DOCSLIB.ORG

GWAS of Epigenetic Aging Rates in Blood Reveals a Critical Role for TERT

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
GWAS of Epigenetic Aging Rates in Blood Reveals a Critical Role for TERT ARTICLE DOI: 10.1038/s41467-017-02697-5 OPEN GWAS of epigenetic aging rates in blood reveals a critical role for TERT Ake T. Lu et al.# DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9907 individuals, we find gene variants mapping to five loci associated with intrinsic epi- 1234567890():,; genetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggests causal influences of menarche and menopause on IEAA and lipoproteins on IEAA and EEAA. Var- iants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) paradoxically confer higher IEAA (P < 2.7 × 10−11). Causal mod- eling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT- expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the epigenetic clock, in addition to its established role of compensating for cell replication-dependent telomere shortening. Correspondence and requests for materials should be addressed to S.H. (email: [email protected]) #A full list of authors and their affliations appears at the end of the paper NATURE COMMUNICATIONS | (2018) 9:387 | DOI: 10.1038/s41467-017-02697-5 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-017-02697-5 fi 2 = 2 = NA methylation (DNAm) pro les of sets of cytosine cohorts were lower, hIEAA 0.19 and hEEAA 0.19 (Supplementary phosphate guanines (CpGs) allow one to develop accurate Table 2). D fi estimators of chronological age which are referred to as We rst performed GWAS meta-analysis of IEAA and EEAA “DNAm age”, “epigenetic age”, or the “epigenetic clock”. Across only in our European ancestry cohorts (N = 8393). Variants with − the life course the correlation between DNAm age and suggestive associations (P < 1.0 × 10 5) were then evaluated in chronological age is >0.951,2. Individuals whose leukocyte DNAm non-European ancestry cohorts (N = 1514), followed by a age is older than their chronological age (“epigenetic age combined meta-analysis across the two strata (Fig. 1a, b). We acceleration”) display a higher risk of all-cause mortality after found no evidence for genomic inflation in individual studies 3–6 accounting for known risk factors , and offspring of (λGC ¼ 0:99 ~ 1.06, Supplementary Tables 3 and 4) or in the 7 λ = centenarians exhibit a younger DNAm age . Epigenetic age European ancestry meta-analysis ( GC 1.03 ~ 1.05; LD score β ¼ : acceleration in blood is associated with cognitive impairment, regression (LDSC) intercept terms 0;IEAA 1 004 and 8,9 10 β ¼ : neuro-pathology in the elderly , Down syndrome , Werner 0;EEAA 1 004; Supplementary Fig. 1 and Supplementary syndrome11, Parkinson’s disease12, obesity13, HIV infection14, Table 2). Variant associations that were genome-wide − and frailty15, menopause16 but it only displays weak correlations significant (P < 5.0 × 10 8) according to the fixed-effect meta- with clinical biomarkers17,18. DNAm age shows no apparent analysis were also evaluated with the trans-ethnic heterogeneity correlation with leukocyte telomere length (LTL), whose pace of test that is implemented in the MANTRA software21. The shortening in cultured somatic cells has been referred to as the MANTRA software provides a meta-analysis estimate, known as ‘mitotic clock’. In vivo, DNAm age and telomere length appear to Bayes Factor (BF), that is arguably more stringent than the fixed- be independent predictors of mortality19. effects meta-analysis because it accounts for genetic heterogeneity Here we examine two widely used measures of epigenetic age between different study populations. Our study focused on acceleration: (a) intrinsic epigenetic age acceleration (IEAA), genetic variants that met two criteria: fixed effects meta 2 < −8 ≅ < −8 based on 353 CpGs described by Horvath , which is independent P 5.0 × 10 and MANTRA log10BF 6( P 5×10 ). of age-related changes in blood cell composition, and (b) extrinsic For IEAA, we identified 264 associated variants, mapping to five epigenetic age acceleration (EEAA), an enhanced version of that genomic loci (3q25.33, 5p15.33, 6p22.3, 6p22.2, and 17q22, based on 71 CpGs described by Hannum (2013) which up- Table 1, Supplementary Data 1, Fig. 2, and Supplementary Fig. 2). weights the contribution of blood cell count measures1,6. IEAA Conditional analyses revealed a secondary signal for IEAA at and EEAA are only moderately correlated (r = 0.37). IEAA 6p22.3 (Table 1, Supplementary Figs. 3c and h). For EEAA, we measures cell-intrinsic methylation changes, exhibits greater identified 440 associated variants, mapping to three loci (4p16.3, consistency across different tissues, appears unrelated to lifestyle 10p11.1, and 10p11.21; Table 1, Supplementary Data 1, Fig. 2, and factors and probably indicates a