutations in the DNA-methylation modifying enzymes DNMT3A or TET2. We used DNA-methylation array and whole-genome sequencing data from four cohorts together comprising 5522 persons to study the association between CHIP, epigenetic clocks, and health outcomes. CHIP was strongly associated with epigenetic age acceleration, defined as the residual after regressing epigenetic clock age on chronological age, in several clocks, ranging from 1.31 years (GrimAge, p < 8.6 × 10 ) to 3.08 years (EEAA, p < 3.7 × 10 ). Mutations in most CHIP genes except DNA-damage response genes were associated with increases in several measures of age acceleration. CHIP carriers with mutations in multiple genes had the largest increases in age acceleration and decrease in estimated telomere length. Finally, we found that ~40% of CHIP carriers had acceleration >0 in both Hannum and GrimAge (referred to as AgeAccelHG+). This group was at high risk of all-cause mortality (hazard ratio 2.90, p < 4.1 × 10 ) and coronary heart disease (CHD) (hazard ratio 3.24, p < 9.3 × 10 ) compared to those who were CHIP-/AgeAccelHG-. In contrast, the other ~60% of CHIP carriers who were AgeAccelHG- were not at increased risk of these outcomes. In summary, CHIP is strongly linked to age acceleration in multiple clocks, and the combination of CHIP and epigenetic aging may be used to identify a population at high risk for adverse outcomes and who may be a target for clinical interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/acel.13366DOI Listing
May 2021

An epigenetic clock to estimate the age of living beluga whales.

Evol Appl 2021 May 3;14(5):1263-1273. Epub 2021 Feb 3.

Department of Biostatistics School of Public Health University of California-Los Angeles Los Angeles CA USA.

DNA methylation data facilitate the development of accurate molecular estimators of chronological age or "epigenetic clocks." We present a robust epigenetic clock for the beluga whale, , developed for an endangered population in Cook Inlet, Alaska, USA. We used a custom methylation array to measure methylation levels at 37,491 cytosine-guanine sites (CpGs) from skin samples of dead whales ( = 67) whose chronological ages were estimated based on tooth growth layer groups. Using these calibration data, a penalized regression model selected 23 CpGs, providing an  = 0.92 for the training data; and an  = 0.74 and median absolute age error = 2.9 years for the leave one out cross-validation. We applied the epigenetic clock to an independent dataset of 38 skin samples collected with a biopsy dart from living whales between 2016 and 2018. Age estimates ranged from 11 to 27 years. We also report sex correlations in CpG data and describe an approach of identifying the sex of an animal using DNA methylation. The epigenetic estimators of age and sex presented here have broad applications for conservation and management of Cook Inlet beluga whales and potentially other cetaceans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/eva.13195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127720PMC
May 2021

Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci.

Genome Med 2021 Apr 30;13(1):74. Epub 2021 Apr 30.

Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.

Background: DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach.

Methods: The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses.

Results: We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development.

Conclusions: We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-021-00877-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088054PMC
April 2021

Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer's patients.

Cell Stem Cell 2021 Apr 21. Epub 2021 Apr 21.

Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA. Electronic address:

Sporadic Alzheimer's disease (AD) exclusively affects elderly people. Using direct conversion of AD patient fibroblasts into induced neurons (iNs), we generated an age-equivalent neuronal model. AD patient-derived iNs exhibit strong neuronal transcriptome signatures characterized by downregulation of mature neuronal properties and upregulation of immature and progenitor-like signaling pathways. Mapping iNs to longitudinal neuronal differentiation trajectory data demonstrated that AD iNs reflect a hypo-mature neuronal identity characterized by markers of stress, cell cycle, and de-differentiation. Epigenetic landscape profiling revealed an underlying aberrant neuronal state that shares similarities with malignant transformation and age-dependent epigenetic erosion. To probe for the involvement of aging, we generated rejuvenated iPSC-derived neurons that showed no significant disease-related transcriptome signatures, a feature that is consistent with epigenetic clock and brain ontogenesis mapping, which indicate that fibroblast-derived iNs more closely reflect old adult brain stages. Our findings identify AD-related neuronal changes as age-dependent cellular programs that impair neuronal identity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.stem.2021.04.004DOI Listing
April 2021

Postpartum sleep loss and accelerated epigenetic aging.

Sleep Health 2021 Apr 23. Epub 2021 Apr 23.

Department of Psychology, University of California, Los Angeles, Los Angeles, California, USA.

