bims-caglex 2026-02-01 papers

Cells. 2026 Jan 16. pii: 168. [Epub ahead of print]15(2):

Partial Reprogramming Is Conserved from Insect to Mammal.

Nicholas S Tolwinski, Sheng Fong, Sujithra Shankar, Jan Gruber.

As we become older, systems throughout the body gradually decline in function. Contributing factors include the accumulation of senescent cells and the dysfunction and exhaustion of stem and progenitor cells. A promising approach to mitigate these changes and enhance cellular function in aged animals is the discovery that differentiated cells retain plasticity, enabling them to revert to pluripotent states when exposed to Yamanaka factors. This method has shown promise in models of rapid aging, and recent studies have demonstrated notable life extension in both flies and mice. These findings, along with the development of senolytics and aging clocks, could revolutionize aging research and interventions. Here, we review recent discoveries in the field and propose new directions for intervention discovery.

Keywords: OKSM; OSKM; Senotherapeutic; aging; longevity; reprogramming

DOI: https://doi.org/10.3390/cells15020168

Aging Cell. 2026 Feb;25(2): e70390

In Vivo Chemical Reprogramming Is Associated With a Toxic Accumulation of Lipid Droplets Hindering Rejuvenation.

Wayne Mitchell, Cecília G de Magalhães, Alexander Tyshkovskiy, Yushi Uchida, Ludger J E Goeminne, Takaharu Ichimura, Emery L Ng, Alibek Moldakozhayev, Joseph V Bonventre, Vadim N Gladyshev.

Partial reprogramming has emerged as a promising strategy to reset the epigenetic landscape of aged cells towards more youthful profiles. Recent advancements have included the development of chemical reprogramming cocktails that can lower the epigenetic and transcriptomic age of cells and upregulate mitochondrial biogenesis and oxidative phosphorylation. However, the ability of these cocktails to affect biological age in a mammalian aging model has yet to be tested. Here, we have characterized the effects of partial chemical reprogramming on mitochondrial structure and function in aged mouse fibroblasts and tested its in vivo efficacy in genetically diverse male UM-HET3 mice. This approach increases the size of mitochondria, alters cristae morphology, causes an increased fusing of mitochondrial networks, and speeds up movement velocity. At lower doses, the chemical reprogramming cocktail can be safely administered to middle-aged mice using implantable osmotic pumps, albeit with no effect on the transcriptomic age of kidney or liver tissues and only a modest effect on the expression of OXPHOS complexes. However, at higher doses, the cocktail causes a drastic reduction in body weight necessitating euthanasia. In the livers and kidneys of these animals, we observe significant increases in lipid droplet accumulation, as well as changes in mitochondrial morphology in the livers that are associated with mitochondrial stress. Thus, partial chemical reprogramming may induce mitochondrial stress and lead to significant lipid accumulation, which may cause toxicity and hinder the rejuvenation of cells and tissues in aged mammals.

Keywords: aging; aging biomarkers; chemical reprogramming; lipid droplets; mitochondria; mitochondrial morphology; oxidative phosphorylation; rejuvenation; reprogramming

DOI: https://doi.org/10.1111/acel.70390

Aging Cell. 2026 Feb;25(2): e70380

Pan-Epigenetic Age Prediction in Mammals.

Zane Koch, Adam Li, Trey Ideker.

Epigenetic remodeling is a hallmark of aging, yet which epigenetic layers are most affected during aging-and the extent to which they are interrelated-is not well understood. Here, we perform a comprehensive analysis of epigenetic aging encompassing 6 histone marks and DNA methylation measured across 12 tissues from > 1000 humans and mice. We identify a synchronized pattern of age-related changes across these epigenetic layers, with all changes converging upon a common set of genes. Notably, an epigenetic clock based on these genes can accurately predict age using data from any layer (Spearman ρ: 0.70 in humans, 0.81 in mice). Applying this "pan-epigenetic" clock, we observe that histone modification and DNA methylation profiles agree in the prediction of which individuals are aging more rapidly or slowly. These results demonstrate that epigenetic modifications are subject to coordinated remodeling over the lifespan, offering a unified view of epigenetic aging.

DOI: https://doi.org/10.1111/acel.70380

Front Mol Biosci. 2025 ;12 1734464

DNA methylation and prediction of biological age.

Yanfang Chen, Xiangshu Cheng, Shaoping Ji.

