Biology subjects

Seale, K.

Publications and source records attributed to Seale, K..

7 recordsLinked to original sources

bioRxiv2026

Whole-blood DNA-methylation patterns during portable-sauna use in firefighters: an exploratory, single-arm pilot study

Research in model organisms has consistently shown that mild, non ethal heat stress can prolong lifespan. Although causal data are lacking in more complex animals, human observational research has linked sauna bathing to cardiovascular protection and improved age related outcomes. To examine whether sauna use may influence aging related biology, we retrospectively analyzed longitudinal whole-blood methylomic data from 18 firefighters who used a portable sauna. A separately processed cohort of 36 matched adults provided descriptive context; firefighters showed higher DNA methylation estimated maximal oxygen uptake (DNAmVO2 max), lower AdaptAge, and higher DamAge. After 8 to 18 weeks, eight predictors met a within family Benjamini Hochberg false discovery rate (FDR) threshold of <0.05 underage/sex-adjusted epigenetic age acceleration: PCDNAmTL, DepressionBarbu, SystemsAge Blood, SystemsAge Lung, DNAmPulsePressure, DNAmHDL, DNAmCystatinC, and DNAmDHEAS. DNAmDHEAS increased, whereas the other predictors changed in directions consistent with short term findings for high intensity interval training, another hormetic stressor. None met the within family FDR threshold after adjustment for 12 cell leukocyte composition, although effect estimates were not uniformly eliminated. At individual cytosine-phosphate-guanine (CpG) sites, BACON empirical null calibration retained 126 acute and 329 long-term candidates at P<0.0001; none was FDR-significant. DMRcate identified five acute and 140 long-term differentially methylated regions using a harmonic mean of individual CpG FDR values <0.05. Long-term gometh analysis also identified ATP binding cassette (ABC) transporter enrichment (FDR=0.026). These exploratory findings suggest that portable-sauna use may influence the blood methylome within 8 to 18 weeks while underscoring the importance of leukocyte-composition and technical sensitivity analyses.

physiology↗

bioRxiv2026

Creating DNAm Algorithms Using the Illumina Methylation Screening Array (MSA)

Most established DNA methylation (DNAm) biomarkers were developed on legacy Illumina EPIC arrays. The Infinium Methylation Screening Array (MSA) offers a lower-cost, higher-throughput alternative with reduced probe content, but EPIC-trained algorithms cannot be assumed to transfer directly. Here we present a reproducibility-based framework for developing and transferring DNAm algorithms on the MSA. Using paired biological replicates profiled on EPICv1 and MSA (1,764 EPICv1-MSA sample pairs, plus within-array MSA replicates on the same and different beadchips), we quantified probe-level agreement using mean absolute error (MAE) and intraclass correlation coefficients (ICC). Of 140,150 CpG sites shared between EPICv1 and MSA, 40,786 (29.1%) met both stability criteria (MAE < 0.05 and ICC(2,k) > 0.6). This stable feature space supported two modelling streams. First, we trained 134 epigenetic biomarker proxies (EBPs) natively on MSA, with and without kernel principal component analysis (kPCA) for sample-level harmonisation. All 134 reached same-beadchip ICC(2,1) >= 0.80 (median 0.97) and 96.3% reached different-beadchip ICC(2,1) >= 0.60 (median 0.81), with a median Spearman correlation of 0.48 against observed values. Among the 72 kPCA-selected models with a comparable stable-probe baseline, 70 (97%) showed higher cross-beadchip ICC (median improvement +0.18). Second, we transferred three established clocks using model-specific strategies: OMICmAge and SystemsAge were retrained to estimate their EPICv1-derived values (held-out test-set rho = 0.944 and 0.912-0.949), whereas DunedinPACE required stable-probe normalisation and robust linear calibration, which raised cross-array ICC(2,1) from 0.784-0.810 to 0.891-0.925 and reduced MAE from 0.085-0.089 to 0.041-0.050 across three sample sets. Reduced probe content does not preclude reproducible DNAm biomarker measurement, and transfer strategy must be matched to model architecture.

bioinformatics↗

bioRxiv2026

Skin DNA Methylation Encodes Multidimensional Facial Aging Phenotypes with Distinct Biological Architectures