Background: Insufficient sleep has been linked to accelerated biological aging in adults, providing a possible mechanism through which sleep may influence disease risk. In the current paper, we test the hypothesis that short sleep in postpartum would predict older biological age in women one year post birth, as indicated by accelerated epigenetic aging.

Methods: As part of a larger study of pregnancy and postpartum health (Healthy Babies Before Birth, HB3), 33 mothers provided blood samples for epigenetic aging clock estimates. intrinsic epigenetic age acceleration (IEAA), extrinsic apigenetic age acceleration, phenotypic epigenetic age acceleration (PEAA), GrimAge, DNAmPAI-1, and DNAm telomere length (TL) were calculated using established protocols. Sleep duration was categorized as insufficient sleep (<7 hours per night) or healthy sleep duration (7+ hours per night). Sleep quality was determined using the Pittsburgh Sleep Quality Index (Global score >5).

Results: Maternal postpartum sleep duration at 6 months, but not 12 months, following a birth was predictive of older 12-month IEAA, B (SE) = 3.0 (1.2), P = .02, PEAA, B (SE) = 7.3 (2.0), P = .002, and DNAmTL, B (SE) = -0.18 (0.07), P = .01, but not other indices, all P> .127. Self-reported poor sleep quality at 6 and 12 months was not significantly related to epigenetic age.

Conclusions: These findings suggest that insufficient sleep duration during the early postpartum period is associated with accelerated biological aging. As the sample size is small, additional research is warranted with a larger sample size to replicate these findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.sleh.2021.02.002DOI Listing
April 2021

Epigenetically mediated electrocardiographic manifestations of sub-chronic exposures to ambient particulate matter air pollution in the Women's Health Initiative and Atherosclerosis Risk in Communities Study.

Environ Res 2021 07 22;198:111211. Epub 2021 Apr 22.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA; Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.

Background: Short-duration exposure to ambient particulate matter (PM) air pollution is associated with cardiac autonomic dysfunction and prolonged ventricular repolarization. However, associations with sub-chronic exposures to coarser particulates are relatively poorly characterized as are molecular mechanisms underlying their potential relationships with cardiovascular disease.

Materials And Methods: We estimated associations between monthly mean concentrations of PM < 10 μm and 2.5-10 μm in diameter (PM PM) with time-domain measures of heart rate variability (HRV) and QT interval duration (QT) among U.S. women and men in the Women's Health Initiative and Atherosclerosis Risk in Communities Study (n = 82,107; n = 76,711). Then we examined mediation of the PM-HRV and PM-QT associations by DNA methylation (DNAm) at three Cytosine-phosphate-Guanine (CpG) sites (cg19004594, cg24102420, cg12124767) with known sensitivity to monthly mean PM concentrations in a subset of the participants (n = 7,169; n = 6,895). After multiply imputing missing PM, electrocardiographic and covariable data, we estimated associations using attrition-weighted, linear, mixed, longitudinal models adjusting for sociodemographic, behavioral, meteorological, and clinical characteristics. We assessed mediation by estimating the proportions of PM-HRV and PM-QT associations mediated by DNAm.

Results: We found little evidence of PM-HRV association, PM-QT association, or mediation by DNAm.

Conclusions: The findings suggest that among racially/ethnically and environmentally diverse U.S. populations, sub-chronic exposures to coarser particulates may not exert appreciable, epigenetically mediated effects on cardiac autonomic function or ventricular repolarization. Further investigation in better-powered studies is warranted, with additional focus on shorter duration exposures to finer particulates and non-electrocardiographic outcomes among relatively susceptible populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envres.2021.111211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179344PMC
July 2021

Epigenetic Aging and Hematopoietic Cell Transplantation in Patients With Severe Aplastic Anemia.

Transplant Cell Ther 2021 Apr 16;27(4):313.e1-313.e8. Epub 2021 Jan 16.

Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

Cellular aging in hematopoietic cell transplantation (HCT) is important in the context of immune reconstitution and age-related complications. Recently, several DNA-methylation (DNAm)-based biomarkers of aging known as "epigenetic clocks" have been introduced as novel tools to predict cellular age. Here, we used Cox proportional hazards models to assess the possible associations of donor pre-HCT DNAm age, and its post-HCT changes, using the recently published lifespan-associated epigenetic clock known as "DNAm-GrimAge," with outcomes among patients with severe aplastic anemia (SAA). The study included 732 SAA patients from the Transplant Outcomes in Aplastic Anemia project, who underwent unrelated donor HCT and for whom a donor pre-HCT blood DNA sample was available; 41 also had a post-HCT sample collected at day 100. In multivariable analyses, we found similar associations for donor chronological age and pre-HCT DNAm-GrimAge with post-HCT survival (hazard ratio [HR] per decade = 1.13; 95% confidence interval [CI], 0.99-1.28; P = .07 and HR = 1.14; 95% CI, 0.99-1.28; P = .06, respectively). In donors with 10+ years of GrimAge acceleration (ie, deviation from expected DNAm age for chronological age), elevated risks of chronic graft versus host disease (HR = 2.4; 95% CI, 1.21-4.65; P = .01) and possibly post-HCT mortality (HR = 1.79; 95% CI, 0.96-3.33; P = .07) were observed. In the subset with post-HCT samples, we observed a significant increase in DNAm-GrimAge in the first 100 days after HCT (median change 12.5 years, range 1.4 to 26.4). Higher DNAm-GrimAge after HCT was associated with inferior survival (HR per year = 1.11; 95% CI, 1.02-1.21; P = .01), predominantly within the first year after HCT. This study highlights the possible role cellular aging may play in HCT outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036238PMC
April 2021

Epigenetic clock and methylation study of oocytes from a bovine model of reproductive aging.

Aging Cell 2021 05 2;20(5):e13349. Epub 2021 Apr 2.

Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

Cattle are an attractive animal model of fertility in women due to their high degree of similarity relative to follicle selection, embryo cleavage, blastocyst formation, and gestation length. To facilitate future studies of the epigenetic underpinnings of aging effects in the female reproductive axis, several DNA methylation-based biomarkers of aging (epigenetic clocks) for bovine oocytes are presented. One such clock was germane to only oocytes, while a dual-tissue clock was highly predictive of age in both oocytes and blood. Dual species clocks that apply to both humans and cattle were also developed and evaluated. These epigenetic clocks can be used to accurately estimate the biological age of oocytes. Both epigenetic clock studies and epigenome-wide association studies revealed that blood and oocytes differ substantially with respect to aging and the underlying epigenetic signatures that potentially influence the aging process. The rate of epigenetic aging was found to be slower in oocytes compared to blood; however, oocytes appeared to begin at an older epigenetic age. The epigenetic clocks for oocytes are expected to address questions in the field of reproductive aging, including the central question: how to slow aging of oocytes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/acel.13349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135012PMC
May 2021

Incorporation of a nucleoside analog maps genome repair sites in postmitotic human neurons.

Science 2021 04;372(6537):91-94

Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037-1002, USA.

Neurons are the longest-lived cells in our bodies and lack DNA replication, which makes them reliant on a limited repertoire of DNA repair mechanisms to maintain genome fidelity. These repair mechanisms decline with age, but we have limited knowledge of how genome instability emerges and what strategies neurons and other long-lived cells may have evolved to protect their genomes over the human life span. A targeted sequencing approach in human embryonic stem cell-induced neurons shows that, in neurons, DNA repair is enriched at well-defined hotspots that protect essential genes. These hotspots are enriched with histone H2A isoforms and RNA binding proteins and are associated with evolutionarily conserved elements of the human genome. These findings provide a basis for understanding genome integrity as it relates to aging and disease in the nervous system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.abb9032DOI Listing
April 2021

The Effects of Lifetime Estrogen Exposure on Breast Epigenetic Age.

Cancer Epidemiol Biomarkers Prev 2021 Jun 26;30(6):1241-1249. Epub 2021 Mar 26.

Medicine, Hematology-Oncology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.

Background: Estrogens are thought to contribute to breast cancer risk through cell cycling and accelerated breast aging. We hypothesize that lifetime estrogen exposure drives early epigenetic breast aging observed in healthy women. In this study, we examined associations between hormonal factors and epigenetic aging measures in healthy breast tissues.

Methods: We extracted DNA from breast tissue specimens from 192 healthy female donors to the Susan G. Komen Tissue Bank at the Indiana University Simon Cancer Center. Methylation experiments were performed using the Illumina EPIC 850K array platform. Age-adjusted regression models were used to examine for associations between factors related to estrogen exposure and five DNA methylation-based estimates: Grim age, pan-tissue age, Hannum age, phenotypic age, and skin and blood clock age.

