SEARCH · PubMed Health

Results for “Epigenetic clocks”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

35 records · Page 2Linked to original sources

PubMed2026

Methylation profiling of normal tissue adjacent to breast tumors reveals two distinct groups with divergent tumor microenvironment features.

We previously identified diverse genetic evolutionary patterns in whole-genome sequencing of paired normal tissue adjacent to tumor (NAT) and tumor tissues from Hong Kong breast cancer (HKBC) patients. Here, we investigated whether DNA methylation (DNAm) contributes to NAT heterogeneity and shapes the tumor microenvironment (TME). Genome-wide DNAm profiling was performed on paired NAT and tumor tissues from 188 HKBC patients using the Infinium 850 K array. RNA-seq data were available for 76 NATs and 177 tumors. Cellular composition was inferred using MethylCIBERSORT, CIBERSORTx, and EpiDISH, and histopathologic features were assessed on 115 H&E-stained sections. Unsupervised clustering identified two distinct NAT subtypes with divergent TME characteristics. Cluster 1 (N = 139) showed higher epithelial and fibroblast content and enrichment of estrogen response pathways. Cluster 2 (N = 49) exhibited an immune-metabolic phenotype characterized by increased fat and immune cells, stromal disruption, inflammatory pathway activation, and greater macrophage infiltration. Cluster 2 patients also demonstrated significantly younger epigenetic age estimated using multiple epigenetic clocks. These DNAm-defined NAT subtypes and associated TME features were validated in 97 NAT samples from TCGA breast cancer patients. Overall, our findings identify DNAm-driven NAT heterogeneity with distinct TME landscapes, providing new insights into field cancerization and tumor evolution in breast cancer.

Journal Article↗

PubMed2026

GT-Mamba: a Topology-Aware Graph-State space model for robust and interpretable epigenetic age prediction.

MOTIVATION: Current epigenetic clocks face a trade-off between predictive accuracy and biological interpretability, often relying on dataset-specific correction to generalize across cohorts. We propose GT-Mamba, a novel architecture that integrates a Structure-Aware Graph Transformer with the Mamba state space model. This design captures CpG topological correlations and genome-wide long-range dependencies. RESULTS: GT-Mamba demonstrates strong out-of-the-box robustness across heterogeneous independent validation cohorts, achieving a weighted average MAE of 4.43 years. Notably, it effectively generalizes to EPIC 850k arrays despite partial feature missingness, and maintains consistent performance across homologous age distribution shifts (MAE 2.94 years in a young cohort). Ablation studies confirm that graph topology contributes to improved robustness against noise. Mechanistic analysis suggests that the model captures methylation patterns associated with both developmental and functional processes. AVAILABILITY: Source code and pre-trained models are freely available at https://github.com/NENUBioCompute/GT-Mamba and archived on Zenodo (DOI: 10.5281/zenodo.19703155).

Epigenesis, Genetic↗

PubMed2026

Understanding and making sense of epigenetic age misalignment across different aging clocks.

The output of an epigenetic aging clock can vary depending on the training method utilized, cell type composition, the nature of the training dataset, the technology used to generate the methylomic data, acute stressors, and other factors. On an individual level, epigenetic age can fluctuate across different clocks purely due to differences in model training. Among aging clock researchers, it is well-known that the epigenetic age of a single sample can vary across different models. Based on our observations and conversations with longevity scientists and stakeholders, however, this fact is often unappreciated among non-aging clock experts. To help bring more awareness to this important topic, we highlight key literature and, as an illustrative example, use eight blood-trained clocks to show that epigenetic age is frequently misaligned in a publicly available whole blood dataset. Our simple analysis revealed that the average sample difference between the youngest and oldest predicted ages across these clocks was 17 years. The smallest and largest individual-level differences observed were 4 and 45 years, respectively. Clock misalignment has implications for choosing which clock to utilize, interpreting the impact of an intervention on epigenetic age, personalized tracking, and relating epigenetic age to the abstract concept of biological age.

Humans↗

PubMed2026

The effects of tildrakizumab in the epigenetic aging deviation of psoriasis: A 52-week open-label study.