Whether distinct visible aging traits, e.g., wrinkling, pigmentation, and inflammation, reflect shared or independent epigenetic programs remains unknown; existing clocks compress aging into a single chronological axis, leaving the phenotype-specific architecture of cutaneous aging uncharacterized. Here, we integrate AI-derived facial phenotypes with skin DNA methylation profiles from 706 individuals to develop EpiVision, a panel of 21 epigenetic predictors spanning structural, pigmentary, inflammatory, and textural aging traits. Predictors reveal shared and trait-specific pathways, including developmental patterning, epithelial remodeling, hormonal signaling, and UV damage responses, and capture environmentally induced acceleration in sun-exposed skin alongside lifestyle and topical treatment-associated variation. These findings establish that visible skin aging comprises molecularly distinct axes with shared regulatory substrates and trait-specific drivers, providing a scalable epigenetic framework for intervention evaluation and aging biology research.

genomics↗

bioRxiv2025

DNA Methylation Ageing Atlas Across 17 Human Tissues

Aging involves widespread epigenetic remodeling across tissues, yet the nature and consistency of these changes remain unclear. We conducted a meta-analysis of more than 15,000 human methylomes spanning 17 tissues, identifying both conserved and tissue-specific aging signatures. We examined linear changes via differentially methylated positions, variability shifts via variably methylated positions, and Shannon-entropy to capture methylation disorder. Network analysis revealed fragile co-methylation modules largely resistant to beneficial perturbation. Key disruptors, including PCDHGA1, MEST, HDAC4, and HOX genes, exacerbated aging signals across tissues. Notably, a resilient module enriched for NAD{square} salvage metabolism supports therapeutic targeting of NAD{square} in aging. PCDHGA1 emerged as a conserved cross-tissue driver, suggesting protocadherin-mediated adhesion plays a broader role in maintaining structural and signaling stability in multiple organ systems. Our open-access atlas provides a foundational resource for dissecting the molecular architecture of human aging and identifying testable targets for intervention, biomarkers, and translational epigenetic therapies.

bioinformatics↗

bioRxiv2023

A comprehensive map of the ageing blood methylome

During ageing, the human methylome exhibits both differential (i.e. change in mean) and variable (i.e. change in variance) shifts, along with a general rise in entropy. However, it remains unclear whether DNA methylation sites that increasingly diverge between people (i.e. variably methylated positions (VMPs)) are distinct from those undergoing changes in mean methylation levels (i.e. differentially methylated positions (DMPs)), which changes drive entropy, how they contribute to epigenetic age measured by epigenetic clocks, and whether cell type heterogeneity plays a role in these alterations. To address these questions, we conducted a comprehensive analysis using > 32,000 human blood methylomes from 56 datasets (age range = 6-101 years). Our findings revealed an unprecedented proportion of the blood methylome that is differentially methylated with age (48% DMPs; FDR< 0.005) and variably methylated with age (37% VMPs; FDR< 0.005), with many sites overlapping between the two groups (59% of DMPs are VMPs). We observed that bivalent and Polycomb regions become increasingly methylated and divergent between individuals, while quiescent regions lose methylation in a more homogeneous manner between individuals. Unexpectedly, both chronological and biological clocks, but not pace-of-aging clocks, show a strong enrichment for those CpGs that accrue both mean and variance changes during aging. Furthermore, we uncovered that it is the accumulation of DMPs shifting towards a methylation fraction of 50% that drive the increase in entropy, resulting in an overall smoothening of the epigenetic landscape. However, approximately a quarter of DMPs oppose this direction of change, exhibiting anti-entropic effects. While DMPs were mostly unaffected by changes in cell type composition, VMPs and entropy measurements showed moderate sensitivity to such alterations. This investigation represents the largest to date of genome-wide DNA methylation changes and ageing in a single tissue, offering valuable insights into primary molecular changes that hold meaning for chronological and biological ageing.

molecular biology↗

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

Exercise rejuvenates the skeletal muscle methylome and transcriptome in humans

Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late-life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta-analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle samples (n = 3,176). We show that: 1) individuals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, 2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns towards a younger profile, and 3) muscle disuse "ages" the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted towards a younger state after exercise training interventions, while the transcriptome shifted towards an older state after forced muscle disuse. We demonstrate that exercise training targets many of the age-related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity.

molecular biology↗