scholarly journals Novel Epigenetic Clock for Fetal Brain Development Predicts Fetal Epigenetic Age for iPSCs and iPSC-Derived Neurons.

2020 ◽  
Author(s):  
Leonard C Steg ◽  
Gemma L Shireby ◽  
Jennifer Imm ◽  
Jonathan P Davies ◽  
Robert Flynn ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Brain Development ◽  
Fetal Brain ◽  
Cell Types ◽  
Biological Research ◽  
Epigenetic Clock ◽  
Cellular Model ◽  
Neuronal Precursor Cells ◽  
Age Related ◽  
Epigenetic Age

Abstract Induced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the early stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age, and is has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons, here, we establish the fetal brain clock (FBC), a bespoke epigenetic clock trained in prenatal neurodevelopmental samples. Our data show that the FBC outperforms other established epigenetic clocks in predicting the age of fetal brain samples. We then applied the FBC to DNA methylation data of cellular datasets that have profiled iPSCs and iPSC-derived neuronal precursor cells and neurons and find that these cell types are characterized by a fetal epigenetic age. Furthermore, while differentiation from iPSCs to neurons significantly increases the epigenetic age, iPSC-neurons are still predicted as having fetal epigenetic age. Together our findings reiterate the need for better understanding of the limitations of existing epigenetic clocks for answering biological research questions and highlight a potential limitation of iPSC-neurons as a cellular model for the research of age-related diseases as they might not fully recapitulate an aged phenotype.

scholarly journals Novel epigenetic clock for fetal brain development predicts fetal epigenetic age for iPSCs and iPSC-derived neurons

2020 ◽  
Author(s):  
Leonard C. Steg ◽  
Gemma L. Shireby ◽  
Jennifer Imm ◽  
Jonathan P. Davies ◽  
Robert Flynn ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Brain Development ◽  
Fetal Brain ◽  
Cell Types ◽  
Biological Research ◽  
Epigenetic Clock ◽  
Cellular Model ◽  
Neuronal Precursor Cells ◽  
Age Related ◽  
Epigenetic Age

AbstractInduced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the early stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age, and is has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons, here, we establish the fetal brain clock (FBC), a bespoke epigenetic clock trained in prenatal neurodevelopmental samples. Our data show that the FBC outperforms other established epigenetic clocks in predicting the age of fetal brain samples. We then applied the FBC to DNA methylation data of cellular datasets that have profiled iPSCs and iPSC-derived neuronal precursor cells and neurons and find that these cell types are characterized by a fetal epigenetic age. Furthermore, while differentiation from iPSCs to neurons significantly increases the epigenetic age, iPSC-neurons are still predicted as having fetal epigenetic age. Together our findings reiterate the need for better understanding of the limitations of existing epigenetic clocks for answering biological research questions and highlight a potential limitation of iPSC-neurons as a cellular model for the research of age-related diseases as they might not fully recapitulate an aged phenotype.

scholarly journals Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Leonard C. Steg ◽  
Gemma L. Shireby ◽  
Jennifer Imm ◽  
Jonathan P. Davies ◽  
Alice Franklin ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Brain Development ◽  
Embryonic Stem ◽  
Fetal Brain ◽  
Biological Research ◽  
Epigenetic Clock ◽  
Cellular Model ◽  
Neuronal Precursor Cells ◽  
Epigenetic Age

AbstractInduced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the earliest stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age. It has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, we developed the fetal brain clock (FBC), a bespoke epigenetic clock trained in human prenatal brain samples in order to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons. The FBC was tested in two independent validation cohorts across a total of 194 samples, confirming that the FBC outperforms other established epigenetic clocks in fetal brain cohorts. We applied the FBC to DNA methylation data from iPSCs and embryonic stem cells and their derived neuronal precursor cells and neurons, finding that these cell types are epigenetically characterized as having an early fetal age. Furthermore, while differentiation from iPSCs to neurons significantly increases epigenetic age, iPSC-neurons are still predicted as being fetal. Together our findings reiterate the need to better understand the limitations of existing epigenetic clocks for answering biological research questions and highlight a limitation of iPSC-neurons as a cellular model of age-related diseases.

