Biology subjects

Horvath, S.

Publications and source records attributed to Horvath, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Cross Tissue DNAm Biomarker Prediction using Transfer Learning

DNA methylation (DNAm) is an epigenetic mechanism vital for regulating gene expression and influencing disease states. Developing accurate DNAm biomarkers often requires data from specific tissues, which are sometimes difficult to access. This study explores the use of Transfer Learning (TL) to predict blood DNAm biomarkers using saliva DNAm data, aiming to overcome limitations posed by sample size and tissue accessibility. We developed TL-based algorithms that integrate DNAm data from multiple tissues. These algorithms were evaluated against traditional Lasso regression and direct saliva DNAm estimates. Our results show that TL significantly improves the prediction accuracy of DNAm biomarkers, outperforming traditional methods in 20 out of 26 biomarkers. We further validated our models using independent datasets, demonstrating that TL-derived predictions reflect known biological relationships, such as sex differences in telomere length and the impact of smoking on DNAm biomarkers. Our findings highlight the potential of TL in enhancing DNAm biomarker prediction across tissues, providing a valuable tool for epigenetic research. The developed algorithms and methodologies are accessible to researchers, fostering advancements in personalized medicine and aging research. This study establishes a framework for utilizing TL to bridge the gap between accessible and pertinent tissue data, paving the way for more accurate and versatile DNAm biomarker applications. ACM Reference FormatKristen M McGreevy, Brian H Chen, Steve Horvath, and Donatello Telesca. 2024. Cross Tissue DNAm Biomarker Prediction using Transfer Learning. 1, 1 (June 2024), 43 pages. https://doi.org/10.1145/nnnnnnn.nnnnnnn

bioinformatics↗

bioRxiv2024

The CALERIE™ Genomic Data Resource

Caloric restriction (CR) slows biological aging and prolongs healthy lifespan in model organisms. Findings from CALERIE-2 - the first ever randomized, controlled trial of long-term CR in healthy, non-obese humans - broadly supports a similar pattern of effects in humans. To expand our understanding of the molecular pathways and biological processes underpinning CR effects in humans, we generated a series of genomic datasets from stored biospecimens collected from n=218 participants during the trial. These data constitute the first publicly-accessible genomic data resource for a randomized controlled trial of an intervention targeting the biology of aging. Datasets include whole-genome SNP genotypes, and three-timepoint-longitudinal DNA methylation, mRNA, and small RNA datasets generated from blood, skeletal muscle, and adipose tissue samples (total sample n=2327). The CALERIE Genomic Data Resource described in this article is available from the Aging Research Biobank. This multi-tissue, multi-omic, longitudinal data resource has great potential to advance translational geroscience.

genomics↗

bioRxiv2024

A torpor-like state (TLS) in mice slows blood epigenetic aging and prolongs healthspan

Torpor and hibernation are extreme physiological adaptations of homeotherms associated with pro-longevity effects. Yet the underlying mechanisms of how torpor affects aging, and whether hypothermic and hypometabolic states can be induced to slow aging and increase health span, remain unknown. We demonstrate that the activity of a spatially defined neuronal population in the avMLPA, which has previously been identified as a torpor-regulating brain region, is sufficient to induce a torpor like state (TLS) in mice. Prolonged induction of TLS slows epigenetic aging across multiple tissues and improves health span. We isolate the effects of decreased metabolic rate, long-term caloric restriction, and decreased core body temperature (Tb) on blood epigenetic aging and find that the pro-longevity effect of torpor-like states is mediated by decreased Tb. Taken together, our findings provide novel mechanistic insight into the pro-longevity effects of torpor and hibernation and support the growing body of evidence that Tb is an important mediator of aging processes.

physiology↗

bioRxiv2024

MYB68 orchestrates cork differentiation by regulating stem cell proliferation and suberin deposition