Results: Women were aged 19-90 years, with 95 premenopausal, and 97 nulliparous women. The age difference (Grim age - chronologic age) was higher at earlier ages close to menarche. We found significant associations between earlier age at menarche and age-adjusted accelerations according to the Grim clock, the skin and blood clock, and between higher body mass index (BMI) and age-adjusted accelerations in the Grim clock, Hannum clock, phenotypic clock, and skin and blood clock.

Conclusions: Earlier age at menarche and higher BMI are associated with elevations in DNA methylation-based age estimates in healthy breast tissues, suggesting that cumulative estrogen exposure drives breast epigenetic aging.

Impact: Epigenetic clock measures may help advance inquiry into the relationship between accelerated breast tissue aging and an elevated incidence of breast cancer in younger women.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-20-1297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172523PMC
June 2021

DNA methylation biomarker for cumulative lead exposure is associated with Parkinson's disease.

Clin Epigenetics 2021 Mar 22;13(1):59. Epub 2021 Mar 22.

Department of Neurology, David Geffen School of Medicine, 73-320B CHS Campus, Los Angeles, CA, 177220, USA.

Lead, a known neurotoxicant, has previously received attention in Parkinson's disease (PD) research, but epidemiologic studies have been limited in sample size and findings are equivocal. We generated two methylation-based biomarkers for cumulative tibia and patella bone-measured lead exposure in 1528 PD patients and 1169 controls. PD status was associated with increased levels of the DNAm biomarker for tibia-lead levels. We estimated a meta-OR for PD of 1.89 per unit DNAm tibia-lead increase (95% CI 1.59, 2.24; p = 8.1E-13). The current study supports the notion that chronic and long-term lead exposure tracked via DNAm may contribute to PD pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-021-01051-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983295PMC
March 2021

DNA methylation predicts age and provides insight into exceptional longevity of bats.

Nat Commun 2021 03 12;12(1):1615. Epub 2021 Mar 12.

Instituto de Ecología, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City, Mexico.

Exceptionally long-lived species, including many bats, rarely show overt signs of aging, making it difficult to determine why species differ in lifespan. Here, we use DNA methylation (DNAm) profiles from 712 known-age bats, representing 26 species, to identify epigenetic changes associated with age and longevity. We demonstrate that DNAm accurately predicts chronological age. Across species, longevity is negatively associated with the rate of DNAm change at age-associated sites. Furthermore, analysis of several bat genomes reveals that hypermethylated age- and longevity-associated sites are disproportionately located in promoter regions of key transcription factors (TF) and enriched for histone and chromatin features associated with transcriptional regulation. Predicted TF binding site motifs and enrichment analyses indicate that age-related methylation change is influenced by developmental processes, while longevity-related DNAm change is associated with innate immunity or tumorigenesis genes, suggesting that bat longevity results from augmented immune response and cancer suppression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-21900-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955057PMC
March 2021

Long-term maturation of human cortical organoids matches key early postnatal transitions.

Nat Neurosci 2021 03 22;24(3):331-342. Epub 2021 Feb 22.

Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Human stem-cell-derived models provide the promise of accelerating our understanding of brain disorders, but not knowing whether they possess the ability to mature beyond mid- to late-fetal stages potentially limits their utility. We leveraged a directed differentiation protocol to comprehensively assess maturation in vitro. Based on genome-wide analysis of the epigenetic clock and transcriptomics, as well as RNA editing, we observe that three-dimensional human cortical organoids reach postnatal stages between 250 and 300 days, a timeline paralleling in vivo development. We demonstrate the presence of several known developmental milestones, including switches in the histone deacetylase complex and NMDA receptor subunits, which we confirm at the protein and physiological levels. These results suggest that important components of an intrinsic in vivo developmental program persist in vitro. We further map neurodevelopmental and neurodegenerative disease risk genes onto in vitro gene expression trajectories to provide a resource and webtool (Gene Expression in Cortical Organoids, GECO) to guide disease modeling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41593-021-00802-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109149PMC
March 2021

Accelerated epigenetic aging in adolescents living with HIV is associated with altered development of brain structures.

J Neurovirol 2021 Feb 7. Epub 2021 Feb 7.

Department of Neurology, David Geffen School of Medicine, at the University of California, Los Angeles, CA, USA.