scholarly journals Different epigenetic clocks reflect distinct pathophysiological features of multiple sclerosis

Epigenomics ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1429-1439 ◽  
Author(s):  
Eleftheria Theodoropoulou ◽  
Lars Alfredsson ◽  
Fredrik Piehl ◽  
Francesco Marabita ◽  
Maja Jagodic
Keyword(s):  
Multiple Sclerosis ◽  
Dna Methylation ◽  
Positive Association ◽  
Cell Types ◽  
Gene Expression Omnibus ◽  
Methylation Data ◽  
Accession Number ◽  
Age Related ◽  
Epigenetic Age ◽  
Epigenetic Age Acceleration

Aim: Accumulating evidence links epigenetic age to diseases and age-related conditions, but little is known about its association with multiple sclerosis (MS). Materials & methods: We estimated epigenetic age acceleration measures using DNA methylation from blood or sorted cells of MS patients and controls. Results: In blood, sex (p = 4.39E-05) and MS (p = 2.99E-03) explained the variation in age acceleration, and isolated blood cell types showed different epigenetic age. Intrinsic epigenetic age acceleration and extrinsic epigenetic age acceleration were only associated with sex (p = 2.52E-03 and p = 1.58E-04, respectively), while PhenoAge Acceleration displayed positive association with MS (p = 3.40E-02). Conclusion: Different age acceleration measures are distinctly influenced by phenotypic factors, and they might measure separate pathophysiological aspects of MS. Data deposition: DNA methylation data can be accessed at Gene Expression Omnibus database under accession number GSE35069, GSE43976, GSE106648, GSE130029, GSE130030.

scholarly journals Epigenetic Clock, Circadian Rhythms and Cell Aging

2021 ◽  
Author(s):  
Ekaterina Samoilova ◽  
Vladimir Belopasov ◽  
Evgenia Ekusheva ◽  
Chao Zhang ◽  
Alexander Troitskiy ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cell ◽  
Circadian Rhythms ◽  
Cpg Islands ◽  
Adult Stem Cell ◽  
Cell Aging ◽  
Regulation Of Transcription ◽  
Epigenetic Clock ◽  
Age Related ◽  
Epigenetic Age

This review summarizes current understanding of the interaction between circadian rhythms of gene expression and epigenetic clocks characterized by the specific profile of DNA methylation in CpG-islands which mirror the chronological age of individual cells and the entire organism. Basic mechanisms of regulation for circadian genes CLOCK- BMAL1 as well as downstream clock-controlled genes (ССG) are also discussed here. It has been shown that circadian rhythms operate by finely tuned regulation of transcription and rely on various epigenetic mechanisms including activation of enhancers / suppressors, acetylation / deacetylation of histones and other proteins as well as DNA methylation. Overall, up to 20% of all genes expressed by the cell are subject to expression oscillations associated with circadian rhythms. Also included in the review is a brief list of genes involved in the regulation of circadian rhythms, along with genes important for metabolic control, aging, and oncogenesis. Knocking out some of them (for example, Sirt1) accelerates the aging process, while overexpression of Sirt1, on the contrary, protects against age-related changes. Circadian regulators control a number of genes that activate the cell cycle (Wee1, c-Myc, p20, p21, and Cyclin D1) and regulate histone modification and DNA methylation. Approaches for determining the epigenetic age from methylation profiles across CpG islands in individual cells are described. DNA methylation, which characterizes the function of the epigenetic clock, appears to link together such key biological processes as regeneration and functioning of stem cells, aging and malignant transformation. Finally, main features of adult stem cell aging in stem cell niches and current possibilities for modulating the epigenetic clock as part of antiaging therapy are discussed.

