Biology subjects

Horvath, S.

Publications and source records attributed to Horvath, S..

At least 91 records · Page 5Linked to original sources

bioRxiv2020

An epigenetic clock to estimate the age of living beluga whales

IntroductionDNA 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, Delphinapterus leucas, developed for an endangered population in Cook Inlet, Alaska, USA. Methods and ResultsWe used a custom methylation array to measure methylation levels at 37,491 cytosine-guanine sites (CpGs) from skin samples of dead whales (n = 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 R2 = 0.92 for the training data; and an R2 = 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 data set 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. DiscussionThe epigenetic estimators of age and sex presented here have broad applications for conservation and management of Cook Inlet beluga whales and potentially other cetaceans.

developmental biology↗

bioRxiv2020

Meta-analysis of genome-wide DNA methylation and integrative OMICs in human skeletal muscle.

Knowledge of age-related DNA methylation changes in skeletal muscle is limited, yet this tissue is severely affected by aging in humans. Using a large-scale epigenome-wide association study (EWAS) meta-analysis of age in human skeletal muscle from 10 studies (total n = 908 human muscle methylomes), we identified 9,986 differentially methylated regions at a stringent false discovery rate < 0.005, spanning 8,748 unique genes, many of which related to skeletal muscle structure and development. We then integrated the DNA methylation results with known transcriptomic and proteomic age-related changes in skeletal muscle, and found that even though most differentially methylated genes are not altered at the mRNA or protein level, they are nonetheless strongly enriched for genes showing age-related differential expression. We provide here the most comprehensive picture of DNA methylation aging in human skeletal muscle, and have made our results available as an open-access, user-friendly, web-based tool called MetaMeth (https://sarah-voisin.shinyapps.io/MetaMeth/).

genetics↗

bioRxiv2020

Pair bonding slows epigenetic aging and alters methylation in brains of prairie voles

The quality of romantic relationships can be predictive of health consequences related to aging. DNA methylation-based biomarkers of aging have been developed for humans and many other mammals and could be used to assess how pair bonding impacts aging. Prairie voles (Microtus ochrogaster) have emerged as a model to study social attachment among adult pairs. Here we describe DNA methylation-based estimators of age for prairie voles based on novel DNA methylation data generated on highly conserved mammalian CpGs measured with a custom array. The multi-tissue epigenetic clock for voles was trained on 3 tissue sources (ear, liver, and samples of brain tissue from within the pair bonding circuit). A novel dual species human-vole clock accurately measured relative age defined as the ratio of chronological age to maximum age. According to the human-vole clock of relative age, sexually inexperienced voles exhibit accelerated epigenetic aging in brain tissue (p = 0.02) when compared to pair bonded animals of the same chronological age. Epigenome wide association studies identified CpGs in four genes that were strongly associated with pair bonding across the three tissue types (brain, ear, and liver): Hnrnph1, Fancl, Fam13b, and Fzd1. Further, four CpGs (near the Bmp4 exon, Eif4g2 3 prime UTR, Robo1 exon, and Nfat5 intron) exhibited a convergent methylation change between pair bonding and aging. This study describes highly accurate DNA methylation-based estimators of age in prairie voles and provides evidence that pair bonding status modulates the methylome.

developmental biology↗

bioRxiv2020

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

DNA 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 (Chize 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.