fundamental cell aging process Supplementary Fig. 4); however, the two lead SNPs, rs71007656 that is largely conserved across cell types2,6. By contrast, EEAA and rs1005277 at 10p11.1 and 10p11.21, respectively, are 2 = captures age-related changes in leukocyte composition and moderately correlated (rEUR 0.35, Table 1). Conditional analysis correlates with lifestyle and health-span related characteristics, showed that the association of the INDEL variant rs71007656 yielding a stronger predictor of all-cause mortality6,18. To dissect partially derived from its association with rs1005277 because the the genetic architecture underlying DNAm age of blood, we P-value of rs71007656 was no longer genome-wide significant in a performed genome-wide association studies (GWAS) of conditional model of rs1005277. By contrast, the SNP rs1005277 IEAA and EEAA based on leukocyte DNA samples from almost remained genome-wide significant in a conditional model of 10,000 individuals. Our GWAS identifies a total of five rs71007656 (Supplementary Fig. 5b, c and e, f). Associations were loci associated with IEAA and three loci associated with consistent across studies (Supplementary Figs. 6 and 7), except for EEAA at genome-wide significance. One of the loci associated one locus (6p22.3: Cochran’s I2 = 58%, MANTRA posterior with IEAA co-locates with the Telomerase Reverse Transcriptase probability of heterogeneity = 0.64, Table 1 and Supplementary (TERT) gene on chromosome 5. Variants in TERT that are Data 1). At each of the five IEAA related loci, the risk alleles associated with increased IEAA are also associated with longer conferred between 0.41 and 1.68 years higher IEAA (Table 1). Of telomeres. Our in vitro experiments indicate that hTERT the five loci associated with IEAA, four also exhibited at least expression is required for DNAm aging in human primary suggestive and sign-consistent associations with EEAA (most − fibroblast cells. Finally, our Mendelian randomization analyses significant P = 6.6 × 10 7, Supplementary Data 2. By contrast, reveal that age at menarche and age at menopause have a causal SNPs in the three loci associated with EEAA were not associated effect on IEAA. (P > 0.05) with IEAA (Supplementary Data 2). Analysis of published chromatin state marks22 showed that most lead variants are in chromosomal regions that are transcribed in multiple cell Results lines (Supplementary Fig. 8). Two loci, 6p22.2 and 6p22.3, co- GWAS meta-analyses for IEAA and EEAA. Genomic analyses locate (within 1 Mb) with CpGs that contribute to the Horvath were performed in 9907 individuals (aged 10–98 years), from 15 estimate of DNAm age (Table 1 and Supplementary Data 1), and data sets, adjusted for chronological age and sex (Supplementary it is possible that these genotypic associations with IEAA arise Table 1, Fig. 1, and Supplementary Note 1). Eleven data sets from direct SNP effects on local methylation (Supplementary comprised individuals of European ancestry (84.7%) and four Note 2 and Supplementary Figs. 9 and 10). comprised individuals of African (10.3%) or Hispanic ancestry (5.0%). GWAS genotypes were imputed to ~7.4 million variants using the 1000 genomes reference panel. To estimate the herit- Transcriptomic studies in leukocytes. To learn about potential ability of epigenetic age acceleration in blood, we used both functional consequences of these associations, we conducted pedigree- and SNP-based methods (Methods section). Our cis-eQTL analysis for each locus associated with IEAA or EEAA, 2 = pedigree-based estimates of heritability were hIEAA 0.37 and using data on leukocyte mRNA expression in up to 15,295 2 = fi fi hEEAA 0.33 in individuals of European ancestry, which is con- samples from ve studies (Fig. 1c; Methods section). We identi ed sistent with previous heritability estimates in twins2 and with 11 putative cis-eQTLs located in seven of the eight associated loci those obtained in other tissues (e.g., adipose and brain)9,13,20. (Supplementary Data 3). Each putative cis-eQTL was then SNP-based estimates of heritability in our European ancestry analyzed by summary data-based Mendelian randomization 2 NATURE COMMUNICATIONS | (2018) 9:387 | DOI: 10.1038/s41467-017-02697-5 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | DOI: 10.1038/s41467-017-02697-5 ARTICLE a Study data sets b Meta-analysis Stage 1: (N=8393) I. Fixed effects models II. Combining non-EUR 11 studies of EUR ancestry combining EUR studies studies only on on all markers M SNPs P < 1.0×10–5 at stage 1 Stage 2: (N=1514) 4 studies of non-EUR ancestry Combined stage : (N=9907) III. Combining all studies on M SNPs 15 studies -> Meta combined stage P IV. Bayesian trans-ancestry analysis on SNPs with Meta P < 5.0×10–8 –8 ≥ Genome-wide significant SNPs : Meta P < 5.0×10 & log10BF 6 c Transcriptomic studies in blood (N =15,295) Study N I.