BACKGROUND: While biologic therapies targeting interleukin-23 control cutaneous inflammation in psoriasis, their impact on epigenetic aging has not been previously demonstrated. OBJECTIVES: To evaluate the effects of tildrakizumab treatment in the epigenetic aging deviation of moderate-to severe psoriasis. METHODS: In an open-label 52-week clinical trial, 20 adults with psoriasis were treated with tildrakizumab-asmn 100 mg injections until week 28. Ten age-matched controls without psoriasis were enrolled. Genome-wide DNA methylation was profiled in peripheral blood leukocyte DNA (MethylationEPICv2.0, Illumina) to calculate epigenetic aging clocks predictive of all-cause-mortality, phenotypic age, chronological age, pace of aging, and telomere length. Epigenetic age deviation was calculated as the residuals against chronological age. RESULTS: Psoriasis patients had increased epigenetic age deviation in clocks predictive of mortality: PCGrimAge (P = .008), cytosine-phosphate-guanine (CpG) PTPCGrimAge3 (P = .019), CpGPTGrimAge3 (P = .019), GrimAge2 (P = .049). PCGrimAge was reversed by 0.3 years (week 28, P = .005) and 0.5 years (week 52, P = .04) after the use of tildrakizumab-asmn. The pace of aging was increased in psoriasis patients: DunedinPACE (P = .049). LIMITATIONS: Pilot study (small sample size). CONCLUSIONS: Psoriasis patients presented accelerated epigenetic aging in mortality-predictive clocks. Treatment with tildrakizumab-asmn (interleukin-23 inhibition) showed partial reversal of those clocks in 28 weeks. (Funded by Sun Pharmaceutical Industries, Inc; ClinicalTrials.gov number, NCT05110313).

DNA methylation clocks↗

PubMed2025

Multiomic clocks to predict phenotypic age in mice.

Biological age refers to a person's overall health in aging, as distinct from their chronological age. Diverse measures of biological age, referred to as "clocks," have been developed in recent years and enable risk assessments and an estimation of the efficacy of longevity interventions in animals and humans. Although most clocks are trained to predict chronological age, clocks have been developed to predict more complex composite biological age outcomes, at least in humans. These composite outcomes can be made up of a combination of phenotypic data, chronological age, and disease or mortality risk. Here, we develop the first such composite biological age measure for mice: the mouse phenotypic age model (Mouse PhenoAge). This outcome is based on frailty measures, complete blood counts, and mortality risk in a longitudinally assessed cohort of male and female C57BL/6 mice. We then develop clocks to predict Mouse PhenoAge, based on multiomic models using metabolomic and DNA methylation data. Our models accurately predict Mouse PhenoAge, and residuals of the models are associated with remaining lifespan, even for mice of the same chronological age. These methods offer novel ways to accurately predict mortality in laboratory mice, thus reducing the need for lengthy and costly survival studies.

Animals↗

PubMed2026

Differences between mitotically old and young endometrial tumors.

Human tumors likely differ in their mitotic ages, reflecting how many divisions elapse between the final tumor progenitor cell and surgical removal. We used a rapidly fluctuating CpG (fCpG) methylation clock to infer relative endometrial adenocarcinomas (EAC) mitotic ages. Experimentally, young tumors initiated from single cells show low-diversity, high-variance fCpG distributions with trimodal peaks near 0%, 50%, and 100%, reflecting inherited progenitor methylation states. fCpG methylation becomes polymorphic with divisions, and older tumors exhibit higher diversity, lower variance, and unimodal distributions centered around 50%. Mitotic ages varied across EAC samples. Synchronous hyperplasia and invasive regions generally shared similar ages, and primary-metastatic EAC pairs showed both synchronous and stepwise progression. The Cancer Genome Atlas (TCGA) EACs also showed variable mitotic ages: younger tumors were enriched for proliferation pathways, whereas older tumors showed more immune infiltration, immune-pathway activation, and evidence of T-cell exhaustion. These results show that human tumors can be ranked by mitotic age and suggest that the growth of older cancers is restrained by immune surveillance. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Humans↗

PubMed2026

Spatial niche remodeling of senescent liver-resident immune cells and its role in chronic liver diseases.