evolutionary biology↗

bioRxiv2020

Epigenetic clock and methylation studies in the rhesus macaque

Methylation levels at specific CpG positions in the genome have been used to develop accurate estimators of chronological age in humans, mice, and other species. Although epigenetic clocks are generally species-specific, the principles underpinning them appear to be conserved at least across the mammalian class. This is exemplified by the successful development of epigenetic clocks for mice and several other mammalian species. Here, we describe epigenetic clocks for the rhesus macaque (Macaca mulatta), the most widely used nonhuman primate in biological research. Using a custom methylation array (HorvathMammalMethylChip40), we profiled n=281 tissue samples (blood, skin, adipose, kidney, liver, lung, muscle, and cerebral cortex). From these data, we generated five epigenetic clocks for macaques. These clocks differ with regards to applicability to different tissue types (pan-tissue, blood, skin), species (macaque only or both humans and macaques), and measure of age (chronological age versus relative age). Additionally, the age-based human-macaque clock exhibits a high age correlation (R=0.89) with the vervet monkey (Chlorocebus sabaeus), another Old World species. Four CpGs within the KLF14 promoter were consistently altered with age in four tissues (adipose, blood, cerebral cortex, skin). It is expected that the macaque clocks will reveal an epigenetic aging rate associated with a host of health conditions and thus lend themselves for identifying and validating anti-aging interventions.

developmental biology↗

bioRxiv2020

Epigenetic clock and methylation studies in elephants

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 combing 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, targets of polycomb repressive complexes, and TFAP2C binding sites. These readily available epigenetic clocks can be used for elephant conservation efforts where accurate estimates of age are needed to predict demographic trends.

developmental biology↗

bioRxiv2020

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

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 chronological age of the oocyte donor. Both epigenetic clock studies and epigenome wide association studies revealed that blood and oocytes differ substantially with respect 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.

developmental biology↗

bioRxiv2020

Epigenetic clock and methylation studies in vervet monkeys

DNA methylation-based biomarkers of aging have been developed for many mammals but not yet for the vervet monkey (Chlorocebus sabaeus), which is a valuable non-human primate model for biomedical studies. We generated novel DNA methylation data from vervet cerebral cortex, blood, and liver using highly conserved mammalian CpGs represented on a custom array (HorvathMammalMethylChip40). We present six DNA methylation-based estimators of age: vervet multi-tissue epigenetic clock and tissue-specific clocks for brain cortex, blood, and liver. In addition, two dual species clocks (human-vervet clocks) for measuring chronological age and relative age, respectively. Relative age was defined as ratio of chronological age to maximum lifespan to address the species differences in maximum lifespan. The high accuracy of the human-vervet clocks demonstrates that epigenetic aging processes are evolutionary conserved in primates. When applying these vervet clocks to tissue samples from another primate species, rhesus macaque, we observed high age correlations but strong offsets. We characterized CpGs that correlate significantly with age in the vervet. CpG probes hypermethylated with age across tissues were located near the targets of Polycomb proteins SUZ12 and EED, and genes possessing the trimethylated H3K27 mark in their promoters. The epigenetic clocks are expected to be useful for age estimation of wild-born animals and anti-aging studies in vervets.

developmental biology↗

bioRxiv2020

Epigenetic clock and methylation studies in cats

Human DNA methylation profiles have been used successfully to develop highly accurate biomarkers of aging ("epigenetic clocks"). Although these human epigenetic clocks are not immediately applicable to all species of the animal kingdom, the principles underpinning them appear to be conserved even in animals that are evolutionarily far removed from humans. This is exemplified by recent development of epigenetic clocks for mice and other mammalian species. Here, we describe epigenetic clocks for the domestic cat (Felis catus), based on methylation profiles of CpGs with flanking DNA sequences that are highly conserved between multiple mammalian species. Methylation levels of these CpGs are measured using a custom-designed Infinium array (HorvathMammalMethylChip40). From these, we present 3 epigenetic clocks for cats; of which, one applies only to blood samples from cats, while the remaining two dual-species human-cat clocks apply both to cats and humans. As the rate of human epigenetic ageing is associated with a host of health conditions and pathologies, it is expected that these epigenetic clocks for cats would do likewise and possess the potential to be further developed for monitoring feline health as well as being used for identifying and validating anti-aging interventions.