Load more

Recommended publications
  • Cpg DNA Methylation Is a Key Epigenetic Modification in Vertebrates
    1/22/2018 Epigenetic aging clocks for mammals CpG DNA methylation is a key epigenetic Steve Horvath University of California, Los Angeles modification in vertebrates • DNAm is known to be involved in – cell differentiation and development – regulation of gene expression – DNA structure – control of transposable elements, cryptic translation Opportunity for collaboration: • Increasing evidence that it can help • Looking for collaborators who have access to tissue/DNA samples explain why vertebrates age… from mammals of varying ages. • Will generate high quality DNA methylation data. Acknowledgement: Paul G. Allen Frontiers Group Human multi-tissue DNAm age estimator applies to the entire age span from cradle to grave Human multi-tissue DNAm age estimator • Step 1: Measure the DNA methylation levels of 353 CpGs. • Step 2: Form a weighted average • Step 3: Transform the average so it is in units of “years” Result: age estimate (a number) that is known as “epigenetic age” or “DNA methylation age” The human multi-tissue DNAm age estimator is the most accurate molecular biomarker of age to date. Hence the name “epigenetic clock”. Test set validation in multiple tissues Epigenetic age estimators in other mammals based on Reduced Representation Bisulfite Sequencing 1 1/22/2018 Several articles describe epigenetic clocks for mice. Gold standard anti-aging intervention slow aging. Technical and scientific challenges Overarching goal: Develop an epigenetic age estimator that applies • It is technically difficult to validate epigenetic age to all mammals (universal epigenetic clock) estimators based on Reduced Representation Bisulfite Sequencing due to Step 1: Develop a mammalian DNA methylation –non-overlapping sets of CpGs chip for CpGs in highly conserved DNA sequences –low sequencing depth Step 2: Develop an age estimator for each of 50 • Large number of species species.
    [Show full text]
  • Accelerated Epigenetic Aging in HIV Steve Horvath University of California, Los Angeles DNA Methylation: Epigenetic Modification of DNA
    Accelerated epigenetic aging in HIV Steve Horvath University of California, Los Angeles DNA methylation: epigenetic modification of DNA Illustration of a DNA molecule that is methylated at the two center cytosines. DNA methylation plays an important role for epigenetic gene regulation in development and disease. Epigenetic clock applies to three Ilumina platforms 1. EPIC chip: measures over 850k locations on the DNA. 2. Infinium 450K: 486k CpGs. 3. Infinium 27K: 27k CpGs. Each CpG specifies the amount of methylation that is present at this location. – Number between 0 and 1 Personal definition of biological aging clock • Definition: an accurate molecular marker for chronological age (in years) • Definition of “accurate” – high correlation (r>0.80) between estimated value and chronological age in subjects aged between 0 and 100. – validation in independent test data • Candidate aging clocks 1. based on telomere length 2. based on gene expression levels 3. based on protein expression levels 4. DNA methylation levels Multi-tissue biomarker of aging based on DNA methylation levels was published less than 3 years ago Development of the epigenetic clock • Downloaded 82 publicly available DNA methylation data sets (over 8000 samples). • Regressed chronological age (transformed) on CpGs using an elastic net regression model – The regression model automatically selected 353 CpGs. Epigenetic clock method • Step 1: Measure the DNA methylation levels of 353 CpGs. • Step 2: Form a weighted average • Step 3: Transform the average so it is in units of “years” Result: age estimate (a number) that is known as “epigenetic age” or “DNA methylation age” Comment: same definition for every tissue and cell type.