DNA methylation plays a critical role in gene expression regulation and has emerged as a robust biomarker of biological age. This modification will become heavier or site drift along with aging. Recently, it is termed epigenetic clocks-such as Horvath, Hannum, PhenoAge, and GrimAge-leverage specific methylation patterns to accurately predict age-related decline, disease risk, and mortality. These tools are now widely applied across diverse tissues, populations, and disease contexts. Beyond age-related loss of methylation control, accelerated DNA methylation age has been linked to environmental exposures, lifestyle factors, and chronic diseases, further reinforcing its value as a dynamic and clinically relevant marker of biological aging. DNA methylation is reshaping our understanding of aging and disease risk, with promising implications for preventive medicine and interventions aimed at promoting healthy longevity. However, it must be admitted that some challenges remain, including limited generalizability across populations, an unclear mechanism, and inconsistent longitudinal performance. In this review, we examine the biological foundations of DNA methylation, major advances in epigenetic clock development, and their expanding applications in aging research, disease prediction and health monitoring.

Keywords: DNA methylation; aging; biological age; chronic diseases; epigenetic clock

DOI: https://doi.org/10.3389/fmolb.2025.1734464

NPJ Precis Oncol. 2026 Jan 27.

Non-invasive epidermis sampling for DNA methylation-based prediction of skin cancer phenotypes.

Manuel Rodríguez-Paredes, Yan Feng, Oliver Gilliam, Katrin Wegner, Günter Raddatz, Elke Grönniger, Frank Lyko.

The epidermis is uniquely exposed to the effects of environmental factors, such as ultraviolet radiation, which induce progressive genetic and epigenetic modifications contributing to aging and the onset of keratinocyte carcinomas. DNA methylation is the best-characterized epigenetic modification and a valuable biomarker for assessing epidermal health. However, broad screening approaches have been hindered by the limited quantity and quality of the genomic DNA obtained from the epidermis and the resulting need for invasive sampling methods. Here we describe an integrated method that enables the non-invasive sampling of epidermal DNA for subsequent analysis by DNA methylation microarrays. This procedure combines a gel-based adhesive tape for keratinocyte collection, a robust gDNA extraction protocol and a curated selection of microarray probes optimized for low-input DNA conditions. Analysis of >100 corresponding methylomes demonstrates that our approach can be used for both the training of epigenetic clocks capable of predicting epidermal age with high accuracy, as well as the investigation of various DNA methylation-based biomarkers relevant to keratinocyte cancer development. These findings underscore the potential of our method for broad and non-invasive skin health assessment and cancer prevention strategies.

DOI: https://doi.org/10.1038/s41698-026-01302-7

Clin Mol Hepatol. 2026 Jan 27.

DNMT1 Facilitates the Progression of MASLD by Impeding Transcription Mediated by HNF4α and PPARα.

Background/Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide. Aberrant DNA methylation, which is primarily maintained by DNA methyltransferase 1 (DNMT1), has been linked to metabolic dysregulation; however, its contribution to MASLD pathogenesis remains poorly defined. This study aimed to elucidate the role of DNMT1-mediated methylation in transcriptional regulation during MASLD progression and to determine whether DNMT1 inhibition can reverse disease-associated epigenetic and transcriptional alterations.
Methods: We conducted integrated analyses of the liver transcriptome (n = 131) and DNA methylome (n = 106) of patients with biopsy-proven MASLD. We evaluated the effect of DNMT1 inhibition with 5-aza-4'-thio-2'-deoxycytidine (Aza-TdC) on a diet-induced MASLD mouse model. Multiomics approaches, including DNA methylome profiling, lipidomics, bulk and single-nucleus RNA sequencing, and chromatin immunoprecipitation sequencing, were applied to elucidate the role of DNMT1-mediated DNA methylation in regulating pathogenic gene expression.
Results: DNA methylome profiling revealed increased methylation variability associated with increased DNMT1 expression in MASLD patients. DNMT1 inhibition ameliorated dysregulated lipid metabolism by reducing hepatic triacylglycerol accumulation and inflammation. Aza-TdC treatment partially reversed MASLD-related hypermethylation of hepatocyte nuclear factor 4 alpha (HNF4α)- and peroxisome proliferator-activated receptor alpha (PPARα)-regulated genes, restoring their transcriptional activity. Notably, Aza-TdC reactivated the gluconeogenic enzyme-encoding gene phosphoenolpyruvate carboxykinase 1 (PCK1), which was hypermethylated and transcriptionally repressed in MASLD. Targeted DNA methylation of the PCK1 promoter using CRISPRoff confirmed the direct epigenetic regulation of PCK1 expression.
Conclusions: Targeting DNMT1 may mitigate lipid dysregulation and inflammation by reversing hypermethylation and restoring HNF4α- and PPARα-dependent gene transcription, highlighting DNMT1 as a potential therapeutic target for MASLD.

Keywords: DNA methylation; DNMT1; HNF4α; MASLD; PPARα

DOI: https://doi.org/10.3350/cmh.2025.1099