scholarly journals The aging DNA methylome reveals environment-by-aging interactions in a model teleost

2021 ◽  
Author(s):  
Emily M Bertucci ◽  
Marilyn W Mason ◽  
Olin E Rhodes ◽  
Benjamin B Parrott
Keyword(s):  
Dna Methylation ◽  
Environmental Factors ◽  
Environmental Drivers ◽  
Chronological Age ◽  
Epigenetic Clock ◽  
Ongoing Research ◽  
Dna Methylome ◽  
Age Related ◽  
Epigenetic Aging ◽  
Epigenetic Age

The rate at which individuals age underlies variation in life history and attendant health and disease trajectories. Age specific patterning of the DNA methylome (epigenetic aging) is strongly correlated with chronological age in humans and can be modeled to produce epigenetic age predictors. However, epigenetic age estimates vary among individuals of the same age, and this mismatch is correlated to the onset of age-related disease and all-cause mortality. Yet, the origins of epigenetic-to-chronological age discordance are not resolved. In an effort to develop a tractable model in which environmental drivers of epigenetic aging can be assessed, we investigate the relationship between aging and DNA methylation in a small teleost, medaka (Oryzias latipes). We find that age-associated DNA methylation patterning occurs broadly across the genome, with the majority of age-related changes occurring during early life. By modeling the stereotypical nature of age-associated DNA methylation dynamics, we built an epigenetic clock, which predicts chronological age with a mean error of 29.1 days (~4% of average lifespan). Characterization of clock loci suggests that aspects of epigenetic aging are functionally similar across vertebrates. To understand how environmental factors interact with epigenetic aging, we exposed medaka to four doses of ionizing radiation for seven weeks, hypothesizing that exposure to such an environmental stressor would accelerate epigenetic aging. While the epigenetic clock was not significantly affected, radiation exposure accelerated and decelerated patterns of normal epigenetic aging, with radiation-induced epigenetic alterations enriched at loci that become hypermethylated with age. Together, our findings advance ongoing research attempting to elucidate the functional role of DNA methylation in integrating environmental factors into the rate of biological aging.

scholarly journals DNA methylation differs extensively between strains of the same geographical origin and changes with age in Daphnia magna

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jack Hearn ◽  
Fiona Plenderleith ◽  
Tom J. Little
Keyword(s):  
Dna Methylation ◽  
Caloric Restriction ◽  
Daphnia Magna ◽  
Single Gene ◽  
Methylation Status ◽  
Strain Differences ◽  
Life History Trait ◽  
Food Level ◽  
Epigenetic Clock ◽  
Age Related

Abstract Background Patterns of methylation influence lifespan, but methylation and lifespan may also depend on diet, or differ between genotypes. Prior to this study, interactions between diet and genotype have not been explored together to determine their influence on methylation. The invertebrate Daphnia magna is an excellent choice for testing the epigenetic response to the environment: parthenogenetic offspring are identical to their siblings (making for powerful genetic comparisons), they are relatively short lived and have well-characterised inter-strain life-history trait differences. We performed a survival analysis in response to caloric restriction and then undertook a 47-replicate experiment testing the DNA methylation response to ageing and caloric restriction of two strains of D. magna. Results Methylated cytosines (CpGs) were most prevalent in exons two to five of gene bodies. One strain exhibited a significantly increased lifespan in response to caloric restriction, but there was no effect of food-level CpG methylation status. Inter-strain differences dominated the methylation experiment with over 15,000 differently methylated CpGs. One gene, Me31b, was hypermethylated extensively in one strain and is a key regulator of embryonic expression. Sixty-one CpGs were differentially methylated between young and old individuals, including multiple CpGs within the histone H3 gene, which were hypermethylated in old individuals. Across all age-related CpGs, we identified a set that are highly correlated with chronological age. Conclusions Methylated cytosines are concentrated in early exons of gene sequences indicative of a directed, non-random, process despite the low overall DNA methylation percentage in this species. We identify no effect of caloric restriction on DNA methylation, contrary to our previous results, and established impacts of caloric restriction on phenotype and gene expression. We propose our approach here is more robust in invertebrates given genome-wide CpG distributions. For both strain and ageing, a single gene emerges as differentially methylated that for each factor could have widespread phenotypic effects. Our data showed the potential for an epigenetic clock at a subset of age positions, which is exciting but requires confirmation.