We recently demonstrated that adolescents perinatally infected with HIV-1 (PHIV+) have accelerated aging as measured by a highly accurate epigenetic biomarker of aging known as the epigenetic clock. However, whether epigenetic age acceleration in PHIV+ impacts brain development at the macro- and microstructural levels of brain anatomy has not been studied. We report on a cross-sectional study of PHIV+ enrolled in the Cape Town Adolescent Antiretroviral Cohort (CTAAC). The Illumina Infinium Methylation EPIC array was used to generate DNA methylation data from the blood samples of 180 PHIV+ aged 9 to 12 years. The epigenetic clock software and method was used to estimate two measures, epigenetic age acceleration (AgeAccelerationResidual) and extrinsic epigenetic age acceleration (EEAA). Each participant underwent T1 structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). In order to investigate the associations of chronological age, sex, epigenetic age acceleration and treatment variables (CNS penetration effectiveness score (CPE)) of antiretroviral regimen on brain structure in PHIV+, we developed stepwise multiple regression models in R (version 3.4.3, 2017) including grey and white matter volumes, cortical thickness, cortical surface area and DTI measures of white matter microstructural integrity. The mean DNAm age (16.01 years) of the participants was higher than their mean chronological age (10.77 years). Epigenetic age acceleration contributed more to regional alterations of brain volumes, cortical thickness, cortical surface areas and neuronal microstructure than chronological age, in a range of regions. CPE positively contributed to volume of the brain stem. Understanding the drivers of epigenetic age acceleration could lead to valuable insights into structural brain alterations, and the persistence of neurocognitive disorders in seen in PHIV+ .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13365-021-00947-3DOI Listing
February 2021

The Effects of Anti-retroviral Therapy on Epigenetic Age Acceleration Observed in HIV-1-infected Adults.

Pathog Immun 2020 22;5(1):291-311. Epub 2020 Oct 22.

Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine, UCLA.

Background: HIV-1 infection is associated with acceleration of age-related methylation patterns in peripheral blood and brain of infected individuals although the relative contributions of HIV-1 infection versus its treatment to the observed accelerations in biological aging have not yet been investigated.

Methods: In this longitudinal study of the effects of antiretroviral therapy (ART) on epigenetic aging patterns, we extracted DNA from peripheral blood mononuclear cells from 15 HIV-1-infected individuals infected at three time points: 6 months-1year pre-ART, 6-12 months post-initiation of ART, and 18-24 months after initiating ART. We compared these trajectories with those of 15 age-matched uninfected control participants at three time points with similar intervals. Methylation studies were performed using the Infinium methylation 450 arrays. We examined four epigenetic clock measurements: Age acceleration residual (AAR), Extrinsic (EEAA), Phenotypic (PEAA), and Grim (GEAA) epigenetic age acceleration. Weighted correlation network (WGCNA) analysis was used to identify clusters of highly co-methylated CpGs.

Results: We found that prior to the initiation of ART all four epigenetic measures were significantly higher in HIV-1-infected individuals compared with uninfected individuals (0.001 for AAR, =0.008 for EEAA, =0.012 for GEAA, <0.001 for PEAA using Wilcoxon rank sum tests between serostatus groups). These effects persisted after the initiation of ART, although the magnitude of these differences diminished. At 18-24 months post-ART initiation (time point 3), PEAA and GEAA were no longer significantly different between HIV-1-infected and uninfected individuals (=0.059 for PEAA, =0.11 for GEAA), while AAR and EEAA remained significantly higher in HIV-1-infected individuals compared with uninfected individuals. We further examined for global patterns of methylation differences between HIV-1-infected and uninfected at each time point, and found 14 groups of co-methylated CpGs that were significantly different between groups at baseline, and remained different after the initiation of ART. Conclusion: We confirm that epigenetic age acceleration associated with HIV-1 infection is most dramatic before ART initiation, and this observation is consistent across four epigenetic clock measurements, as well as in additional groups of co-methylated CpGs identified using WGCNA. Following initiation of ART, there is a partial reduction in age acceleration in all measures, with loss of any significant difference in PEAA and GEAA between serostatus groups. Our findings support the need for future studies examining for a link between epigenetic age acceleration and clinical outcomes in HIV-1-infected individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.20411/pai.v5i1.376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815056PMC
October 2020

Early life adversity, pubertal timing, and epigenetic age acceleration in adulthood.

Dev Psychobiol 2021 Jan 10. Epub 2021 Jan 10.

University of California, San Francisco, CA, USA.

Background: Given associations linking early life adversity, pubertal timing, and biological aging, we examined the direct and indirect effects of early life trauma on adult biological aging (via age of menarche).