The liver serves the triple functions of metabolism, detoxification, and immune surveillance. Its unique immune microenvironment is shaped by continuous exposure to gut-derived antigens, pathogen-associated molecular patterns (PAMPs), and metabolites arriving via the portal vein, necessitating a delicate equilibrium between immune tolerance and effector activation. This equilibrium relies on the coordinated activities of diverse liver-resident immune cell populations-including Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), dendritic cells (DCs), tissue-resident memory T cells (TRM), innate-like T cells, including mucosal-associated invariant T (MAIT) cells, natural killer T (NKT) cells, and γδ T cells, innate lymphoid cells (ILCs, encompassing conventional NK cells and helper ILC subsets), and neutrophils. With advancing age and chronic injury, these resident immune cell populations undergo profound senescence-associated phenotypic reprogramming that is spatially organized along the portal-to-central axis of the hepatic lobule. Key mechanisms include: telomere dysfunction and DNA damage accumulation driving persistent activation of p53/p21 and p16/Rb pathways; mitochondrial dysfunction with mitochondrial DNA (mtDNA) leakage fueling the senescence-associated secretory phenotype (SASP) via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway; epigenetic age acceleration, including genome-wide H3K27me3 heterochromatinization; and metabolic reprogramming toward glycolysis and lipid accumulation. This review proposes a "spatial niche remodeling" framework to integrate these cell-intrinsic senescence programs with their lobular context, intercellular communication network rewiring, and pathogenic roles across the spectrum of chronic liver disease-from steatosis through steatohepatitis, fibrosis, cirrhosis, to hepatocellular carcinoma. We critically evaluate emerging senotherapeutic strategies targeting specific liver-resident immune cell subsets, discuss the barriers to clinical translation, and identify priority areas for future investigation, including the application of spatial multi-omics, humanized models, and epigenetic clock-guided clinical trials.

Kupffer cells↗

PubMed2026

Ensemble DNA methylation clock demonstrates Immune-metabolic aging signatures associated with mortality.

Aging is a multifactorial process that is best described in terms of the progressive acquisition of multiple layers of phenotypic changes, such as epigenetic modifications, inflammation, and metabolic dysregulation. DNA methylation clocks have been extensively used to construct epigenetic clocks based on the DNAm profiles that can be used to estimate biological age and predict age-associated outcomes. Nevertheless, the vast majority of clocks constructed so far have been based on linear models, which are unlikely to fully account for the heterogeneity and non-linearity of survival-related DNAm signatures. In this work, we constructed a heterogeneous stacked ensemble survival model based on DNAm data obtained from the Framingham Heart Study. We first identified 190 CpG loci using elastic net Cox regression and subsequently constructed a survival prediction model based on the fusion of five complementary survival models by means of a neural network meta-learner. The prediction power of the survival model was evaluated in an external validation cohort, where we observed strong performance for predicting all-cause mortality that significantly exceeded PhenoAge and was statistically comparable to GrimAge. These performance estimates were derived in cohorts of European ancestry and externally validated in postmenopausal women aged 50-79 years, and should therefore be interpreted as applicable only to demographically similar populations.

Humans↗

PubMed2026

Age-associated epigenomic heterogeneity in papillary tumors of the pineal region: a multicenter YoungNOA investigation.

BACKGROUND: Papillary tumors of the pineal region (PTPR) are rare CNS neoplasms with adult and pediatric presentations, but whether age defines distinct molecular biology is unclear. METHODS: We assembled a multicenter retrospective cohort of 86 histologically confirmed PTPR with genome-wide DNA methylation data, comprising 62 adult and 24 pediatric tumors. Molecular subgroup, array platform, sex, and tumor purity were incorporated into multivariable models. Analyses included DNA methylation class assignment, differential methylation, copy-number variation (CNV), epigenetic mitotic-clock scores, methylation-based tumor microenvironment deconvolution, and descriptive survival evaluation. RESULTS: Adult and pediatric tumors mapped within the established PTPR-A and PTPR-B methylation framework rather than forming age-defined methylation classes. Pediatric tumors were enriched for PTPR-B (22 of 24 tumors [91.7%]) compared with adult tumors (39 of 62 [62.9%]). After adjustment for methylation-based subgroup as well as technical and biological covariates, 2,923 CpG probes were associated with age at a false discovery rate (FDR) threshold below 0.05, and 530 also met the prespecified effect-size threshold. Global methylation summaries were similar between age groups. CNV patterns were dominated by molecular subgroup; adjusted genomic CNV load was not independently associated with pediatric age. In contrast, epiTOC2 intrinsic rate score and the methylation signature represented by the first principal component (PC1) showed age-associated effects independent of molecular subgroup. Methylation-based deconvolution suggested a limited microenvironmental signal, with neutrophil fraction showing the most consistent adjusted association. CONCLUSIONS: Adult and pediatric PTPR share the established PTPR-A/PTPR-B framework. Pediatric tumors, particularly within PTPR-B, showed age-associated DNA methylation differences and higher epigenetic mitotic-clock (epiTOC2) scores in this retrospective cohort. These tissue-level associations do not establish clinical risk or treatment implications and require prospective clinical annotation and orthogonal validation.

