Clinical Epigenetics

Biological ageing begins before birth, with early-life exposures shaping late-life health. These exposures drive health inequities early, yet specific exposures and the composition of the ageing exposome remain largely undefined. This gap may persist as the field lacks agnostic investigations accounting for non-linearity, interactions and subtle signals. We aimed to identify exposures predictive of epigenetic ageing accumulated during childhood and adolescence and explore the composition of the...

BackgroundPATZ1 fusion-positive central nervous system (CNS) tumors frequently harbor MN1::PATZ1 fusions as driver mutations, provisionally classified as a rare DNA methylation class of low-grade neuroepithelial tumors. Radiographically, they resemble pilocytic astrocytomas with tumor and cystic components, but their supratentorial cortex location and higher recurrence rates are distinguishing features. An intermediate clinical course, despite focal high-grade histopathology, underscores the nee...

Epigenetic clocks estimate biological age from DNA methylation patterns at CpG sites, providing robust predictions of mortality and morbidity risk. "Blue zones"--regions of exceptional longevity--offer a unique opportunity to investigate how biological aging diverges from chronological age. However, standard clocks are typically trained on large, heterogeneous datasets, reflecting average population trends rather than region-specific dynamics. Using data from the Costa Rican Longevity and Health...

Meningiomas are the most common primary brain tumors and, despite their benign reputation, often behave aggressively. Meningiomas are morphologically heterogeneous, yet the full significance of their histologic diversity is unclear. This is in large part because many features are not readily quantifiable by traditional observer-based light microscopy. Molecular testing improves prognostic stratification, but is not universally accessible. We therefore sought to determine whether an artificial in...

Ewing sarcoma (EwS) is a rare, aggressive pediatric malignancy driven by FET::ETS family fusions (EWSR1::FLI1 in >85% of cases) with no established environmental risk factors. To investigate germline predisposition, we analyzed 2,014 EwS cases and 10,525 cancer-free controls in a two-stage analysis that combined an international genome-wide association study and a case{square}parent trio study. The combined meta-analysis identified 18 variants at 14 susceptibility loci (9 novel, 5 replicated) wi...

Study question: How is glycodelin, a glycoprotein secreted by reproductive tissues, causally related to reproductive diseases and traits? Summary answer: We present evidence for a causal role of sex hormones in determining glycodelin levels, but limited evidence that glycodelin subsequently causally impacts reproductive traits. What is known already: Glycodelin is expressed in female and male reproductive tissues and has four glycoforms (-A, -C, -F and -S), with the glycosylation pattern determi...

Very preterm infants (<30 weeks gestation) are at elevated risk for neurodevelopmental and social-behavioral challenges. DNA methylation (DNAm) may provide a biological link between preterm birth and later behavioral outcomes. We examined associations between DNAm profiles at neonatal intensive care unit (NICU) discharge and at age 5 with Social Responsiveness Scale (SRS) scores which measure social communication, social interaction, and repetitive behaviors at age 5, including sex-specific effe...

BackgroundColorectal carcinoma (CRC) remains a significant cause of cancer morbidity and mortality worldwide. Right- and left-sided tumours differ in clinical, morphological, and molecular features. Microsatellite instability-high (MSI-H) tumours, often right-sided, are associated with distinct histopathological characteristics and prognostic implications. In Sri Lanka, molecular MSI testing is currently unavailable, highlighting the need for alternative predictive approaches. ObjectivesGeneral...

BackgroundThe present study examines the link between DNA methylation at the nerve growth factor-induced protein A (NGFI-A) binding domain of the NR3C1 1F promoter and later cognitive functions in children from families living in disadvantaged psychosocial conditions. MethodsParticipants were 132 children who took part in a Swiss Parents as Teachers (PAT) randomized controlled trial (72 in the intervention group, 60 in the control group). DNA methylation was quantified from saliva samples colle...

IntroductionUnderstanding the links between metabolism, ageing and age-related phenotypes may clarify the role of ageing in disease onset and improve risk prediction. MethodsWe conducted a cross-cohort assessment of biological age using broad-spectrum LC-MS metabolomics in 2,295 participants, aged 20-89, from the UK Airwave study (N=960) and The Irish Longitudinal Study of Ageing (N=1,335). ResultsN2,N2-dimethylguanosine, C-glycosyltryptophan, bile acid glucuronides, and zeta-carotene were ass...