Methods: Participants were premenopausal women (N = 183). Path models evaluated whether early life trauma predicted early pubertal timing and thereby, adult epigenetic age acceleration (indexed via four epigenetic clocks: Horvath DNAm Age, Hannum DNAm Age, DNAm PhenoAge, and DNAm GrimAge). Secondary analyses explored the effects of type of trauma (abuse and neglect) and adult chronic stress status (caregiver of child with autism and non-caregiver).

Results: Early life trauma and earlier age at menarche independently predicted accelerated aging based on one of the four epigenetic clocks, DNAm GrimAge, though early life trauma was not associated with age of menarche. Childhood abuse, but not neglect, predicted faster epigenetic aging; results did not differ by chronic stress status.

Conclusions: Early trauma and early menarche appear to exert independent effects on DNAm GrimAge, which has been shown to be the strongest epigenetic predictor of mortality risk. This study identifies a potential correlate or determinant of accelerated epigenetic aging-menarcheal age. Future research should address the limitations of this study by using racially diverse samples.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/dev.22085DOI Listing
January 2021

ARDD 2020: from aging mechanisms to interventions.

Aging (Albany NY) 2020 12 30;12(24):24484-24503. Epub 2020 Dec 30.

Blavatnik Institute, Department of Genetics, Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School, Boston, MA 94107, USA.

Aging is emerging as a druggable target with growing interest from academia, industry and investors. New technologies such as artificial intelligence and advanced screening techniques, as well as a strong influence from the industry sector may lead to novel discoveries to treat age-related diseases. The present review summarizes presentations from the 7 Annual Aging Research and Drug Discovery (ARDD) meeting, held online on the 1 to 4 of September 2020. The meeting covered topics related to new methodologies to study aging, knowledge about basic mechanisms of longevity, latest interventional strategies to target the aging process as well as discussions about the impact of aging research on society and economy. More than 2000 participants and 65 speakers joined the meeting and we already look forward to an even larger meeting next year. Please mark your calendars for the 8 ARDD meeting that is scheduled for the 31 of August to 3 of September, 2021, at Columbia University, USA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.202454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803558PMC
December 2020

Epigenome-wide association study of diet quality in the Women's Health Initiative and TwinsUK cohort.

Int J Epidemiol 2021 May;50(2):675-684

Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA.

Background: Diet quality is a risk factor for chronic disease and mortality. Differential DNA methylation across the epigenome has been associated with chronic disease risk. Whether diet quality is associated with differential methylation is unknown. This study assessed whether diet quality was associated with differential DNA methylation measured across 445 548 loci in the Women's Health Initiative (WHI) and the TwinsUK cohort.

Design: The discovery cohort consisted of 4355 women from the WHI. The replication cohort consisted of 571 mono- and dizygotic twins from the TwinsUK cohort. DNA methylation was measured in whole blood using the Illumina Infinium HumanMethylation450 Beadchip. Diet quality was assessed using the Alternative Healthy Eating Index 2010 (AHEI-2010). A meta-analysis, stratified by study cohort, was performed using generalized linear models that regressed methylation on AHEI-2010, adjusting for cell composition, chip number and location, study characteristics, principal components of genetic relatedness, age, smoking status, race/ethnicity and body mass index (BMI). Statistical significance was defined as a false discovery rate < 0.05. Significant sites were tested for replication in the TwinsUK cohort, with significant replication defined by P < 0.05 and a consistent direction.

Results: Diet quality was significantly associated with differential DNA methylation at 428 cytosine-phosphate-guanine (CpG) sites in the discovery cohort. A total of 24 CpG sites were consistent with replication in the TwinsUK cohort, more than would be expected by chance (P = 2.7x10-4), with one site replicated in both the blood and adipose tissue (cg16379999 located in the body of SEL1L).

Conclusions: Diet quality was associated with methylation at 24 CpG sites, several of which have been associated with adiposity, inflammation and dysglycaemia. These findings may provide insight into pathways through which diet influences chronic disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ije/dyaa215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128469PMC
May 2021

Reprogramming to recover youthful epigenetic information and restore vision.

Nature 2020 12 2;588(7836):124-129. Epub 2020 Dec 2.

Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA, USA.

Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity. Changes to DNA methylation patterns over time form the basis of ageing clocks, but whether older individuals retain the information needed to restore these patterns-and, if so, whether this could improve tissue function-is not known. Over time, the central nervous system (CNS) loses function and regenerative capacity. Using the eye as a model CNS tissue, here we show that ectopic expression of Oct4 (also known as Pou5f1), Sox2 and Klf4 genes (OSK) in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2. These data indicate that mammalian tissues retain a record of youthful epigenetic information-encoded in part by DNA methylation-that can be accessed to improve tissue function and promote regeneration in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2975-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752134PMC
December 2020

GrimAge Outperforms Other Epigenetic Clocks in the Prediction of Age-Related Clinical Phenotypes and All-Cause Mortality.

