bims-caglex 2025-11-23 papers

Front Pharmacol. 2025 ;16 1699296

Epigenetic pharmacology in aging: from mechanisms to therapies for age-related disorders.

Haikuan Yu, Taojin Feng, Chengcheng Zhang, Zhouguang Jiao, Wenkai Fan, Rongxian Jiang, Dewen Kong, Fubing Li.

Aging is a multidimensional process regulated by the interplay of genetic and environmental factors, with epigenetic alterations serving as a central regulatory hub. Aberrant DNA methylation patterns, dysregulation of histone-modifying enzymes (e.g., SIRT1, EZH2), and non-coding RNA-mediated mechanisms collectively remodel gene expression networks, impacting critical pathways such as cellular senescence and mitochondrial homeostasis. This establishes an "environment-epigenome-disease" causal axis, closely associated with pathologies including β-amyloid deposition in Alzheimer's disease, atherosclerosis, immunosenescence, osteoporosis, sarcopenia, and tumorigenesis. Capitalizing on the reversible nature of epigenetic modifications, pharmacological epigenetics has emerged as a cutting-edge field for intervening in aging and age-related diseases. Targeting key epigenetic modifiers such as DNA methyltransferases and histone deacetylases enables the modulation of disease-associated epigenetic states, providing a promising avenue for therapeutic intervention in aging and age-related diseases. This review synthesizes the molecular mechanisms of epigenetic regulation in aging, their role in age-related diseases, and advances in pharmacological epigenetics-from basic research to clinical translation. It further situates key challenges such as target specificity, long-term safety, and tissue-specific delivery within a translational framework, aiming to inform strategies for the diagnosis and intervention of age-related conditions.

Keywords: DNA methylation; age-related diseases; aging; epigenetic modifiers; epigenetics; histone modification; non-coding RNA; pharmacological epigenetics

DOI: https://doi.org/10.3389/fphar.2025.1699296

Postepy Biochem. 2025 06 30. 71(1): 61-78

Mechanisms regulating chromatin structure and alterations associated with senescence

Agnieszka Gadecka, Anna Bielak-Żmijewska.

The expected average human lifespan is constantly increasing. The negative effect of this phenomenon is more frequent incidences of age-related diseases. Experimental data have shown that cellular senescence is the cause of organismal aging. Cellular senescence is an irreversible cell cycle arrest while maintaining metabolic functions and can occur through the exhaustion of proliferative potential (replicative senescence - RS) or stress conditions (stress-induced premature senescence - SIPS). Both types of senescence cause a number of morphological changes, in particular, in the cell nucleus and gene expression. A gradual decrease of condensed heterochromatin in favor of relaxed euchromatin is observed. This is caused by the loss of histones, a disturbance of the balance between repressive and activating post-translational modifications of histones, the impairment in the activity of histone-decorating enzymes and proteins stabilizing the chromatin structure. This review detailed nuclear architecture and chromatin structure alterations during cellular senescence.

DOI: https://doi.org/10.18388/pb.2021_590

bioRxiv. 2025 Nov 02. pii: 2025.10.03.680371. [Epub ahead of print]

Meenakshi Chakraborty, Sophia M Shi, Imani E Porter, Daniel J Richard, Georgi K Marinov, Ashley A Moore, Jenna L E Blum, Aravind Natarajan, James W Jahng, Joseph C Wu, Sydney X Lu, Shawn M Davidson, William J Greenleaf, Nay L Saw, Mehrdad Shamloo, Anne Brunet, Tony Wyss-Coray, Ami S Bhatt.

The gut microbiome generates diverse metabolites that can enter the bloodstream and alter host biology, including brain function. Hundreds of physiologically relevant, gut-brain signaling molecules likely exist; however, there has been no systematic, high-throughput effort to identify and validate them. Here, we integrate computational, in vitro , and in vivo approaches to pinpoint microbiome-derived metabolites whose blood levels change during aging, and that induce corresponding changes in the mouse brain. First, we mine large-scale metabolomics datasets from human cohorts (each n ≥ 1200) to identify 30 microbiome-associated metabolites whose blood levels change with age. We then screen this panel in an in vitro transcriptomic assay to identify metabolites that perturb genes linked to age-related neurodegeneration. We then test four metabolites in an acute-exposure mouse model, and use multi-omic approaches to evaluate their impact on cellular functions in the brain. We confirm the known neurodegeneration-promoting effects of trimethylamine N-oxide (TMAO), including mitochondrial dysfunction, and further discover its disruptive impact on the pathways of glycolysis, GABAergic signaling, and RNA splicing. Additionally, we identify glycodeoxycholic acid (GDCA), a microbiome-derived secondary bile acid, as a potent regulator of chromatin accessibility and suppressor of genes that protect the brain from age-related, neurodegeneration-promoting insults. GDCA also acutely reduces mobility. In summary, we present a scalable framework for linking microbiome metabolites to host pathologies, and apply it to identify microbial metabolites that induce molecular changes related to neurodegeneration.

DOI: https://doi.org/10.1101/2025.10.03.680371