    [Show full text]
  • Epigenetic Clock and DNA Methylation Analysis of Porcine Models of Aging and Obesity
    bioRxiv preprint doi: https://doi.org/10.1101/2020.09.29.319509; this version posted October 1, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Epigenetic clock and DNA methylation analysis of porcine models of aging and obesity Kyle M. Schachtschneider1,2,3, Lawrence B Schook1,4, Jennifer J. Meudt5, Dhanansayan Shanmuganayagam5,6, Joseph A. Zoller7, Amin Haghani7, Caesar Z. Li7, Joshua Zhang8, Andrew Yang7, Ken Raj9, Steve Horvath7,8 1 Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA; 2 Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA; 3 National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign, Urban, IL, USA; 4 Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA; 5 Biomedical & Genomic Research Group, Department of Animal and Dairy Sciences, University of Wisconsin – Madison, Madison, Wisconsin, USA; 6 Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA; 7 Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, California, USA; 8 Human Genetics, David Geffen School of Medicine, University of California, Los Angeles CA 90095, USA; 9 Radiation Effects Department, Centre for
    [Show full text]
  • Transient Reprogramming for Multifaceted Reversal of Aging Phenotypes a Dissertation Submitted to the Department of Applied Phys
    TRANSIENT REPROGRAMMING FOR MULTIFACETED REVERSAL OF AGING PHENOTYPES A DISSERTATION SUBMITTED TO THE DEPARTMENT OF APPLIED PHYSICS AND THE COMMITTEE ON GRADUATE STUDIES OF STANFORD UNIVERSITY IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY TAPASH SARKAR MAY 2019 © 2019 by Tapash Jay Sarkar. All Rights Reserved. Re-distributed by Stanford University under license with the author. This dissertation is online at: http://purl.stanford.edu/vs728sz4833 ii I certify that I have read this dissertation and that, in my opinion, it is fully adequate in scope and quality as a dissertation for the degree of Doctor of Philosophy. Vittorio Sebastiano, Primary Adviser I certify that I have read this dissertation and that, in my opinion, it is fully adequate in scope and quality as a dissertation for the degree of Doctor of Philosophy. Andrew Spakowitz, Co-Adviser I certify that I have read this dissertation and that, in my opinion, it is fully adequate in scope and quality as a dissertation for the degree of Doctor of Philosophy. Vinit Mahajan Approved for the Stanford University Committee on Graduate Studies. Patricia J. Gumport, Vice Provost for Graduate Education This signature page was generated electronically upon submission of this dissertation in electronic format. An original signed hard copy of the signature page is on file in University Archives. iii iv Abstract Though aging is generally associated with tissue and organ dysfunction, these can be considered the emergent consequences of fundamental transitions in the state of cellular physiology. These transitions have multiple manifestations at different levels of cellular architecture and function but the central regulator of these transitions is the epigenome, the most upstream dynamic regulator of gene expression.
