bims-caglex 2025-12-21 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2025–12–21
six papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

From population science to the clinic? Limits of epigenetic clocks as personal biomarkers.
TRIM37-PARP1-TET1 axis maintains stemness and prevents osteoporosis by inhibiting DNMT1 alternative splicing via 5hmC regulation.
Between defence and delivery: the DNA sensing response to gene electrotransfer.
A novel role of Mef2a in mitochondrial homeostasis and muscle regeneration during sarcopenia.
Polyelectrolyte complex micelles embedded in hyaluronic acid gels enable local, targeted miR-92a inhibition to accelerate diabetic wound repair.
Small Extracellular Vesicles From Human Amniotic Membrane Mesenchymal Stem Cells Rejuvenate Senescent β Cells and Cure Age-Related Diabetes in Mice.

Epigenomics. 2025 Dec 16. 1-15

From population science to the clinic? Limits of epigenetic clocks as personal biomarkers.

Abner T Apsley, Laura Etzel, Qiaofeng Ye, Idan Shalev.

  Epigenetic clocks are machine-learning algorithms which use DNA methylation patterns to predict aging-related phenotypes, such as chronological age, composite indicators of health, time-to-death, and the pace of biological aging. These clocks have been instrumental at the population level in revealing how disease risk emerges from behavioral, environmental, and psychosocial factors, and how certain anti-aging interventions may alter those trajectories. Given the success of epigenetic clocks at the population level, it is reasonable to assume they might also hold value as individual-level biomarkers. We contend, however, that fundamental technical and biological properties of these algorithms prohibit their current use at the individual level. Technical concerns include methods of clock construction, sample collection and processing, data preprocessing, and computational implementations. Biological considerations include the nature of DNA methylation and its dynamics, variation across developmental periods, tissue specificity, and sensitivity to environmental/sociodemographic contexts. We show that clocks fail to meet common standards for clinical utility compared with established biomarkers, and that applying epigenetic clocks in individual-level decision making can be uninformative and potentially harmful. Finally, we argue that even if all technical and biological hurdles can be overcome, epigenetic clocks, as we currently understand them, should not be used to make individual-level decisions.

Keywords:  DNA methylation; Epigenetic clocks; biological aging; biomarkers; machine learning; translational science

DOI:  https://doi.org/10.1080/17501911.2025.2603880
Nat Commun. 2025 Dec 16.

TRIM37-PARP1-TET1 axis maintains stemness and prevents osteoporosis by inhibiting DNMT1 alternative splicing via 5hmC regulation.

Chun-Te Ho, Ling-Hui Li, Wei-Chao Chang, Heng-Hsiung Wu, Ya-Huey Chen, Shih-Chieh Hung.

The significance of DNA hydroxymethylation in replicative senescence of mesenchymal stem cells (MSCs) and aging-related osteoporosis remains unknown. Here, we reveal 5hmC levels positively regulate MSC self-renewal and osteoblast differentiation. Mechanistically, PARP1 recruits TET1 to hydrolyze methylated nucleotides on DNMT1 exons, aiding CTCF in preventing DNMT1 alternative splicing in early MSCs. Additionally, ATM phosphorylates TRIM37 at Th203, promoting its nuclear entry and the monoubiquitination of PARP1, stabilizing the protein. CTCF or TRIM37 knockdown induces replicative senescence of MSCs with loss of full-length DNMT1. Co-treatment with resveratrol (ATM activator) and vitamin C (TET1 activator) rejuvenates late MSCs via the TRIM37/PARP1/DNMT1 pathway and alleviates osteoporosis in aged mice. Gene knockout experiments further reveal the participation of TRIM37 and PARP1 in MSC aging, contributing significantly to bone maintenance and repair in vivo. This study emphasizes the role of DNA hydroxymethylation in stemness, suggesting therapeutic strategies, especially for osteoporosis.

DOI: https://doi.org/10.1038/s41467-025-66281-y
Radiol Oncol. 2025 Dec 01. 59(4): 467-476

Between defence and delivery: the DNA sensing response to gene electrotransfer.

Tanja Jesenko, Masa Omerzel, Loree C Heller, Maja Cemazar.