Plants have developed specialized barriers to protect and isolate the inner tissues from the environment while maintaining homeostasis. Different barriers are present in various organs and at different growth stages. During secondary growth, the periderm acts as the protective tissue, covering roots, stems, and branches as they become thick. The periderm is a dynamic barrier comprising a stem cell niche known as the cork cambium, which bifacially divides to generate the phelloderm inward and the cork outward. Cork cells have a unique cell wall impregnated with suberin and lignin polymers, essential for the barrier function. Despite its importance, the differentiation process that forms new cork cells from the stem cell is largely unknown. In this work, we identify members of the MYB36-subclade transcription factors as key regulators of cork differentiation. On the one hand, this set of transcription factors promotes suberin deposition by inducing the expression of enzymes involved in all steps of suberin biosynthesis, including the recently discovered suberin-polymerizing enzymes GDS Lipases; on the other hand, it represses cork cambium proliferation. Furthermore, we demonstrated that suberin deposition in the cork is a robust process regulated by a complex network of transcription factors, including other MYB transcription factors that activate suberin deposition in the endodermis. However, only members of the MYB36 subclade can repress cell proliferation in different developmental contexts, highlighting general and specific functions for MYB transcription factors. These findings have broad applicability, as tissue-specific manipulation of MYB activity has the potential for improving traits of biotechnological interest, such as thicker periderms and more suberized cork layers, and for assessing how these traits affect plant performance in response to stresses.

plant biology↗

bioRxiv2023

Cross-species and tissue imputation of species-level DNA methylation samples across mammalian species.

DNA methylation data offers valuable insights into various aspects of mammalian biology. The recent introduction and large-scale application of the mammalian methylation array has significantly expanded the availability of such data across conserved sites in many mammalian species. In our study, we consider 13,245 samples profiled on this array encompassing 348 species and 59 tissues from 746 species-tissue combinations. While having some coverage of many different species and tissue types, this data captures only 3.6% of potential species-tissue combinations. To address this gap, we developed CMImpute (Cross-species Methylation Imputation), a method based on a Conditional Variational Autoencoder, to impute DNA methylation for non-profiled species-tissue combinations. In cross-validation, we demonstrate that CMImpute achieves a strong correlation with actual observed values, surpassing several baseline methods. Using CMImpute we imputed methylation data for 19,786 new species-tissue combinations. We believe that both CMImpute and our imputed data resource will be useful for DNA methylation analyses across a wide range of mammalian species.

bioinformatics↗

bioRxiv2023

Epigenetic predictors of species maximum lifespan and other life history traits in mammals

Maximum lifespan is an intrinsic characteristic of a biological species and is defined as the longest time an individual of a species has been reported to survive. By analyzing 15K samples derived from 348 mammalian species representing 25 taxonomic orders we previously identified CpG methylation sites associated with maximum lifespan. Here we present accurate DNA methylation-based (DNAm) predictors of maximum lifespan (r=0.89), average gestation time (r=0.96), and age at sexual maturity (r=0.85). Our DNAm maximum lifespan predictor indicates a potential innate longevity advantage for females over males in 17 mammalian species such as humans, red deer, and cattle. The DNAm maximum lifespan predictions do not vary significantly by caloric restriction and partial reprogramming. Genetic disruptions in the somatotropic axis, which includes growth hormone, IGF-1, and their related receptors, have an impact on DNAm maximum lifespan only in select mouse tissues. Cancer mortality rates in major mammalian orders show no correlation with our epigenetic estimates of life history traits. The DNAm maximum lifespan predictor does not detect variation in lifespan between individuals of the same species, such as between the breeds of dogs. We also present the first prototypes of accurate pan mammalian DNAm predictors of sex and tissue type. Collectively, our findings indicate that maximum lifespan is determined, at least in part, by an epigenetic signature that is an intrinsic property of each species and is distinct from the signatures that relate to individual lifespan, which is unaffected by interventions influencing the mortality risk of individuals.

evolutionary biology↗

bioRxiv2023

MammalMethylClock R package: software for DNA Methylation-Based Epigenetic Clocks in Mammals

Epigenetic clocks are prediction methods that relate cytosine methylation levels at specific genomic sites to chronological age, accounting for nuances such as genome mapping information and possibly life history traits such as age at sexual maturity. Defined as multivariate regression models, these DNA methylation-based biomarkers have gained prominence in species conservation efforts and preclinical studies. Once built, these models predict an individuals age from their tissue samples methylation profile, with great potential for aging research, disease risk prediction, gauging intervention impacts. Through the collaborative efforts of our Mammalian Methylation Consortium, weve described epigenetic clocks for numerous mammalian species. Our R package includes the utility for implementing these pre-existing mammalian clocks. Overall, we present software tools and a dedicated R package called MammalMethylClock, designed for the construction and assessment of epigenetic clocks.