    [Show full text]
  • Research Conference on Aging Will Biological Sciences 17
    Poster Session (Continued) TH 47. Changes in functional connectivity following yoga and 53. Evidence-Based Recommendations for Preparing 20 Annual UCLA memory training interventions for cognition in older adults Homebound Veterans for Disaster with subjective memory complaints: a pilot study M Claver, T Wyte-Lake, and A Dobalian H Yang, HA Eyre, A Leaver, N St. Cyr, K Narr, DS Khalsa, and H 54. Aging Research, California Center for Population Lavretsky Research 48. Biomedical Informatics Program D Costa DS Bell 55. Cost-Sharing, Physician Utilization, and Adverse Social Research, Policy, and Practice Selection Among Medicare Beneficiaries With Chronic Health Conditions promotion of the social well-being of older adults through Research Conference G Hoffman the scientific study of the social, political, and economic contexts of aging 56. Elder Abuse and Legislation: Public Awareness E Ionescu and W Lozano 49. Organizational challenges to implementing 57. Patient-centered goals for dementia care on Aging hospital-based palliative care LA Jennings, A Palimaru, X Cagigas, K Ramirez, T Zhao, R Hays, K Bikson N Wenger, and DB Reuben 50. Differences in Nursing Home Quality between Medicare 58. Caregiver burden, perceived competence, and Advantage and Traditional Medicare Patients knowledge following an intensive dementia caregiving E Chang, T Ruder, C Setodji, D Saliba, M Hanson, DS Zingmond, training course NS Wenger, and DA Ganz K Lee, M Pokhriyal, T Zhao, K Ramirez, LA Jennings, and ZS Tan 51. Preferences for Advance Care Planning and 59. Exploring Ethnic Differences in Advance Directive Communication Among Chinese Elders in Southern Completion and Care Preferences California J Portanova JY Cho and S Enguidanos 60.
    [Show full text]
  • Accelerated Epigenetic Aging in Down Syndrome
    Aging Cell (2015) 14, pp491–495 Doi: 10.1111/acel.12325 Accelerated epigenetic aging in Down syndrome Steve Horvath,1,2,* Paolo Garagnani,3,4,5,* Maria Giulia and segmental, involving some but not all organs and tissues. Of Bacalini,3,4,6 Chiara Pirazzini,3,4 Stefano Salvioli,3,4 Davide particular interest are the brain (Lott & Head, 2005; Teipel & Hampel, Gentilini,7 Anna Maria Di Blasio,7 Cristina Giuliani,8 Spencer 2006) and the immune system (Cuadrado & Barrena, 1996). Certain Tung,9 Harry V. Vinters9 and Claudio Franceschi4,10 functional abnormalities of lymphocytes can be interpreted as precocious immunosenescence (Kusters et al., 2011) but alternative interpretations 1Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA are possible (Cuadrado & Barrena, 1996). 2Biostatistics, Fielding School of Public Health, University of California Los Due to the limited availability of biomarkers of aging, it has been Angeles, Los Angeles, CA 90095, USA difficult to rigorously test whether DS is associated with accelerated 3Department of Experimental, Diagnostic and Specialty Medicine, University aging effects, per se, versus specific vulnerabilities to conditions typically of Bologna, Bologna 40126, Italy associated with old age (e.g., increased risk for Alzheimer’s disease). One 4Interdepartmental Center ‘L. Galvani’, University of Bologna, Bologna basic tenet is that a suitable biomarker of aging should detect 40126, Italy 5 accelerated aging effects in tissues (e.g., brain and blood)
    [Show full text]
  • Maintenance of Age in Human Neurons Generated By
    SHORT REPORT Maintenance of age in human neurons generated by microRNA-based neuronal conversion of fibroblasts Christine J Huh1,2, Bo Zhang1, Matheus B Victor1,3, Sonika Dahiya4, Luis FZ Batista1,5, Steve Horvath6,7, Andrew S Yoo1* 1Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States; 2Program in Molecular and Cellular Biology, Washington University School of Medicine, St. Louis, United States; 3Program in Neuroscience, Washington University School of Medicine, St. Louis, United States; 4Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States; 5Department of Medicine, Washington University School of Medicine, St. Louis, United States; 6Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States; 7Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, United States Abstract Aging is a major risk factor in many forms of late-onset neurodegenerative disorders. The ability to recapitulate age-related characteristics of human neurons in culture will offer unprecedented opportunities to study the biological processes underlying neuronal aging. Here, we show that using a recently demonstrated microRNA-based cellular reprogramming approach, human fibroblasts from postnatal to near centenarian donors can be efficiently converted into neurons that maintain multiple age-associated signatures. Application of an epigenetic biomarker *For correspondence: yooa@ of aging (referred to as epigenetic clock) to DNA methylation data revealed that the epigenetic wustl.edu ages of fibroblasts were highly correlated with corresponding age estimates of reprogrammed neurons. Transcriptome and microRNA profiles reveal genes differentially expressed between Competing interests: The young and old neurons.