   BACKGROUND: Gene therapy has emerged as a transformative biomedical approach, offering new therapeutic possibilities from many so far uncurable diseases through the introduction of recombinant nucleic acids into target cells. Among non-viral delivery techniques, gene electrotransfer (GET) has become one of the frequently applied methods in clinical trials. It is based on the application of short, high-intensity electric pulses that transiently permeabilize cell membranes and enable the efficient transfer of plasmid DNA or other types of recombinant nucleic acids into various cell types. Beyond its role in gene delivery, GET can trigger complex cellular responses, as the introduced DNA interacts with intracellular DNA sensing pathways involved in innate immunity and inflammation. These responses can influence the therapeutic outcome - either by enhancing antitumour and vaccine-related immune activation or by reducing transfection efficiency when excessive inflammation or cell death occur. Our experimental findings in tumour, muscle, and skin models have shown that even non-coding plasmid DNA delivered by GET can induce local immune stimulation and tissue-specific inflammatory signaling, suggesting that the delivered DNA itself contributes to therapeutic efficacy.
CONCLUSIONS: The dual nature of cellular responses following plasmid DNA GET represents both an opportunity and a challenge. Controlled activation of innate immunity can be harnessed to amplify antitumour or vaccine efficacy, while excessive responses may hinder applications requiring cell survival and sustained expression. Understanding these mechanisms enables the rational optimization of GET parameters and plasmid vector design to fully exploit the adjuvant effect or reduce the off-target effect of DNA sensing after GET, based on the desired application.

Keywords:  DNA sensors; gene electrotransfer; gene therapy; immune response; plasmid DNA

DOI:  https://doi.org/10.2478/raon-2025-0063
Cells Dev. 2025 Dec 11. pii: S2667-2901(25)00070-1. [Epub ahead of print]185 204063

A novel role of Mef2a in mitochondrial homeostasis and muscle regeneration during sarcopenia.

Xin Tao, Suhong Zhang, Yue Li, Gongbing Tu, Dianfu Zhang, Liping Yin.

  Sarcopenia, characterized by an age-related decline in skeletal muscle mass and function, is closely associated with mitochondrial dysfunction. This study aimed to explore the role of myocyte enhancer factor 2A (MEF2A) in alleviating sarcopenia, focusing on its regulatory effect on mitochondrial homeostasis. AAV9-MEF2A was administered to 24-month-old male SAMP8 mice, and their endurance capacity and muscle histology were assessed. In vitro, MEF2A was overexpressed in C2C12 cells to examine its impact on myoblast proliferation and differentiation. Chromatin immunoprecipitation (ChIP), luciferase assays, and rescue experiments were conducted to identify downstream targets and validate the MEF2A-regulated signaling pathway. MEF2A overexpression significantly enhanced endurance performance, with a 1.17-fold increase in muscle mass, a 2.4 to 4.9-fold decrease in muscle atrophy markers compared to the AAV9-NC group, and a nearly 2 to 3-fold increase in mitochondrial biogenesis and antioxidant enzyme expression in aged mice. In C2C12 cells, MEF2A stimulated proliferation (1.8 fold increase in EdU-positive cells vs vector group) and differentiation (2 to 3-fold increase in differentiation markers vs vector group) while improving mitochondrial function through 1.5 to 2-fold increases in both OxPhos complex proteins and mitochondrial biogenesis genes compared to vector control. Mechanistically, MEF2A directly activated the PGC-1α/NRF2 axis, as validated by ChIP and reporter assays. Rescue experiments further verified the critical role of this pathway in MEF2A-mediated effects. These findings demonstrate that MEF2A mitigates sarcopenia by improving mitochondrial function and promoting muscle regeneration via activation of the PGC-1α/NRF2 signaling axis. MEF2A represents a promising therapeutic target for combating age-related muscle degeneration.

Keywords:  MEF2A; Mitochondrial biogenesis; Myogenic differentiation; PGC-1α/NRF2; Sarcopenia

DOI:  https://doi.org/10.1016/j.cdev.2025.204063
bioRxiv. 2025 Nov 28. pii: 2025.11.25.690510. [Epub ahead of print]

Polyelectrolyte complex micelles embedded in hyaluronic acid gels enable local, targeted miR-92a inhibition to accelerate diabetic wound repair.

Brian Xi, Siyang Wang, Aaron Alpar, Jeffrey A Hubbell, Matthew V Tirrell, Yun Fang.