developmental biology↗

bioRxiv2020

Reversing age: dual species measurement of epigenetic age with a single clock

Young blood plasma is known to confer beneficial effects on various organs in mice. However, it was not known whether young plasma rejuvenates cells and tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly-accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=593 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=850 human tissue samples to the training data. We employed these six clocks to investigate the rejuvenation effects of a plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. Cellular senescence, which is not associated with epigenetic aging, was also considerably reduced in vital organs. Overall, this study demonstrates that a plasma-derived treatment markedly reverses aging according to epigenetic clocks and benchmark biomarkers of aging.

developmental biology↗

bioRxiv2020

Association of 4 epigenetic clocks with measures of functional health, cognition, and all-cause mortality in The Irish Longitudinal Study on Ageing (TILDA)

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. The present study examines the associations of four epigenetic clocks - Horvath, Hannum, PhenoAge, GrimAge - with a wide range of clinical phenotypes, 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. 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.

genomics↗

bioRxiv2020

Incorporation of a nucleoside analog maps genome repair sites in post-mitotic human neurons

Neurons are the longest-living cells in our bodies, becoming post-mitotic in early development upon terminal differentiation. Their lack of DNA replication makes them reliant on DNA repair mechanisms to maintain genome fidelity. These repair mechanisms decline with age, potentially giving rise to genomic dysfunction that may influence cognitive decline and neurodegenerative diseases. Despite this challenge, our knowledge of how genome instability emerges and what mechanisms neurons and other long-lived cells may have evolved to protect their genome integrity over the human life span is limited. Using a targeted sequencing approach, we demonstrate that neurons consolidate much of their DNA repair efforts into well-defined hotspots that protect genes that are essential for their identity and function. Our findings provide a basis to understand genome integrity as it relates to aging and disease in the nervous system. One Sentence SummaryRecurrent DNA repair hotspots in neurons are linked to genes essential for identity and function.

neuroscience↗

bioRxiv2020

Epigenetic clocks predict prevalence and incidence of leading causes of death and disease burden

Individuals of the same chronological age display different rates of biological ageing. A number of measures of biological age have been proposed which harness age-related changes in DNA methylation profiles. These include methylation-based predictors of chronological age (HorvathAge, HannumAge), all-cause mortality (DNAm PhenoAge, DNAm GrimAge) and telomere length (DNAm Telomere Length). In this study, we test the association between these epigenetic markers of ageing and the prevalence and incidence of the leading causes of disease burden and mortality in high-income countries. Furthermore, we test the clocks relationships with phenotypic measures associated with these conditions, including spirometric and biochemical traits. We carry out these analyses in 9,537 individuals from the Generation Scotland: Scottish Family Health Study. We find that DNAm GrimAge outperforms other epigenetic clocks in its associations with self-report disease prevalence and related clinical traits. DNAm GrimAge associates with chronic obstructive pulmonary disease (COPD) prevalence (Odds Ratio = 3.29, P = 3.0 x 10-4) and pulmonary spirometry tests ({beta} = [-0.10 to -0.15], P = [1.4 x 10-4 to 1.4 x 10-6]) at study baseline after adjusting for possibly confounding risk factors including alcohol, body mass index, deprivation, education and smoking. After adjusting for these confounding risk factors, DNAm GrimAge, DNAm PhenoAge and DNAm Telomere Length, measured at study baseline, predict incidence of ICD-10-coded disease states including COPD, type 2 diabetes and cardiovascular disease after thirteen years of follow-up (Hazard Ratios = [0.80 (telomere length) to 2.19 (GrimAge)], P = [9.9 x 10-4, 1.9 x 10-14]). Our data show that despite accounting for several possible confounding variables, epigenetic markers of ageing predict incidence of common disease. This may have significant implications for their potential utility in clinical settings to complement gold-standard methods of clinical assessment and management.