J Gerontol A Biol Sci Med Sci 2021 Apr;76(5):741-749

Department of Medical Gerontology, Trinity College Dublin, Ireland.

The aging process is characterized by the presence of high interindividual variation between individuals of the same chronical age prompting a search for biomarkers that capture this heterogeneity. Epigenetic clocks measure changes in DNA methylation levels at specific CpG sites that are highly correlated with calendar age. The discrepancy resulting from the regression of DNA methylation age on calendar age is hypothesized to represent a measure of biological aging with a positive/negative residual signifying age acceleration (AA)/deceleration, respectively. The present study examines the associations of 4 epigenetic clocks-Horvath, Hannum, PhenoAge, GrimAge-with a wide range of clinical phenotypes (walking speed, grip strength, Fried frailty, polypharmacy, Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MOCA), Sustained Attention Reaction Time, 2-choice reaction time), and with all-cause mortality at up to 10-year follow-up, in a sample of 490 participants in the Irish Longitudinal Study on Ageing (TILDA). HorvathAA and HannumAA were not predictive of health; PhenoAgeAA was associated with 4/9 outcomes (walking speed, frailty MOCA, MMSE) in minimally adjusted models, but not when adjusted for other social and lifestyle factors. GrimAgeAA by contrast was associated with 8/9 outcomes (all except grip strength) in minimally adjusted models, and remained a significant predictor of walking speed, .polypharmacy, frailty, and mortality in fully adjusted models. Results indicate that the GrimAge clock represents a step-improvement in the predictive utility of the epigenetic clocks for identifying age-related decline in an array of clinical phenotypes promising to advance precision medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gerona/glaa286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087266PMC
April 2021

DNA Methylation Age Is More Closely Associated With Infection Risk Than Chronological Age in Kidney Transplant Recipients.

Transplant Direct 2020 Aug 15;6(8):e576. Epub 2020 Jul 15.

Division of General Internal Medicine and Health Services Research, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Older kidney transplant recipients demonstrate increased rates of infection but decreased rates of rejection compared with younger recipients, suggesting that older transplant patients are functionally overimmunosuppressed. We hypothesized that this is a consequence of reduction in immunological activity due to biological aging and that an immune biological age, as determined by DNA methylation (DNAm), would be associated more strongly with incidence of infection than chronological age.

Methods: DNAm analysis was performed on peripheral blood mononuclear cell collected from 60 kidney transplant recipients representing older (≥age 60 y) and younger (aged 30-59 y) patients 3 months after transplantation. DNAm age was calculated based on methylation status of a panel of CpG sites, which have been previously identified as indicative of biological age.

Results: Correlation was seen between chronological and DNAm age; however, there were many patients with significant differences (either acceleration or slowing) between DNAm age and chronological age. A statistically significant association was seen between increased DNAm age and incidence of infection in the first year after kidney transplantation, whereas no significant association was seen between chronological age and infection.

Conclusions: Assessment of DNAm age holds promise as an approach for patient evaluation and individualization of immune suppression regimens. This analysis may provide insights into the immunological mechanism behind increased incidence of infection observed in older transplant patients. The ability to measure biological age would allow for patient risk stratification and individualization of immunosuppression, improving outcomes for the growing numbers of older patients undergoing kidney transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TXD.0000000000001020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581059PMC
August 2020

Epigenetic mutation load is weakly correlated with epigenetic age acceleration.

Aging (Albany NY) 2020 Sep 29;12(18):17863-17894. Epub 2020 Sep 29.

Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA 90095, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.103950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585066PMC
September 2020

Occurrence of Accelerated Epigenetic Aging and Methylation Disruptions in Human Immunodeficiency Virus Infection Before Antiretroviral Therapy.

J Infect Dis 2021 May;223(10):1681-1689

Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada.

Background: Whether accelerated aging develops over the course of chronic human immunodeficiency virus (HIV) infection or can be observed before significant immunosuppression on is unknown. We studied DNA methylation in blood to estimate cellular aging in persons living with HIV (PLWH) before the initiation of antiretroviral therapy (ART).