    [Show full text]
  • DNA Methylation Analysis Validates Organoids As a Viable Model for Studying Human Intestinal Aging
    UCLA UCLA Previously Published Works Title DNA Methylation Analysis Validates Organoids as a Viable Model for Studying Human Intestinal Aging. Permalink https://escholarship.org/uc/item/0ww6s1tx Journal Cellular and molecular gastroenterology and hepatology, 9(3) ISSN 2352-345X Authors Lewis, Sophia K Nachun, Daniel Martin, Martin G et al. Publication Date 2020 DOI 10.1016/j.jcmgh.2019.11.013 Peer reviewed eScholarship.org Powered by the California Digital Library University of California ORIGINAL RESEARCH DNA Methylation Analysis Validates Organoids as a Viable Model for Studying Human Intestinal Aging Sophia K. Lewis,1,2 Daniel Nachun,3 Martin G. Martin,2,4 Steve Horvath,5 Giovanni Coppola,3,6 and D. Leanne Jones1,2 1Department of Molecular, Cell and Developmental Biology, 2Eli and Edythe Broad Stem Cell Research Center, 3Department of Psychiatry and Semel Institute, 4Division of Gastroenterology and Nutrition, Department of Pediatrics, Mattel Children’s Hospital and David Geffen School of Medicine, 6Department of Neurology, University of California Los Angeles, Los Angeles, California; 5Department of Human Genetics, Gonda Research Center, David Geffen School of Medicine, Los Angeles, California – SUMMARY biomarker of age to analyze in vitro derived, 3-dimensional, stem cell–enriched intestinal organoids. We found that human intestinal organoids maintain the age RESULTS: We found that human stem cell–enriched organoids of the patient from whom they are derived, as measured by maintained segmental differences in methylation patterns and the epigenetic clock. Unexpectedly, we found that crypts and that age, as measured by the epigenetic clock, also was main- spheroids derived from small intestine showed striking tained in vitro.
    [Show full text]
  • Synchrony and Asynchrony Between an Epigenetic Clock And
    www.nature.com/scientificreports OPEN Synchrony and asynchrony between an epigenetic clock and developmental timing Received: 26 October 2018 Akina Hoshino1, Steve Horvath2, Akshayalakshmi Sridhar1, Alex Chitsazan3 & Thomas A. Reh1 Accepted: 28 January 2019 Epigenetic changes have been used to estimate chronological age across the lifespan, and some studies Published: xx xx xxxx suggest that epigenetic “aging” clocks may already operate in developing tissue. To better understand the relationship between developmental stage and epigenetic age, we utilized the highly regular sequence of development found in the mammalian neural retina and a well-established epigenetic aging clock based on DNA methylation. Our results demonstrate that the epigenetic age of fetal retina is highly correlated with chronological age. We further establish that epigenetic aging progresses normally in vitro, suggesting that epigenetic aging is a property of individual tissues. This correlation is also retained in stem cell-derived retinal organoids, but is accelerated in individuals with Down syndrome, a progeroid-like condition. Overall, our results suggest that epigenetic aging begins as early as a few weeks post-conception, in fetal tissues, and the mechanisms underlying the phenomenon of epigenetic aging might be studied in developing organs. Human and mouse studies have shown that DNA methylation-based biomarkers can provide a way to measure chronological age across the entire age spectrum and in all tissues, despite the fact that patterns of DNA methyla- tion vary considerably across tissues1–4. Remarkably, so-called DNA methylation epigenetic clocks provide highly accurate age estimators for individuals from 0 to 100 years old3,5,6. Te Horvath clock is based on the weighted average of 353 CpGs, whereby methylation of 193 CpGs is positively correlated with age, while methylation of the other 160 CpGs is negatively correlated with age7.
