Biology subjects

Dwaraka, V. B.

Publications and source records attributed to Dwaraka, V. B..

11 recordsLinked to original sources

bioRxiv2025

Epigenetic markers of middle-age: non-linear DNA methylation changes with aging in humans

BackgroundHuman DNA is known to exhibit an overall tendency toward demethylation with aging. However, assuming a simple linear relationship between DNA methylation and age does not align with the phenotype of human development and the aging process. This study aimed to investigate the existence of DNA methylation patterns with peaks or troughs at specific ages in addition to simple linear changes. MethodsA large-scale dataset of genome-wide DNA methylation data from 10,420 individuals was analyzed. Hierarchical multiple regression models were applied to detect patterns of the association between age and DNA methylation: linear increase, linear decrease, U-shaped curve, and inverse U-shaped curve. ResultsAmong the 864,627 CpG sites analyzed, 8.4% exhibited an increase in DNA methylation with age, 23.9% showed a decrease, and 5.5% were better explained by a quadratic model (P < 5.7815x10 ). Within the non-linear subset, inverse U-shaped CpG sites peaking in methylation during middle age were predominant. Genes exhibiting quadratic association patterns between DNA methylation and age, and those linked to diseases with common onset during middle age, were also detected. ConclusionsNon-linear age-related DNA methylation patterns, with peaks or troughs occurring at specific ages, were detected. This suggests that humans do not simply age linearly, but that programmed mechanisms or cascade-like processes may exist to promote or suppress the expression of specific genes at certain ages, contributing onset of certain diseases at specific timings.

genomics↗

bioRxiv2025

Brain-epigenome wide association study (BEWAS) on the effects of two emerging psychedelics: ketamine & MDMA

Psychedelic compounds such as ketamine and MDMA have shown therapeutic promise for mood and trauma-related disorders, yet their molecular mechanisms remain unclear. This study applied a Brain-Epigenome-Wide Association Study (BEWAS) to assess DNA methylation changes in brain-enriched genes following treatment. Pre- and post-treatment blood (ketamine, N = 20) and saliva (MDMA, N = 16) samples from clinical trial participants were analyzed. Ketamine altered methylation at 1,210 CpG sites; MDMA affected 2,074 CpG sites. Functional enrichment analyses revealed changes in genes involved in neuroplasticity, immune regulation, and mental processes. Overlapping effects were observed in genes such as PTPRN2 and SHANK2, suggesting shared epigenetic mechanisms in driving increased neuroplasticity. These findings highlight psychedelics capacity to induce coordinated, lasting molecular changes relevant to neuroimmune function and psychiatric health.

genomics↗

bioRxiv2025

Non-linear Age-related Change in Human Interleukin-11 and the receptor subunit alpha DNA Methylation

IntroductionInterleukin-11 (IL-11) is a cytokine involved in inflammatory processes and a previous study showed that blocking or knocking down IL11 in mice prolongs a healthy lifespan. This study investigates DNA methylation (DNAm) changes in the IL11 and IL-11 receptor subunit alpha (IL-11RA) gene across ages to reveal how aging might influence IL-11 production and sensitivity. MethodsA genome-wide DNAm database focusing on Cytosine-phosphate-Guanine (CpG) sites within the IL11 and IL11RA was analyzed. Hierarchical regression analyses examined the relationship between DNAm, age, and the squared age term for quadratic associations. ResultsThe database comprised 10,297 samples (5,156 males and 5,141 females) with a mean age of 53.9 years (SD = 14.1 years). The majority of IL11 and IL11RA CpG sites in the TSS1500 and 3UTR regions exhibited significant inverse U-shaped associations with age. DNAm levels were low during youth, increased in middle age (40s-50s), and decreased again in older age. ConclusionThe observed inverse U-shaped DNAm patterns in the IL11 and IL11RA suggest n non-linear, age-related regulation of IL-11 expression and sensitivity. These findings indicate that IL-11 may have different roles across life stages and suggest that therapeutic interventions targeting IL-11 should consider age-specific effects.

genetics↗

bioRxiv2024

DNAm aging biomarkers are responsive: Insights from 51 longevity interventional studies in humans