Diabetic wounds are characterized by various cellular deficiencies, particularly insufficient angiogenesis. MicroRNA 92a (miR-92a) is a known factor in diabetic wounds that perpetuates non-healing wound phenotypes by inhibiting angiogenesis. Therefore, its local inhibition at wound sites has therapeutic potential. To achieve this, we combine a nanoparticle formulation of polyelectrolyte complex micelles (PCMs) delivering miR-92a inhibitors with a hyaluronic acid (HA) gel formulation suitable for topical application to wound sites. The nanoparticles, formed by polyelectrolyte complexation of poly(ethylene glycol)-block-poly(L-lysine) with RNA cargo, are functionalized with targeting peptides against vascular cell adhesion molecule 1 (VCAM-1) to improve affinity for inflamed endothelial cells. We demonstrate effective PCM encapsulation and controlled release from gel formulations in vitro and in vivo . These PCMs are taken up in vivo by endothelial cells and exert functional transcriptional effects on miR-92a and its downstream targets. Furthermore, our composite PCM-gel formulation significantly accelerates wound closure in diabetic mouse models and improves angiogenesis, consistent with the known role of miR-92a inhibition in vascular regeneration. This work demonstrates a highly translatable formulation for improved wound healing, and lays the framework for modular nanoparticle-gel systems that can achieve local, cell-targeted RNA delivery.
Highlights: Polyelectrolyte complex micelles (PCMs) can be combined with hyaluronic acid gels.VCAM-1 targeted PCMs released from gels are taken up by endothelial cells. PCM-gels deliver miR-92a inhibitors to modulate downstream gene expression in vivo . PCM-gels accelerate wound healing and enhance angiogenesis in diabetic mice.

DOI: https://doi.org/10.1101/2025.11.25.690510
Aging Cell. 2025 Dec 14. e70327

Small Extracellular Vesicles From Human Amniotic Membrane Mesenchymal Stem Cells Rejuvenate Senescent β Cells and Cure Age-Related Diabetes in Mice.

Lei Xiao, Zicheng Zhang, Tong Li, Yuyin Jiang, Yuanxin Liu, Tingting Lv, Lianju Qin, Yunxia Zhu, Wei Tang.

  Targeting senescent pancreatic β-cells represents a promising therapeutic avenue for age-related diabetes; however, current anti-senescence strategies often compromise β-cell mass. In this study, human amniotic mesenchymal stem cell-derived small extracellular vesicles (hAMSC-sEVs) were identified as a novel intervention that can be used to effectively counteract cellular senescence and preserve β-cell integrity. We aimed to systemically delineate the molecular mechanisms underlying hAMSC-sEV-mediated reversal of β-cell senescence in age-related diabetes. In oxidative stress-induced and naturally aged β-cell models, hAMSC-sEVs mitigated senescence-associated phenotypes, restored mitochondrial homeostasis, and enhanced insulin secretion capacity. In aged diabetic mice, administering these vesicles significantly ameliorated hyperglycemia, improved glucose tolerance, and reversed β-cell functional decline by reducing senescent β-cell populations, reinstating β-cell identity markers, and suppressing senescence-associated secretory phenotype (SASP) component production. Mechanistic investigations revealed that the miR-21-5p-enriched hAMSC-sEVs directly target the interleukin (IL)-6 receptor α subunit (IL-6RA), thereby inhibiting signal transducer and activator of transcription 3 (STAT3) phosphorylation at tyrosine 705 and its subsequent nuclear translocation. This epigenetic modulation alleviated STAT3-mediated transcriptional repression of the mitochondrial calcium uniporter (MCU), rectifying age-related mitochondrial calcium mishandling and insulin secretion defects. Genetic ablation of MCU clearly established the central role of the miR-21-5p/IL-6RA/STAT3/MCU axis in this regulatory cascade. Our findings reveal hAMSC-sEVs as a novel senotherapeutic strategy for age-related diabetes, elucidating the pivotal role of miR-21-5p-driven epigenetic-mitochondrial calcium homeostasis in reversing β-cell dysfunction, establishing a framework for targeting cellular senescence in metabolic disorders.

Keywords:  age‐related diabetes; human amniotic membrane mesenchymal stem cell; miR‐21‐5p; mitochondrial calcium homeostasis; small extracellular vesicles; β‐cell senescence

DOI:  https://doi.org/10.1111/acel.70327