Diet is an essential factor influencing biological aging, yet few exsiting dietary indices were specifically developed to target biological aging. We developed a data-driven food-based Empirical Dietary Index for Slower Epigenetic Aging (EDISEA) in the US Health and Retirement Study (HRS, n=7,398), which predicted deceleration of GrimAge, an established DNA methylation-based epigenetic clock. Participants in the highest versus lowest EDISEA quintile had 4.65-year deceleration in GrimAge (P value...

IntroductionResearch has shown that social and physical stressors of early-life adversity (ELA) can negatively affect long-term health trajectories. Despite differences in types of ELA exposure, previous studies have identified common health-related outcomes in adults who had experienced less favourable conditions during developmentally sensitive periods. This meta-analysis investigates the potential role of DNA methylation in mediating these adverse health trajectories by identifying common bio...

BackgroundEpigenetic clocks based on DNA methylation (DNAm) provide quantitative indicators of biological aging. However, the extent to which diverse lifestyle factors influence DNAm-based aging measures remains unclear, especially in Japanese populations. We aimed to evaluate the associations between 52 lifestyle-related factors and multiple epigenetic aging indicators, including six DNAm ages (Horvath, Hannum, PhenoAge, GrimAge, GrimAge v2, and PCPhenoAge specific to Japanese Population), the ...

Cellular senescence increases in frequency with age and is implicated in age-related pathologies, and identifying circulating biomarkers of senescence holds great diagnostic potential. Circulating senescence signatures are predictive of many age-related traits and diseases, though cell type-specific senescence signatures have not been comprehensively explored. In this study, senescence signatures from the Senescence Catalog (SenCat), including 14 human cell types such as peripheral blood mononuc...

Advances in our understanding of the biology of skeletal muscle ageing are being made at pace, with great potential for these findings to inform the identification of novel treatments for sarcopenia. However, translation of findings from animal models to humans has been hampered by limitations of existing human muscle biopsy studies. Devised to directly address this challenge, the Muscle Ageing and Sarcopenia Study (MASS) Lifecourse is a unique resource for the study of human muscle ageing acros...

BackgroundCurrent British Society of Gastroenterology (BSG) guidelines misclassify metachronous lesion risk after polypectomy in approximately 40% of patients. Building on evidence that immune exclusion drives progression of adenomas to colorectal cancer, this study examined immune profiles in screen-detected adenomas as a predictive biomarker for metachronous lesion risk. MethodsPatients undergoing polypectomy within the Scottish Bowel Screening Programme, with surveillance colonoscopy between...

BackgroundThe risk of chronic diseases and multimorbidity increases with age, yet, individuals of the same age can strongly differ in healthspan, ranging from early manifestation of age-related disease to robust health into very old age. Plasma biomarkers, including metabolites and proteins, can capture intrinsic health status, thereby providing insights into the nature of this variation. These biomarkers have been widely explored to understand chronic and early disease risk but less so for dise...

Micro- and nanoplastics (MNPs) are increasingly detected in human tissues, yet their causal contribution to cardiovascular disease remains poorly understood. Here we show that oral exposure to polyethylene (PE) and polyvinyl chloride (PVC) -- the most abundant polymers found in human atheromas -- accelerates atherosclerosis in ApoE-/-mice through distinct, polymer-specific molecular mechanisms. While both polymers increased plaque burden and reduced contractile smooth muscle cell (SMC) markers, ...

Aging is accompanied by molecular changes across multiple biological systems that contribute to functional decline and increased disease risk, but the underlying mechanisms and inter-individual variation remain poorly understood. We investigated whether multi-omics integration can reveal coordinated molecular processes associated with accelerated PhenoAge, a clinical biomarker-based estimate of biological aging. Using UK Biobank data from [~]20,000 participants, we integrated plasma proteomics a...

The gut microbiome has been linked to breast cancer, largely through microbial functions involved in estrogen metabolism (the "estrobolome"); however, specific microbial targets remain poorly defined in human studies. Here, we profiled the gut microbiome using whole-metagenome shotgun sequencing, and plasma and stool metabolites were quantified using targeted metabolomics, in a study of 70 postmenopausal female cases with treatment-naive ER-positive breast cancer and 70 controls. Reduced species...