Aging biomarkers can potentially allow researchers to rapidly monitor the impact of an aging intervention, without the need for decade-spanning trials, by acting as surrogate endpoints. Prior to testing whether aging biomarkers may be useful as surrogate endpoints, it is first necessary to determine whether they are responsive to interventions that target aging. Epigenetic clocks are aging biomarkers based on DNA methylation with prognostic value for many aging outcomes. Many individual studies are beginning to explore whether epigenetic clocks are responsive to interventions. However, the diversity of both interventions and epigenetic clocks in different studies make them difficult to compare systematically. Here, we curate TranslAGE-Response, a harmonized database of 51 public and private longitudinal interventional studies and calculate a consistent set of 16 prominent epigenetic clocks for each study, along with 95 other DNAm biomarkers that help explain changes in each clock. With this database, we discover patterns of responsiveness across a variety of interventions and DNAm biomarkers. For example, clocks trained to predict mortality or pace of aging have the strongest response across all interventions and show consistent agreement with each other, pharmacological and lifestyle interventions drive the strongest response from DNAm biomarkers, and study population and study duration are key factors in driving responsiveness of DNAm biomarkers in an intervention. Some classes of interventions such as TNF-alpha inhibitors have strong, consistent effects across multiple studies, while others such as senolytic drugs have inconsistent effects. Clocks with multiple sub-scores (i.e. "explainable clocks") provide specificity and greater mechanistic insight into responsiveness of interventions than single-score clocks. Our work can help the geroscience field design future clinical trials, by guiding the choice of interventions, specific subsets of epigenetic clocks to minimize multiple testing, study duration, study population, and sample size, with the eventual aim of determining whether epigenetic clocks can be used as surrogate endpoints.

systems biology↗

bioRxiv2024

The Impact of a Natural Ingredients based Intervention Targeting the Nine Hallmarks of Aging on DNA methylation

Aging interventions have progressed in recent years due to the growing curiosity about how lifestyle impacts longevity. This study assessed the effects of SRW Laboratories Cel System nutraceutical range on epigenetic methylation patterns, inflammation, physical performance, body composition, and epigenetic biomarkers of aging. A 1-year study was conducted with 51 individuals, collecting data at baseline, 3 months, 6 months, and 12 months. Participants were encouraged to walk 10 minutes and practice 5 minutes of mindfulness daily. Significant improvements in muscle strength, body function, and body composition metrics were observed. Epigenetic clock analysis showed a decrease in biological age with significant reductions in stem cell division rates. Immune cell subset analysis indicated significant changes, with increases in eosinophils and CD8T cells and decreases in B memory, CD4T memory, and T-regulatory cells. Predicted epigenetic biomarker proxies (EBPs) showed significant changes in retinol/TTHY, a regulator of cell growth, proliferation, and differentiation, and deoxycholic acid glucuronide levels, a metabolite of deoxycholic acid generated in the liver. Gene ontology analysis revealed significant CpG methylation changes in genes involved in critical biological processes related to aging, such as oxidative stress-induced premature senescence, pyrimidine deoxyribonucleotide metabolic process, TRAIL binding, hyaluronan biosynthetic process, neurotransmitter loading into synaptic vesicles, pore complex assembly, collagen biosynthetic process, protein phosphatase 2A binding activity, and activation of transcription factor binding. Our findings suggest that the Cel System supplement range may effectively reduce biological age and improve health metrics, warranting further investigation into its mechanistic pathways and long-term efficacy.

genomics↗

bioRxiv2024

A genome-wide association study of mass spectrometry proteomics using the Seer Proteograph platform

Genome-wide association studies (GWAS) with proteomics are essential tools for drug discovery. To date, most studies have used affinity proteomics platforms, which have limited discovery to protein panels covered by the available affinity binders. Furthermore, it is not clear to which extent protein epitope changing variants interfere with the detection of protein quantitative trait loci (pQTLs). Mass spectrometry-based (MS) proteomics can overcome some of these limitations. Here we report a GWAS using the MS-based Seer ProteographTM platform with blood samples from a discovery cohort of 1,260 American participants and a replication in 325 individuals from Asia, with diverse ethnic backgrounds. We analysed 1,980 proteins quantified in at least 80% of the samples, out of 5,753 proteins quantified across the discovery cohort. We identified 252 and replicated 90 pQTLs, where 30 of the replicated pQTLs have not been reported before. We further investigated 200 of the strongest associated cis-pQTLs previously identified using the SOMAscan and the Olink platforms and found that up to one third of the affinity proteomics pQTLs may be affected by epitope effects, while another third were confirmed by MS proteomics to be consistent with the hypothesis that genetic variants induce changes in protein expression. The present study demonstrates the complementarity of the different proteomics approaches and reports pQTLs not accessible to affinity proteomics, suggesting that many more pQTLs remain to be discovered using MS-based platforms. Graphical AbstractSummarizing the approach taken to identify potential epitope effects. O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/596028v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@34d11aorg.highwire.dtl.DTLVardef@18c0211org.highwire.dtl.DTLVardef@dbb003org.highwire.dtl.DTLVardef@1009fa7_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2024