Methods: A total of 378 ART-naive PLWH who had CD4 T-cell counts >500/µL and were enrolled in the Strategic Timing of Antiretroviral Therapy trial (Pulmonary Substudy) were compared with 34 HIV-negative controls. DNA methylation was performed using the Illumina MethylationEPIC BeadChip. Differentially methylated positions (DMPs) and differentially methylated regions (DMRs) in PLWH compared with controls were identified using a robust linear model. Methylation age was calculated using a previously described epigenetic clock.

Results: There were a total of 56 639 DMPs and 6103 DMRs at a false discovery rate of <0.1. The top 5 DMPs corresponded to genes NLRC5, VRK2, B2M, and GPR6 and were highly enriched for cancer-related pathways. PLWH had significantly higher methylation age than HIV-negative controls (P = .001), with black race, low CD4 and high CD8 T-cell counts, and duration of HIV being risk factors for age acceleration.

Conclusions: PLWH before the initiation of ART and with preserved immune status show evidence of advanced methylation aging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiaa599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161637PMC
May 2021

DNA methylation study of Huntington's disease and motor progression in patients and in animal models.

Nat Commun 2020 09 10;11(1):4529. Epub 2020 Sep 10.

Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.

Although Huntington's disease (HD) is a well studied Mendelian genetic disorder, less is known about its associated epigenetic changes. Here, we characterize DNA methylation levels in six different tissues from 3 species: a mouse huntingtin (Htt) gene knock-in model, a transgenic HTT sheep model, and humans. Our epigenome-wide association study (EWAS) of human blood reveals that HD mutation status is significantly (p < 10) associated with 33 CpG sites, including the HTT gene (p = 6.5 × 10). These Htt/HTT associations were replicated in the Q175 Htt knock-in mouse model (p = 6.0 × 10) and in the transgenic sheep model (p = 2.4 × 10). We define a measure of HD motor score progression among manifest HD cases based on multiple clinical assessments. EWAS of motor progression in manifest HD cases exhibits significant (p < 10) associations with methylation levels at three loci: near PEX14 (p = 9.3 × 10), GRIK4 (p = 3.0 × 10), and COX4I2 (p = 6.5 × 10). We conclude that HD is accompanied by profound changes of DNA methylation levels in three mammalian species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-18255-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484780PMC
September 2020

Epigenetic age and pregnancy outcomes: GrimAge acceleration is associated with shorter gestational length and lower birthweight.

Clin Epigenetics 2020 08 6;12(1):120. Epub 2020 Aug 6.

Department of Psychology, University of California - Los Angeles, Los Angeles, CA, USA.

Background: Advanced biological aging, as measured by epigenetic aging indices, is associated with early mortality and morbidity. Associations between maternal epigenetic aging indices in pregnancy and pregnancy outcomes, namely gestational length and birthweight, have not been assessed. The purpose of this study was to examine whether epigenetic age during pregnancy was associated with gestational length and birthweight.

Results: The sample consisted of 77 women from the Los Angeles, CA, area enrolled in the Healthy Babies Before Birth study. Whole blood samples for DNA methylation assay were obtained during the second trimester (15.6 ± 2.15 weeks gestation). Epigenetic age indices GrimAge acceleration (GrimAgeAccel), DNAm PAI-1, DNAm ADM, and DNAm cystatin C were calculated. Gestational length and birthweight were obtained from medical chart review. Covariates were maternal sociodemographic variables, gestational age at blood sample collection, and pre-pregnancy body mass index. In separate covariate-adjusted linear regression models, higher early second trimester GrimAgeAccel, b(SE) = - .171 (.056), p = .004; DNAm PAI-1, b(SE) = - 1.95 × 10 (8.5 × 10), p = .004; DNAm ADM, b(SE) = - .033 (.011), p = .003; and DNAm cystatin C, b(SE) = 2.10 × 10 (8.0 × 10), p = .012, were each associated with shorter gestational length. Higher GrimAgeAccel, b(SE) = - 75.2 (19.7), p < .001; DNAm PAI-1, b(SE) = - .079(.031), p = .013; DNAm ADM, b(SE) = - 13.8 (3.87), p = .001; and DNAm cystatin C, b(SE) = - .010 (.003), p = .001, were also associated with lower birthweight, independent of gestational length.

Discussion: Higher maternal prenatal GrimAgeAccel, DNAm PAI-1, DNAm ADM, and DNAm cystatin C were associated with shorter gestational length and lower birthweight. These findings suggest that biological age, as measured by these epigenetic indices, could indicate risk for adverse pregnancy outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-020-00909-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409637PMC
August 2020