bioinformatics↗

bioRxiv2023

Histone mark age of human tissues and cells

BackgroundAging involves intricate epigenetic changes, with histone modifications playing a pivotal role in dynamically regulating gene expression. Our research comprehensively analyzes seven key histone modifications across various tissues to understand their behavior during human aging and formulate age prediction models. ResultsThese histone-centric prediction models exhibit remarkable accuracy and resilience against experimental and artificial noise. They showcase comparable efficacy when compared with DNA methylation age predictors through simulation experiments. Intriguingly, our gene set enrichment analysis pinpoints vital developmental pathways crucial for age prediction. Unlike in DNA methylation age predictors, genes previously recognized in animal studies as integral to aging are amongst the most important features of our models. We also introduce a pan-histone-mark, pan-tissue age predictor that operates across multiple tissues and histone marks, reinforcing that age-related epigenetic markers are not restricted to particular histone modifications. ConclusionOur findings underscore the potential of histone marks in crafting robust age predictors and shed light on the intricate tapestry of epigenetic alterations in aging.

systems biology↗

bioRxiv2023

Reversal of Biological Age in Multiple Rat Organs by Young Porcine Plasma Fraction

Young blood plasma is known to confer beneficial effects on various organs in mice and rats. However, it was not known whether plasma from young pigs rejuvenates old rat 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=613 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=1366 human tissue samples to the training data. We employed these six rat clocks to investigate the rejuvenation effects of a porcine 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. An immunoglobulin G (IgG) N-glycosylation pattern shift from pro-to anti-inflammatory also indicated reversal of glycan aging. Overall, this study demonstrates that a young porcine plasma-derived treatment markedly reverses aging in rats according to epigenetic clocks, IgG glycans, and other biomarkers of aging.

developmental biology↗

bioRxiv2023

COGNITIVE REJUVENATION IN OLD RATS BY HIPPOCAMPAL OSKM GENE THERAPY

Impaired performance in spatial learning and memory during aging in rats is associated with morphological and molecular changes in the brain, particularly in the hippocampus. Here, we assessed the cognitive performance of young (3.5 mo.) untreated rats and old (25.3 mo.) treated and control rats. Treatment was carried out by intrahippocampal injection of an adenovector that carries the GFP reporter gene as well as the 4 Yamanaka genes. Learning and spatial memory performance were assessed by means of the Barnes maze test. The learning performance of the OSKM-treated old rats was significantly improved compared to that of the control old counterparts. A marginal (P=0.06) improvement in the spatial memory was recorded in the treated versus control old rats. OSKM gene expression induced no pathological changes in the brain. The morphology and number of hippocampal cell populations like astrocytes and mature neurons did not show any changes with the treatment in the old rats as compared with the control old counterparts. The rat pan tissue DNAm age marker revealed that old OSKM gene-treated rats show a trend towards a decrease in epigenetic age. The Limma package was used to assess differential methylation by fitting linear models to the methylation data for specific group comparisons. Comparison of differential methylation between old treated and old control hippocampal DNA samples identified 671 differentially methylated CpGs probes (DPMs) in the DNA of OSKM-treated hippocampi (p<0.05). Assessment of the DPMs in old versus young controls revealed the presence of 1,279 hypomethylated CpGs near the promoter regions in young hippocampi (versus old controls) and 914 hypermethylated CpGs near the promoter in young hippocampi compared to old control hippocampi. We found a subset of 174 hypomethylated CpGs in the hippocampal DNA from old OSKM rats and young controls both compared with old control hippocampi. This means that in the hippocampal DNA there is a common set of CpGs which are hypermethylated during aging and are demethylated by the OSKM genes. This observation suggested that in these 174 CpGs the hypermethylation induced by aging is reversed by the demethylation effect of the OSKM genes on the same 174 CpGs. This observation can be interpreted as a rejuvenation effect of the OSKM genes of the old hippocampal methylome. Our results extend to the rat the evidence that viral vector-mediated delivery of the Yamanaka genes in the brain has strong regenerative effects without adverse side effects.

neuroscience↗

bioRxiv2023

Fundamental equations linking methylation dynamics to maximum lifespan in mammals

We establish the mathematical foundation that links the rate of change in any molecular biomarker to species lifespan. Specifically, we propose a robust approach that identifies the strong inverse relationship for certain biomarkers using two comprehensive methylation datasets. After examining 54 chromatin states, we found the rates of change of CpG sites in bivalent chromatin states are negatively associated to the lifespans of 90 dog breeds in the first dataset, and the discoveries are further strengthened with 125 mammalian species in the second dataset. Our research leads to three key findings: First, a reciprocal relationship exists between the average rate of methylation change (AROCM) in bivalent promoter regions and maximum lifespan: AROCM {propto} 1/MaxLifespan. Second, the correlation between age and average methylation bears no relation to maximum lifespan, Cor(Methly,Age) {perp} MaxLifespan. Third, the rate of methylation change in young animals is related to that in old animals: Young animals AROCM {propto} Old AROCM. These findings hinge on the chromatin context, as different results emerge when defining AROCM using different chromatin states. Our analytical framework is versatile and readily extendable to a broad range of other molecular assessments. Overall, our study demonstrates that epigenetic aging rates in specific chromatin states exhibit an inverse relationship with maximum lifespan in mammals.

evolutionary biology↗

bioRxiv2023

Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature aging.