genomics↗

bioRxiv2019

An epigenetic clock for skeletal muscle

BackgroundAgeing is associated with DNA methylation changes in all human tissues, and epigenetic markers can estimate chronological age based on DNA methylation patterns across tissues. However, the construction of the original pan-tissue epigenetic clock did not include skeletal muscle samples, and hence exhibited a strong deviation between DNA methylation and chronological age in this tissue. MethodsTo address this, we developed a more accurate, muscle-specific epigenetic clock based on the genome-wide DNA methylation data of 682 skeletal muscle samples from 12 independent datasets (18-89 years old, 22% women, 99% Caucasian), all generated with Illumina HumanMethylation arrays (HM27, HM450 or HMEPIC). We also took advantage of the large number of samples to conduct an epigenome-wide association study (EWAS) of age-associated DNA methylation patterns in skeletal muscle. ResultsThe newly developed clock uses 200 CpGs to estimate chronological age in skeletal muscle, 16 of which are in common with the 353 CpGs of the pan-tissue clock. The muscle clock outperformed the pan-tissue clock, with a median error of only 4.6 years across datasets (vs 13.1 years for the pan-tissue clock, p < 0.0001) and an average correlation of {rho} = 0.62 between actual and predicted age across datasets (vs {rho} = 0.51 for the pan-tissue clock). Lastly, we identified 180 differentially methylated regions (DMRs) with age in skeletal muscle at a False Discovery Rate < 0.005. However, Gene Set Enrichment Analysis did not reveal any enrichment for Gene Ontologies. ConclusionsWe have developed a muscle-specific epigenetic clock that predicts age with better accuracy than the pan-tissue clock. We implemented the muscle clock in an R package called MEAT available on Bioconductor to estimate epigenetic age in skeletal muscle samples. This clock may prove valuable in assessing the impact of environmental factors, such as exercise and diet, on muscle-specific biological ageing processes.

bioinformatics↗

bioRxiv2019

Epigenetic age provides insight into tissue origin in endometriosis

BackgroundEndometriosis is a common reproductive disease with a heterogeneous presentation. Classification attempts have thus far not offered insight into its cause or its symptoms. Endometriosis may result from the migration of shed endometrium to the peritoneal cavity. However, there are cases reported in girls without uteruses and men. While a non-retrograde menstruation origin of ectopic tissue is certain in these cases, we propose using DNA methylation age (DNAm age) to distinguish between retrograde and non-retrograde etiologies.\n\nMethodsUsing publicly available DNA methylation data and Horvaths pan-tissue epigenetic clock, we compared DNAm age and epigenetic age acceleration (EAA) of ectopic lesions to eutopic endometrium of diseased and control endometrium. We examined EAA in cancer metastasis and teratomas to control for migration and developmental origin.\n\nResultsDisease status does not change DNAm age of eutopic endometrium, but the effect of ectopic status was profound: -16.88 years (p = 4.82 x 10-7). There were no differences between EAA of primary/metastatic tumor pairs, suggesting that the observed effect is not due to migration. Immature or mature teratoma compartments decreased DNAm age by 9.44 and 7.40 years respectively, suggesting that developmental state correlates with DNAm age.\n\nConclusionsEctopic endometriotic tissue exhibits decelerated DNAm age, similar to that observed in teratomas composed of multipotent tissue. The migration process does not change DNAm age and eutopic endometrium is concordant with chronological age regardless of disease status. We conclude that DNAm age of ectopic lesions can classify endometriosis into distinct subtypes that may be clinically relevant.

genetics↗

bioRxiv2019

Schizophrenia is characterized by age- and sex-specific effects on epigenetic aging