Humans↗

PubMed2026

Epigenetic aging of colorectal mucosa in cancer development.

BACKGROUND: The past decade has seen the development of epigenetic models of aging that accurately estimate chronological age and predict disease incidence and mortality. These estimates are modulated by lifestyle and environmental factors linked to carcinogenesis, but to date this has primarily been studied in blood. METHODS: We examined epigenetic aging in normal colonic tissue (n = 96), adjacent mucosa (n = 245) and tumors (n = 208), using models trained on age (Horvath, Hannum, Zhang), mortality (PhenoAge, GrimAge), aging rate (DunedinPACE), cellular mitotic history (EpiTOC, epiTOC2, miAGe), and telomere length (DNAmTL). RESULTS: The Horvath model was the most accurate estimator of chronological age in normal colonic mucosa, with high correlation (r > 0.70) between the Horvath, Hannum, Zhang, PhenoAge and GrimAge models, and between mitotic clocks (r > 0.94). All models showed similar performance in normal tissue and adjacent mucosa, but substantially more variation in estimates in tumors. Significant differences in age acceleration were present between normal and adjacent mucosa by six models (Hannum, Zhang, PhenoAge, EpiTOC, epiTOC2 and miAge), while tumors showed highly significant differences by all models. Age acceleration differed by region of the colon, with varying patterns by model type. Physical activity (PhenoAge), smoking history (GrimAge), and alcohol consumption (Horvath, mitotic clocks) were associated with epigenetic aging in adjacent mucosa, while smoking history, smoking intensity, and alcohol consumption were associated with DNAmTL in tumors. CONCLUSIONS: Our study reveals an impact of tissue type, region, and lifestyle factors on epigenetic aging, but also highlights significant heterogeneity between models and the need for careful consideration within study design.

DNA methylation↗

PubMed2024

The effect of low birth weight as an intrauterine exposure on the early onset of sarcopenia through possible molecular pathways.

Sarcopenia, a musculoskeletal disease characterized by the progressive loss of skeletal muscle mass, strength, and physical performance, presents significant challenges to global public health due to its adverse effects on mobility, morbidity, mortality, and healthcare costs. This comprehensive review explores the intricate connections between sarcopenia and low birth weight (LBW), emphasizing the developmental origins of health and disease (DOHaD) hypothesis, inflammatory processes (inflammaging), mitochondrial dysfunction, circadian rhythm disruptions, epigenetic mechanisms, and genetic variations revealed through genome-wide studies (GWAS). A systematic search strategy was developed using PubMed to identify relevant English-language publications on sarcopenia, LBW, DOHaD, inflammaging, mitochondrial dysfunction, circadian disruption, epigenetic mechanisms, and GWAS. The publications consist of 46.2% reviews, 21.2% cohort studies, 4.8% systematic reviews, 1.9% cross-sectional studies, 13.4% animal studies, 4.8% genome-wide studies, 5.8% epigenome-wide studies, and 1.9% book chapters. The review identified key factors contributing to sarcopenia development, including the DOHaD hypothesis, LBW impact on muscle mass, inflammaging, mitochondrial dysfunction, the influence of clock genes, the role of epigenetic mechanisms, and genetic variations revealed through GWAS. The DOHaD theory suggests that LBW induces epigenetic alterations during foetal development, impacting long-term health outcomes, including the early onset of sarcopenia. LBW correlates with reduced muscle mass, grip strength, and lean body mass in adulthood, increasing the risk of sarcopenia. Chronic inflammation (inflammaging) and mitochondrial dysfunction contribute to sarcopenia, with LBW linked to increased oxidative stress and dysfunction. Disrupted circadian rhythms, regulated by genes such as BMAL1 and CLOCK, are associated with both LBW and sarcopenia, impacting lipid metabolism, muscle mass, and the ageing process. Early-life exposures, including LBW, induce epigenetic modifications like DNA methylation (DNAm) and histone changes, playing a pivotal role in sarcopenia development. Genome-wide studies have identified candidate genes and variants associated with lean body mass, muscle weakness, and sarcopenia, providing insights into genetic factors contributing to the disorder. LBW emerges as a potential early predictor of sarcopenia development, reflecting the impact of intrauterine exposures on long-term health outcomes. Understanding the complex interplay between LBW with inflammaging, mitochondrial dysfunction, circadian disruption, and epigenetic factors is essential for elucidating the pathogenesis of sarcopenia and developing targeted interventions. Future research on GWAS and the underlying mechanisms of LBW-associated sarcopenia is warranted to inform preventive strategies and improve public health outcomes.