Unlike aged somatic cells, which exhibit a decline in molecular fidelity and eventually reach a state of replicative senescence, pluripotent stem cells can indefinitely replenish themselves while retaining full homeostatic capacity. The conferment of beneficial-pluripotency related traits via in vivo partial cellular reprogramming (IVPR) significantly extends lifespan and restores aging phenotypes in mouse models. Although the phases of cellular reprogramming are well characterized, details of the rejuvenation processes are poorly defined. To understand whether epigenetic reprogramming can ameliorate DNA damage, we created reprogrammable accelerated aging mouse model with an ERCC1 mutation. Importantly, using enhanced partial reprogramming by combining small molecules with the Yamanaka factors, we observed potent reversion of DNA damage, significant upregulation of multiple DNA damage repair processes, and restoration of the epigenetic clock. In addition, we present evidence that pharmacological inhibition of ALK5 and ALK2 receptors in TGFb pathway is able to phenocopy some benefits including epigenetic clock restoration suggesting a role in the mechanism of rejuvenation by partial reprogramming.

cell biology↗

bioRxiv2023

Increased hyaluronan by naked mole-rat HAS2 extends lifespan in mice

Abundant high molecular weight hyaluronic acid (HMW-HA) contributes to cancer resistance and possibly longevity of the longest-lived rodent, the naked mole-rat1, 2. To study whether the benefits of HMW-HA could be transferred to other animal species, we generated a transgenic mouse overexpressing naked mole-rat hyaluronic acid synthase 2 gene (nmrHAS2). nmrHAS2 mice showed increase in hyaluronan levels in several tissues, and lower incidence of spontaneous and induced cancer, extended lifespan and improved healthspan. The transcriptome signature of nmrHAS2 mice shifted towards that of longer-lived species. The most striking change observed in nmrHAS2 mice was attenuated inflammation across multiple tissues. HMW-HA reduced inflammation via several pathways including direct immunoregulatory effect on immune cells, protection from oxidative stress, and improved gut barrier function during aging. These findings demonstrate that the longevity mechanism that evolved in the naked mole-rat can be exported to other species, and open new avenues for using HMW-HA to improve lifespan and healthspan.

physiology↗

bioRxiv2023

Pleiotropic Influence of DNA Methylation QTLs on physiological and aging traits

DNA methylation is influenced by genetic and non-genetic factors. Here, we chart quantitative trait loci (QTLs) that modulate levels of methylation at highly conserved CpGs using liver methylome data from mouse strains belonging to the BXD Family. A regulatory hotspot on chromosome 5 had the highest density of trans-acting methylation QTLs (trans-meQTLs) associated with multiple distant CpGs. We refer to this locus as meQTL.5a. The trans-modulated CpGs showed age-dependent changes, and were enriched in developmental genes, including several members of the MODY pathway (maturity onset diabetes of the young). The joint modulation by genotype and aging resulted in a more "aged methylome" for BXD strains that inherited the DBA/2J parental allele at meQTL.5a. Further, several gene expression traits, body weight, and lipid levels mapped to meQTL.5a, and there was a modest linkage with lifespan. DNA binding motif and protein-protein interaction enrichment analysis identified the hepatic nuclear factor, Hnf1a (MODY3 gene in humans), as a strong candidate. The pleiotropic effects of meQTL.5a could contribute to variation in body size and metabolic traits, and influence CpG methylation and epigenetic aging that could have an impact on lifespan.

genomics↗

bioRxiv2022

ERCC1 mice, unlike other premature aging models, display accelerated epigenetic age