Creation and Validation of the First Infinium DNA Methylation Array for the Human Imprintome

BackgroundDifferentially methylated imprint control regions (ICRs) regulate the monoallelic expression of imprinted genes. Their epigenetic dysregulation by environmental exposures throughout life results in the formation of common chronic diseases. Unfortunately, existing Infinium methylation arrays lack the ability to profile these regions adequately. Whole genome bisulfite sequencing (WGBS) is the unique method able to profile these regions, but it is very expensive and it requires not only a high coverage but it is also computationally intensive to assess those regions. FindingsTo address this deficiency, we developed a custom methylation array containing 22,819 probes. Among them, 9,757 probes map to 1,088 out of the 1,488 candidate ICRs recently described. To assess the performance of the array, we created matched samples processed with the Human Imprintome array and WGBS, which is the current standard method for assessing the methylation of the Human Imprintome. We compared the methylation levels from the shared CpG sites and obtained a mean R2 = 0.569. We also created matched samples processed with the Human Imprintome array and the Infinium Methylation EPIC v2 array and obtained a mean R2 = 0.796. Furthermore, replication experiments demonstrated high reliability (ICC: 0.799-0.945). ConclusionsOur custom array will be useful for replicable and accurate assessment, mechanistic insight, and targeted investigation of ICRs. This tool should accelerate the discovery of ICRs associated with a wide range of diseases and exposures, and advance our understanding of genomic imprinting and its relevance in development and disease formation throughout the life course.

genetics↗

bioRxiv2023

Retroelement-Age Clocks: Epigenetic Age Captured by Human Endogenous Retrovirus and LINE-1 DNA methylation states

Human endogenous retroviruses (HERVs), the remnants of ancient viral infections embedded within the human genome, and long interspersed nuclear elements 1 (LINE-1), a class of autonomous retrotransposons, are silenced by host epigenetic mechanisms including DNA methylation. The resurrection of particular retroelements has been linked to biological aging. Whether the DNA methylation states of locus specific HERVs and LINEs can be used as a biomarker of chronological age in humans remains unclear. We show that highly predictive epigenetic clocks of chronological age can be constructed from retroelement DNA methylation states in the immune system, across human tissues, and pan-mammalian species. We found retroelement epigenetic clocks were reversed during transient epigenetic reprogramming, accelerated in people living with HIV-1, responsive to antiretroviral therapy, and accurate in estimating long-term culture ages of human brain organoids. Our findings support the hypothesis of epigenetic dysregulation of retroelements as a potential contributor to the biological hallmarks of aging.

immunology↗

bioRxiv2023

OMICmAge: An integrative multi-omics approach to quantify biological age with electronic medical records

Biological aging is a multifactorial process involving complex interactions of cellular and biochemical processes that is reflected in omic profiles. Using common clinical laboratory measures in ~30,000 individuals from the MGB-Biobank, we developed a robust, predictive biological aging phenotype, EMRAge, that balances clinical biomarkers with overall mortality risk and can be broadly recapitulated across EMRs. We then applied elastic-net regression to model EMRAge with DNA-methylation (DNAm) and multiple omics, generating DNAmEMRAge and OMICmAge, respectively. Both biomarkers demonstrated strong associations with chronic diseases and mortality that outperform current biomarkers across our discovery (MGB-ABC, n=3,451) and validation (TruDiagnostic, n=12,666) cohorts. Through the use of epigenetic biomarker proxies, OMICmAge has the unique advantage of expanding the predictive search space to include epigenomic, proteomic, metabolomic, and clinical data while distilling this in a measure with DNAm alone, providing opportunities to identify clinically-relevant interconnections central to the aging process.

bioinformatics↗

bioRxiv2023

A meta-analysis of immune cell fractions at high resolution reveals novel associations with common phenotypes and health outcomes