    [Show full text]
  • Maintenance of Age in Human Neurons Generated by Microrna-Based Neuronal Conversion of Fibroblasts Christine J
    Washington University School of Medicine Digital Commons@Becker Open Access Publications 2016 Maintenance of age in human neurons generated by microRNA-based neuronal conversion of fibroblasts Christine J. Huh Washington University School of Medicine in St. Louis Bo Zhang Washington University School of Medicine in St. Louis Matheus B. Victor Washington Univeristy School of Medicine in St. Louis Sonika Dahiya Washington University School of Medicine St. Louis Luis FZ Batista Washington University School of Medicine in St. Louis See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Huh, Christine J.; Zhang, Bo; Victor, Matheus B.; Dahiya, Sonika; Batista, Luis FZ; Horvath, Steve; and Yoo, Andrew S., ,"Maintenance of age in human neurons generated by microRNA-based neuronal conversion of fibroblasts." Elife.5,. e18648. (2016). https://digitalcommons.wustl.edu/open_access_pubs/5336 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Christine J. Huh, Bo Zhang, Matheus B. Victor, Sonika Dahiya, Luis FZ Batista, Steve Horvath, and Andrew S. Yoo This open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/open_access_pubs/5336 SHORT REPORT Maintenance of age in human neurons generated by microRNA-based neuronal conversion of fibroblasts Christine J Huh1,2, Bo Zhang1, Matheus B Victor1,3, Sonika Dahiya4, Luis FZ Batista1,5, Steve Horvath6,7, Andrew S Yoo1* 1Department of Developmental Biology, Washington University School of Medicine, St.
    [Show full text]
  • Steve Horvath UCLA
    DNA methylation based biomarkers of aging and lifecourse Steve Horvath UCLA Credit: Nat Rev Genetics What is the biological age of this 71 year old man? • He is probably young according to most clinical biomarkers such as body mass index, grip strengths, blood pressure. • He is probably old according to molecular biomarkers such as the epigenetic clock • Message: Molecular markers will not be misled Dion Friedland Conceptual framework: Molecular biomarkers relate to innate aging processes, confounders, and clinical phenotypes. Innate Aging R=0.9? Process Chronological Age Molecular Age related biomarker Phenotype R=0.5? Accumulation of toxic exposures a) Smoking pack years b) Metabolic stress c) ETC 3 DNA methylation: epigenetic modification of DNA Illustration of a DNA molecule that is methylated at the two center cytosines. DNA methylation plays an important role for epigenetic gene regulation in development and disease. The human pan-tissue DNAm age estimator is the most accurate molecular biomarker of age across tissues. Hence the name “epigenetic clock”. Pros and cons of DNAm based biomarkers • Pros – Exceptional correlation with age – Apply to all sources of DNA, all tissues and cell types – Apply to all vertebrates. – Predictive of a host of health outcomes – Relate to most age related conditions including healthspan – Lend themselves for in vivo studies – Are already being used in human clinical trials – Highly robust and relatively cheap assay (250 US dollars) • Cons – In general, weak correlation with transcriptomic data – Incomplete
    [Show full text]
  • Dual Species Measurement of Epigenetic Age with a Single Clock
    bioRxiv preprint doi: https://doi.org/10.1101/2020.05.07.082917; this version posted May 8, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Reversing age: dual species measurement of epigenetic age with a single clock Steve Horvath1,2#, Kavita Singh3#, Ken Raj4#, Shraddha Khairnar3, Akshay Sanghavi5, Agnivesh Shrivastava5, Joseph A. Zoller 2, Caesar Z. Li2, Claudia B. Herenu6, Martina Canatelli-Mallat7, Marianne Lehmann7, Leah C. Solberg Woods8, Angel Garcia Martinez9, Tengfei Wang9, Priscila Chiavellini7, Andrew J. Levine10, Hao Chen9, Rodolfo G. Goya7, Harold L. Katcher5 Affiliations 1 Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA; 2 Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, California, USA; 3 Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM'S NMIMS University, Mumbai, India; 4 Radiation Effects Department, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton, Didcot, UK; 5 Nugenics Research Pvt Ltd, India; 6 Institute for Experimental Pharmacology of Cordoba (IFEC), School of Chemical Sciences, National University of Cordoba, Cordoba, Argentina; 7 Biochemistry Research Institute of La Plata – Histology B, Pathology B, School of Medicine, University of La Plata, La Plata CC 455 (zip 1900), Argentina; 8 Wake Forest University School of Medicine, 1 Medical Center Drive, Winston Salem, NC 27157, USA; 9 Department of Pharmacology, Addiction Science and Toxicology, The University of Tennessee Health Science Center, Memphis, TN 3993, USA; 10 Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles, CA, 90095, USA.
    [Show full text]