Humans↗

PubMed2026

Developmental roles of LSD1/KDM1A-like (LDL) proteins in plants.

LYSINE-SPECIFIC DEMETHYLASE 1-like (LDL) proteins are conserved FAD-dependent amine oxidases that serve as pivotal regulators in plants. While animal systems typically rely on a single LSD1/KDM1A enzyme, the Arabidopsis thaliana genome encodes an expanded family of LDL homologues (FLD, LDL1, LDL2, and LDL3), resulting in substantial subfunctionalization and specialized recruitment mechanisms. This review explores the diverse developmental roles of plant LDLs, ranging from flowering time and circadian clock regulation to heterochromatin maintenance and epigenetic regulation. We discuss the redundant roles of FLD, LDL1, and LDL2 in repressing the floral repressor FLC and their nonredundant specialized function within the CCA1/LHY-TOC1 circadian feedback loop. A central focus of our review is the emerging mechanism of transcription-coupled demethylation, in which LDLs associate with the phosphorylated C-terminal domain of RNA polymerase II to modify chromatin cotranscriptionally within gene bodies. By integrating findings from Arabidopsis thaliana and crops such as tomato and soybean, we illustrate how the diversified LDL-mediated regulatory toolkit facilitates precise, gene-specific regulation. Ultimately, the LDL family represents a cornerstone of the sophisticated epigenetic strategies that regulate plant phenotypic plasticity in response to developmental and environmental cues.

Circadian clock↗

PubMed2026

Clonal haematopoiesis of indeterminate potential and epigenetic age acceleration: Systematic review and meta-analysis.

Clonal haematopoiesis of indeterminate potential (CHIP) represents somatic mutations in haematopoietic stem cells that drive clonal expansion. Epigenetic age acceleration (EAA), estimated from DNA methylation (DNAm) clocks, may capture age-related changes in haematopoiesis. This systematic review and meta-analysis was conducted to synthesise evidence on associations between CHIP and EAA and explore shared biological mechanisms that may underlie this relationship. Six databases were searched from January 1, 2011, to June 6, 2025, adhering to PRISMA 2020. Random-effects meta-analyses were performed. Five studies comprising 7483 individuals (ages 55-79, 67.1% female) assessing associations between CHIP and DNAm clocks were included. Across studies, CHIP individuals had higher EAA than no-CHIP individuals, and larger clones were associated with higher EAA. Meta-analysis of three cross-sectional studies (n = 6946) showed that CHIP had higher EAA versus no-CHIP for Horvath1Age IEAA (mean difference, MD=2.84 years, 95% confidence interval, CI: 1.49-4.19), HannumAge EEAA (MD=2.31 years, 95% CI: 1.14-3.49), PhenoAge (MD=1.84 years, 95% CI: 0.96-2.71), and GrimAge (MD=1.20 years, 95% CI: 0.80-1.61). Both DNMT3A- and TET2-mutated CHIP were associated with higher EAA with TET2-mutated CHIP showing larger effect sizes and more consistent associations than DNMT3A-mutated CHIP across DNAm clocks tested. Higher EAA may also act as an effect modifier for morbidity and mortality in CHIP. Larger longitudinal studies are needed to verify a temporal relationship and determine whether EAA provides incremental prognostic value for morbidity and mortality in CHIP.

Humans↗

PubMed2025

Adiponectin receptor agonist, AdipoRon, restores hepatic clock gene expression in PCOS-associated NAFLD.

Persistent lower levels of adiponectin are associated with hyperandrogenism, predisposing PCOS women to NAFLD. This study elucidated the therapeutic potential of a small molecule adiponectin receptor agonist-AdipoRon, utilizing an in-vivo PCOS rat model mimicking the manifestation of PCOS along with hepatosteatosis. Our study demonstrated that Adiporon reduced lipid accumulation in PCOS-associated NAFLD by alleviating insulin resistance & lipogenesis. AdipoRon also reversed hyperandrogenism and adiponectin deficiency in PCOS animals. In addition, AdipoRon was found to restore altered PCOS-induced hepatic circadian gene expression (Bmal1, Clock, Per3, Cry2, Reverba, and Rora). Interestingly, at the epigenetic level, global transcription activation marks, i.e., H3K4me3, H3K9/14ac, and H3K36me2, were upregulated in disease conditions. Furthermore, our ChIP data confirmed that circadian genes Bmal1, Reverba, And Rora are epigenetically regulated. ChIP assay data showed an increased H3K36 dimethylation at the Bmal1 and Rora promoter, whereas a significant decrease was observed at the Reverbα promoter in PCOS-associated NAFLD. AdipoRon ameliorated these PCOS-induced epigenetic alterations, modulating the hepatic circadian gene expression. We present the preliminary evidence illustrating the epigenetic modulation of AdipoRon, thereby regulating hepatic circadian gene expression. This study provides insights regarding the therapeutic potential of AdipoRon in PCOS-associated NAFLD, which can be of profound clinical significance.