scholarly journals Epigenetic Age Acceleration and Hearing: Observations From the Baltimore Longitudinal Study of Aging

2021 ◽  
Vol 13 ◽  
Author(s):  
Pei-Lun Kuo ◽  
Ann Zenobia Moore ◽  
Frank R. Lin ◽  
Luigi Ferrucci
Keyword(s):  
Dna Methylation ◽  
Longitudinal Study ◽  
Smoking History ◽  
Future Research ◽  
Age Related ◽  
Epigenetic Age ◽  
Epigenetic Age Acceleration ◽  
Baltimore Longitudinal Study ◽  
Age Related Hearing Loss ◽  
The Relationship

Objectives: Age-related hearing loss (ARHL) is highly prevalent among older adults, but the potential mechanisms and predictive markers for ARHL are lacking. Epigenetic age acceleration has been shown to be predictive of many age-associated diseases and mortality. However, the association between epigenetic age acceleration and hearing remains unknown. Our study aims to investigate the relationship between epigenetic age acceleration and audiometric hearing in the Baltimore Longitudinal Study of Aging (BLSA).Methods: Participants with both DNA methylation and audiometric hearing measurements were included. The main independent variables are epigenetic age acceleration measures, including intrinsic epigenetic age acceleration—“IEAA,” Hannum age acceleration—“AgeAccelerationResidualHannum,” PhenoAge acceleration—“AgeAccelPheno,” GrimAge acceleration—“AgeAccelGrim,” and methylation-based pace of aging estimation—“DunedinPoAm.” The main dependent variable is speech-frequency pure tone average. Linear regression was used to assess the association between epigenetic age acceleration and hearing.Results: Among the 236 participants (52.5% female), after adjusting for age, sex, race, time difference between measurements, cardiovascular factors, and smoking history, the effect sizes were 0.11 995% CI: (–0.00, 0.23), p = 0.054] for Hannum’s clock, 0.08 [95% CI: (–0.03, 0.19), p = 0.143] for Horvath’s clock, 0.10 [95% CI: (–0.01, 0.21), p = 0.089] for PhenoAge, 0.20 [95% CI: (0.06, 0.33), p = 0.004] for GrimAge, and 0.21 [95% CI: (0.09, 0.33), p = 0.001] for DunedinPoAm.Discussion: The present study suggests that some epigenetic age acceleration measurements are associated with hearing. Future research is needed to study the potential subclinical cardiovascular causes of hearing and to investigate the longitudinal relationship between DNA methylation and hearing.

scholarly journals Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging

2021 ◽  
Author(s):  
Csaba Kerepesi ◽  
Bohan Zhang ◽  
Sang-Goo Lee ◽  
Alexandre Trapp ◽  
Vadim N. Gladyshev
Keyword(s):  
Pluripotent Stem Cells ◽  
Prenatal Development ◽  
Biological Age ◽  
Epigenetic Clock ◽  
Ground Zero ◽  
August Weismann ◽  
Age Related ◽  
Epigenetic Age ◽  
Human Prenatal Development ◽  
Changes Over Time

The notion that germline cells do not age goes back to the 19th century ideas of August Weismann. However, being in a metabolically active state, they accumulate damage and other age-related changes over time, i.e., they age. For new life to begin in the same young state, they must be rejuvenated in the offspring. Here, we developed a new multi-tissue epigenetic clock and applied it, together with other aging clocks, to track changes in biological age during mouse and human prenatal development. This analysis revealed a significant decrease in biological age, i.e. rejuvenation, during early stages of embryogenesis, followed by an increase in later stages. We further found that pluripotent stem cells do not age even after extensive passaging and that the examined epigenetic age dynamics is conserved across species. Overall, this study uncovers a natural rejuvenation event during embryogenesis and suggests that the minimal biological age (the ground zero) marks the beginning of organismal aging.