Over the last decades, several premature aging mouse models have been developed to study aging and identify interventions that can delay age-related diseases. Yet, it is still unclear whether these models truly recapitulate natural aging. Here, we analyzed DNA methylation in multiple tissues of four previously reported mouse models of premature aging (ERCC1, LAKI, POLG and XPG). We estimated DNA methylation (DNAm) age of these samples using the Horvath clock. The most pronounced increase in DNAm age could be observed in ERCC1 mice, a strain which exhibits a deficit in DNA nucleotide excision repair. In line with these results, we detected an increase in epigenetic age in fibroblasts isolated from patients with progeroid syndromes associated with mutations in DNA excision repair genes. These findings highlight ERCC1 as a particularly attractive mouse model to study aging in mammals and suggest a strong connection between DNA damage and epigenetic dysregulation during aging.

molecular biology↗

bioRxiv2022

Causal Epigenetic Age Uncouples Damage and Adaptation

Machine learning models based on DNA methylation data can predict biological age but often lack causal insights. By harnessing large-scale genetic data through epigenome-wide Mendelian Randomization, we identified CpG sites potentially causal for aging-related traits. Neither the existing epigenetic clocks nor age-related differential DNA methylation are enriched in these sites. These CpGs include sites that contribute to aging and protect against it, yet their combined contribution negatively affects age-related traits. We established a novel framework to introduce causal information into epigenetic clocks, resulting in DamAge and AdaptAge--clocks that track detrimental and adaptive methylation changes, respectively. DamAge correlates with adverse outcomes, including mortality, while AdaptAge is associated with beneficial adaptations. These causality-enriched clocks exhibit sensitivity to short-term interventions. Our findings provide a detailed land-scape of CpG sites with putative causal links to lifespan and healthspan, facilitating the development of aging biomarkers, assessing interventions, and studying reversibility of age-associated changes.

genetics↗

bioRxiv2022

Refining epigenetic prediction of chronological and biological age

Epigenetic clocks can track both chronological age (cAge) and biological age (bAge). The latter is typically defined by physiological biomarkers and risk of adverse health outcomes, including all-cause mortality. As cohort sample sizes increase, estimates of cAge and bAge become more precise. Here, we aim to refine predictors and improve understanding of the epigenomic architecture of cAge and bAge. First, we perform large-scale (N = 18,413) epigenome-wide association studies (EWAS) of chronological age and all-cause mortality. Next, to improve cAge prediction, we use methylation data from 24,673 participants from the Generation Scotland (GS) study, the Lothian Birth Cohorts (LBC) of 1921 and 1936 and 8 publicly available datasets. Through the inclusion of linear and non-linear age-CpG associations from the EWAS, feature pre-selection/dimensionality reduction in advance of elastic net regression, and a leave-one-cohort-out (LOCO) cross validation framework, we arrive at an improved cAge predictor (median absolute error = 2.3 years across 10 cohorts). In addition, we train a predictor of bAge on 1,214 all-cause mortality events in GS, based on epigenetic surrogates for 109 plasma proteins and the 8 component parts of GrimAge, the current best epigenetic predictor of all-cause mortality. We test this predictor in four external cohorts (LBC1921, LBC1936, the Framingham Heart Study and the Womens Health Initiative study) where it outperforms GrimAge in its association to survival (HRGrimAge = 1.47 [1.40, 1.54] with p = 1.08 x 10-52, and HRbAge = 1.52 [1.44, 1.59] with p = 2.20 x 10-60). Finally, we introduce MethylBrowsR, an online tool to visualize epigenome-wide CpG-age associations.

genomics↗

bioRxiv2022

DNA methylation age studies of humpback whales

Several previous studies have described epigenetic clocks for whale and dolphin species. Here we present a novel and highly robust epigenetic clock for the humpback whale based on methylation levels measured using the Mammalian Methylation Array platform. Skin samples were obtained from 76 individuals that had been studied since their birth year and known to range in age from <1 to 39.5 years. The humpback whale clock provided a highly accurate estimate of chronological age (R=0.96, median error 2.2 years) according to a leave-one-out cross validation analysis. We applied this clock to an independent set of samples from humpback whales of unknown exact age but with sighting histories that were as long as or longer than the upper 20% of the available known-age range. Although there was a strong correlation with minimum age (R=0.89), the clock underestimated age in these older animals by a median error of at least 7.8 years. Finally, we applied the humpback clock to publicly available methylation data from beluga whales. In this data set from a different species, the humpback clock provided an age correlation of R=0.78. While a DNAm age estimator has previously been described for humpback whales, this is the first such clock shown to apply to another cetacean species as well. Our humpback whale clock built from well-studied population lends itself for understanding humpback populations that otherwise lack age data.

developmental biology↗