Animals↗

PubMed2025

Differential methylation clock ages across buffy coat (BC), peripheral blood mononuclear cells (PBMC), and saliva in individuals approaching midlife.

Understanding epigenetic aging prior to midlife is gaining interest as a potentially intervenable period to address factors that influence health and cognitive aging. Epigenetic changes associated with aging may point to differential biological aging rates; however, methylation profiles may not be substitutable across tissues. We compared DNA methylation in three tissues collected in 91 siblings and twins from the Colorado Adoption/Twin Study of Lifespan behavioral development and cognitive aging (CATSLife1): saliva, buffy coat (BC), and peripheral blood mononuclear cells (PBMC). Overall, across five methylation clocks and two blood-derived and one saliva-derived tissues, moderate to strong associations between chronological age and methylation ages were observed. Moreover, PBMC methylation age values correlate more strongly with BC values (Spearman r = 0.66 - 0.87), whereas saliva showed weaker correlations with either form of blood-derived measures (Spearman r = 0.25 - 0.69) although still moderate to strong magnitudes. Saliva demonstrated significantly older methylation ages across four of five clocks, whereas PBMC and BC did not differ. Twins were more strongly correlated for BC and PBMC derived clocks with weaker and inconsistent patterns among Saliva clocks. DunedinPACE age acceleration showed no significant tissue differences and on average demonstrated the largest divergence of similarity between monozygotic (MZ) versus dizygotic (DZ) twins (rMZ= .56, rDZ= .21). In summary, saliva-derived methylation is not a direct substitute for blood-derived methylation whereas blood-derived methylation values were comparable across buffy coat and peripheral blood mononuclear cell tissues.

age acceleration↗

PubMed2024

Understanding the biological processes of kidney carcinogenesis: an integrative multi-omics approach.

Biological mechanisms related to cancer development can leave distinct molecular fingerprints in tumours. By leveraging multi-omics and epidemiological information, we can unveil relationships between carcinogenesis processes that would otherwise remain hidden. Our integrative analysis of DNA methylome, transcriptome, and somatic mutation profiles of kidney tumours linked ageing, epithelial-mesenchymal transition (EMT), and xenobiotic metabolism to kidney carcinogenesis. Ageing process was represented by associations with cellular mitotic clocks such as epiTOC2, SBS1, telomere length, and PBRM1 and SETD2 mutations, which ticked faster as tumours progressed. We identified a relationship between BAP1 driver mutations and the epigenetic upregulation of EMT genes (IL20RB and WT1), correlating with increased tumour immune infiltration, advanced stage, and poorer patient survival. We also observed an interaction between epigenetic silencing of the xenobiotic metabolism gene GSTP1 and tobacco use, suggesting a link to genotoxic effects and impaired xenobiotic metabolism. Our pan-cancer analysis showed these relationships in other tumour types. Our study enhances the understanding of kidney carcinogenesis and its relation to risk factors and progression, with implications for other tumour types.

Kidney Neoplasms↗

PubMed1975

Current theories of biological aging.

Several lines of evidence have led to the notion that biological aging occurs as a result of changes in the information-containing molecules either at the genetic or epigenetic level. The error theory, the redundant message theory, the codon restriction theory, and the transcriptional event theory represent the major current conceptualizations of biological aging as held by most gerontologists. The finding that cultured normal human and animal cells undergo a finite number of population doublings in vitro has provided new insights into age changes at the cellular level. The number of mitotic events that cultured normal animal cells can undergo appears to be inversely related to the age of the donor. A direct proportionality exists, however, between the mean maximum life-span of a species and the number of population doublings that their cultured embryonic cells will undergo. The several biochemical decrements known to occur prior to the cessation of mitotic activity in vitro are thought to herald those manifestations of senescence seen in the whole animal. Yet to be explained is how those cell classes such as the germ plasm and continuously propagable cancer cells escape from the inevitability of biological aging.

Aging↗