BackgroundThe study of biological age acceleration may help identify at-risk individuals and contribute to reduce the rising global burden of age-related diseases. Using DNA methylation (DNAm) clocks, we investigated biological aging in schizophrenia (SCZ), a severe mental illness that is associated with an increased prevalence of age-related disabilities and morbidities. In a multi-cohort whole blood sample consisting of 1,090 SCZ cases and 1,206 controls, we investigated differential aging using three DNAm clocks (i.e. Hannum, Horvath, Levine). These clocks are highly predictive of chronological age and are known to capture different processes of biological aging. ResultsWe found that blood-based DNAm aging is significantly altered in SCZ with age- and sex-specific effects that differ between clocks and map to distinct chronological age windows. Most notably, differential phenotypic age (Levine clock) was most pronounced in female SCZ patients in later adulthood compared to matched controls. Female patients with high SCZ polygenic risk scores (PRS) present the highest age acceleration in this age group with +4.30 years (CI: 2.40-6.20, P=1.3E-05). Phenotypic age and SCZ PRS contribute additively to the illness and together explain up to 22.4% of the variance in disease status in this study. This suggests that combining genetic and epigenetic predictors may improve predictions of disease outcomes. ConclusionsSince increased phenotypic age is associated with increased risk of all-cause mortality, our findings indicate that specific and identifiable patient groups are at increased mortality risk as measured by the Levine clock. These results provide new biological insights into the aging landscape of SCZ with age- and sex-specific effects and warrant further investigations into the potential of DNAm clocks as clinical biomarkers that may help with disease management in schizophrenia.

genomics↗

bioRxiv2019

Reversal of ageing- and injury-induced vision loss by Tet-dependent epigenetic reprogramming

Ageing is a degenerative process leading to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise, which disrupts youthful gene expression patterns that are required for cells to function optimally and recover from damage1-3. Changes to DNA methylation patterns over time form the basis of an ageing clock4, 5, but whether old individuals retain information to reset the clock and, if so, whether this would improve tissue function is not known. Of all the tissues in the body, the central nervous system (CNS) is one of the first to lose regenerative capacity6, 7. Using the eye as a model tissue, we show that expression of Oct4, Sox2, and Klf4 genes (OSK) in mice resets youthful gene expression patterns and the DNA methylation age of retinal ganglion cells, promotes axon regeneration after optic nerve crush injury, and restores vision in a mouse model of glaucoma and in normal old mice. This process, which we call recovery of information via epigenetic reprogramming or REVIVER, requires the DNA demethylases Tet1 and Tet2, indicating that DNA methylation patterns dont just indicate age, they participate in ageing. Thus, old tissues retain a faithful record of youthful epigenetic information that can be accessed for functional age reversal.

molecular biology↗

bioRxiv2019

An epigenetic predictor of death captures multi-modal measures of brain health

Individuals of the same chronological age exhibit disparate rates of biological ageing. Consequently, a number of methodologies have been proposed to determine biological age and primarily exploit variation at the level of DNA methylation (DNAm) - a commonly studied epigenetic mechanism. A novel epigenetic clock, termed DNAm GrimAge has outperformed its predecessors in predicting the risk of mortality as well as a number of age-related morbidities. However, the association between DNAm GrimAge and cognitive or neuroimaging phenotypes remains unknown. We explore these associations in the Lothian Birth Cohort 1936 (n=709, mean age 73 years). Higher DNAm GrimAge was strongly associated with all-cause mortality over twelve years of follow-up (Hazard Ratio per standard deviation increase in GrimAge: 1.81, P < 2.0 x 10-16). Higher DNAm GrimAge was associated with lower age 11 IQ ({beta}=-0.11), lower age 73 general cognitive ability ({beta}=-0.18), decreased brain volume ({beta}=-0.25) and increased brain white matter hyperintensities ({beta}=0.17). Sixty-eight of 137 health- and brain-related phenotypes tested were significantly associated with DNAm GrimAge. Adjusting all models for childhood cognitive ability attenuated to non-significance a small number of associations (12/68 associations; 6 of which were cognitive traits), but not the association with general cognitive ability (33.9% attenuation). Higher DNAm GrimAge cross-sectionally associates with lower cognitive ability and brain vascular lesions in older age, independently of early life cognitive ability. Thus, this epigenetic predictor of mortality is also associated with multiple different measures of brain health and may aid in the prediction of age-related cognitive decline.

neuroscience↗