AbstractO_ST_ABSBackgroundC_ST_ABSChanges in cell-type composition of complex tissues are associated with a wide range of diseases, environmental risk factors and may be causally implicated in disease development and progression. However, these shifts in cell-type fractions are often of a low magnitude, or involve similar cell-subtypes, making their reliable identification challenging. DNA methylation profiling in a tissue like blood is a promising approach to discover shifts in cell-type abundance, yet studies have only been performed at a relatively low cellular resolution and in isolation, limiting their power to detect these shifts in tissue composition. MethodsHere we derive a DNA methylation reference matrix for 12 immune cell-types in human blood and extensively validate it with flow-cytometric count data and in whole-genome bisulfite sequencing data of sorted cells. Using this reference matrix and Stouffers method, we perform a meta-analysis encompassing 25,629 blood samples from 22 different cohorts, to comprehensively map associations between the 12 immune-cell fractions and common phenotypes, including health outcomes. ResultsOur meta-analysis reveals many associations with age, sex, smoking and obesity, many of which we validate with single-cell RNA-sequencing. We discover that T-regulatory and naive T-cell subsets are higher in women compared to men, whilst the reverse is true for monocyte, natural killer, basophil and eosinophil fractions. In a large subset encompassing 5000 individuals we find associations with stress, exercise, sleep and health outcomes, revealing that naive T-cell and B-cell fractions are associated with a reduced risk of all-cause mortality independently of age, sex, race, smoking, obesity and alcohol consumption. We find that decreased natural killer cell counts are associated with smoking, obesity and stress levels, whilst an increased count correlates with exercise, sleep and a reduced risk of all-cause mortality. ConclusionsThis work derives and extensively validates a high resolution DNAm reference matrix for blood, and uses it to generate a comprehensive map of associations between immune cell fractions and common phenotypes, including health outcomes. AvailabilityThe 12 immune cell-type DNAm reference matrices for Illumina 850k and 450k beadarrays alongside tools for cell-type fraction estimation are freely available from our EpiDISH Bioconductor R-package http://www.bioconductor.org/packages/devel/bioc/html/EpiDISH.html

bioinformatics↗

bioRxiv2022

Skeletal muscle DNA methylation and mRNA responses to a bout of higher versus lower load resistance exercise in previously trained men

We sought to determine the skeletal muscle genome-wide DNA methylation and mRNA responses to one bout of lower-load (LL) versus higher-load (HL) resistance exercise. Trained college-aged males (n=11, 23{+/-}4 years old, 4{+/-}3 years self-reported training) performed LL or HL bouts to failure separated by one week. The HL bout (i.e., 80 Fail) consisted of four sets of back squats and four sets of leg extensions to failure using 80% of participants estimated one-repetition maximum (i.e., est. 1-RM). The LL bout (i.e., 30 Fail) implemented the same paradigm with 30% of est. 1-RM. Vastus lateralis muscle biopsies were collected before, 3 hours, and 6 hours after each bout. Muscle DNA and RNA were batch-isolated and analyzed using the 850k Illumina MethylationEPIC array and Clariom S mRNA microarray, respectively. Performed repetitions were significantly greater during the 30 Fail versus 80 Fail (p<0.001), although total training volume (sets x reps x load) was not significantly different between bouts (p=0.571). Regardless of bout, more CpG site methylation changes were observed at 3-versus 6-hours post exercise (239,951 versus 12,419, respectively; p<0.01), and nuclear global ten-eleven translocation (TET) activity, but not global DNA methyltransferase activity, increased 3- and 6-hours following exercise regardless of bout. The percentage of genes significantly altered at the mRNA level that demonstrated opposite DNA methylation patterns was greater 3- versus 6-hours following exercise (~75% versus ~15%, respectively). Moreover, high percentages of genes that were up- or downregulated 6 hours following exercise also demonstrated significantly inversed DNA methylation patterns across one or more CpG sites 3 hours following exercise (65% and 82%, respectively). While 30 Fail decreased DNA methylation across various promoter regions versus 80 Fail, transcriptome-wide mRNA and bioinformatics indicated that gene expression signatures were largely similar between bouts. Bioinformatics overlay of DNA methylation and mRNA expression data indicated that genes related to "Focal adhesion", "MAPK signaling", and "PI3K-Akt signaling" were significantly affected at the 3- and 6-hour time points, and again this was regardless of bout. In conclusion, extensive molecular profiling suggests that post-exercise alterations in the skeletal muscle DNA methylome and mRNA transcriptome elicited by LL and HL training bouts to failure are largely similar, and this could be related to equal volumes performed between bouts.

molecular biology↗