scholarly journals Epigenetic clock and DNA methylation studies of roe deer in the wild

2020 ◽  
Author(s):  
Jean-François Lemaître ◽  
Benjamin Rey ◽  
Jean-Michel Gaillard ◽  
Corinne Régis ◽  
Emmanuelle Gilot ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Evolutionary Biology ◽  
Roe Deer ◽  
Chronological Age ◽  
Epigenetic Clock ◽  
Aging Effects ◽  
Methylation Array ◽  
Biomarkers Of Aging ◽  
Epigenetic Age ◽  
The Relationship

AbstractDNA methylation-based biomarkers of aging (epigenetic clocks) promise to lead to new insights in the evolutionary biology of ageing. Relatively little is known about how the natural environment affects epigenetic aging effects in wild species. In this study, we took advantage of a unique long-term (>40 years) longitudinal monitoring of individual roe deer (Capreolus capreolus) living in two wild populations (Chizé and Trois Fontaines, France) facing different ecological contexts to investigate the relationship between chronological age and levels of DNA methylation (DNAm). We generated novel DNA methylation data from n=90 blood samples using a custom methylation array (HorvathMammalMethylChip40). We present three DNA methylation-based estimators of age (DNAm or epigenetic age), which were trained in males, females, and both sexes combined. We investigated how sex differences influenced the relationship between DNAm age and chronological age through the use of sex-specific epigenetic clocks. Our results highlight that both populations and sex influence the epigenetic age, with the bias toward a stronger male average age acceleration (i.e. differences between epigenetic age and chronological ages) particularly pronounced in the population facing harsh environmental conditions. Further, we identify the main sites of epigenetic alteration that have distinct aging patterns across the two sexes. These findings open the door to promising avenues of research at the crossroad of evolutionary biology and biogerontology.

scholarly journals Exploring Epigenetic Age in Response to Intensive Relaxing Training: A Pilot Study to Slow Down Biological Age

2019 ◽  
Vol 16 (17) ◽  
pp. 3074 ◽  
Author(s):  
Pavanello ◽  
Campisi ◽  
Tona ◽  
Lin ◽  
Iliceto
Keyword(s):  
Myocardial Infarction ◽  
Age Estimation ◽  
Healthy Subjects ◽  
Molecular Mechanisms ◽  
Biological Age ◽  
Chronological Age ◽  
Biological Aging ◽  
Epigenetic Clock ◽  
Age Related ◽  
Epigenetic Age

DNA methylation (DNAm) is an emerging estimator of biological aging, i.e., the often-defined “epigenetic clock”, with a unique accuracy for chronological age estimation (DNAmAge). In this pilot longitudinal study, we examine the hypothesis that intensive relaxing training of 60 days in patients after myocardial infarction and in healthy subjects may influence leucocyte DNAmAge by turning back the epigenetic clock. Moreover, we compare DNAmAge with another mechanism of biological age, leucocyte telomere length (LTL) and telomerase. DNAmAge is reduced after training in healthy subjects (p = 0.053), but not in patients. LTL is preserved after intervention in healthy subjects, while it continues to decrease in patients (p = 0.051). The conventional negative correlation between LTL and chronological age becomes positive after training in both patients (p < 0.01) and healthy subjects (p < 0.05). In our subjects, DNAmAge is not associated with LTL. Our findings would suggest that intensive relaxing practices influence different aging molecular mechanisms, i.e., DNAmAge and LTL, with a rejuvenating effect. Our study reveals that DNAmAge may represent an accurate tool to measure the effectiveness of lifestyle-based interventions in the prevention of age-related diseases.

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