bims-caglex 2025-12-14 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2025–12–14
seven papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

Editing DNA methylation in vivo.
Epigenetic Targeting of Senescent Cells Prevents the Deleterious Effects of Obstructive Sleep Apnea on Growing Skeleton.
Atavistic Genetic Expression Dissociation (AGED) During Aging: Meta-Phylostratigraphic Evidence of Cellular and Tissue-Level Phylogenetic Dissociation.
Tumorigenic p53N236S balances aging and tumorigenesis via regulating DREAM/MMB and downstream telomere DNA replication pathways.
NRF1-mediated innate immune response drives inflammaging.
Fueling for the finish line: Control of human telomerase activity by nucleotide metabolism.
Breaking the pH Code: Acidification Triggers SASP and Inflammation in Cellular Senescence.

Nat Commun. 2025 Dec 10.

Editing DNA methylation in vivo.

Richard Pan, Jingwei Ren, Xinyue Chen, Luis F Flores, Rachel V L Gonzalez, Andre Antonio Adonnino, Brandon Lofts, Jennifer Waldo, Julian Halmai, Orrin Devinsky, Kyle Fink, X Shawn Liu.

DNA methylation is a crucial epigenetic mechanism that regulates gene expression. Precise editing of DNA methylation has emerged as a promising tool for dissecting its biological function. However, challenges in delivery have limited most applications of DNA methylation editing to in vitro systems. Here, we develop two transgenic mouse lines harboring an inducible dCas9-DNMT3A or dCas9-TET1 editor to enable tissue-specific DNA methylation editing in vivo. We demonstrate that targeted methylation of the Psck9 promoter in the liver of dCas9-DNMT3A mice results in decreased Pcsk9 expression and a subsequent reduction in serum low-density lipoprotein cholesterol level. Targeted demethylation of the Mecp2 promoter in dCas9-TET1 mice reactivates Mecp2 expression from the inactive X chromosome and rescues neuronal nuclear size in Mecp2+/- mice. Genome-wide sequencing analyses reveal minimal transcriptional off-targets, demonstrating the specificity of the system. These results demonstrate the feasibility and versatility of methylation editing, to functionally interrogate DNA methylation in vivo.

DOI: https://doi.org/10.1038/s41467-025-67222-5
Adv Sci (Weinh). 2025 Dec 12. e02697

Epigenetic Targeting of Senescent Cells Prevents the Deleterious Effects of Obstructive Sleep Apnea on Growing Skeleton.

Xiaonan Liu, Peilin Zhang, Zhongyi Su, Yong Feng, Zhenger Zhou, Sa Pang, Yicheng Wang, Jiacheng Hu.

  Obstructive Sleep Apnea Syndrome (OSAS) is a common sleep disorder characterized by chronic intermittent hypoxia (CIH), which has been increasingly recognized for its systemic effects on pediatric skeletal development. However, the mechanism by which CIH influences bone growth and homeostasis remains largely unexplored. In this study, it is demonstrated that CIH exposure in young murine models induces cellular senescence within the metaphysis of long bones, resulting in compromised bone formation and growth retardation. Through single cell sequencing and in situ immunostaining, it is identified that the senescent cells predominantly consist of osteoprogenitors. Mechanistically, CIH enhances the activity of hypoxia-inducible factor 1-alpha (HIF-1α) in osteoprogenitors and subsequently downregulates trimethylation of histone H3 at lysine 27 (H3k27me3) through the suppression of polycomb histone methyltransferase enhancer of zeste homolog 2 (EZH2), thereby facilitating the expression of senescence-associated genes. Employing both genetic and pharmacological strategies, it is demonstrated that the restoration of H3K27me3 levels via UTX inhibition (achieved through in vivo knockout or GSK-J4 treatment) effectively prevents CIH-induced senescence, promotes osteogenesis, and alleviates bone loss and growth retardation. These findings elucidate a novel epigenetic mechanism that underlies the skeletal impairments associated with CIH and underscore the therapeutic potential of targeting histone methylation to mitigate hypoxia-induced bone defects.

Keywords:  H3K27me3; HIF‐1α; bone growth; chronic intermittent hypoxia; obstructive sleep apnea; osteoprogenitor senescence

DOI:  https://doi.org/10.1002/advs.202502697
Aging Cell. 2025 Dec 08. e70305

Atavistic Genetic Expression Dissociation (AGED) During Aging: Meta-Phylostratigraphic Evidence of Cellular and Tissue-Level Phylogenetic Dissociation.

Léo Pio-Lopez, Michael Levin.

  Aging is commonly attributed to accumulated damage, or evolved antagonistic genetic trade-offs, which lead to an accumulation of damage causing misexpression of genes necessary for longevity. We propose an atavistic dysregulation of gene expression at cellular and tissue levels during aging, framing aging as a gradual regression toward ancestral cellular states. Similarly to the atavistic model of cancer, in which cells revert to unicellular-like behavior, aging may result from the breakdown of coordinated morphogenetic control, leading organs and tissues toward less integrated, ancient unicellular states. We suggest that aging may involve a progressive reversal of the well-known ontogenetic tracing of prior phylogenetic embryonic characteristics. Moreover, aging could involve a loss of large-scale coordination, with tissues reverting to ancient gene expression to different degrees. We tested this hypothesis using a meta-phylostratigraphic analysis, finding: (1) An atavistic over-representation of differential expression in the most ancient genes and under-representation in the evolutionary youngest genes for two multi-tissue aging databases, and tissues covering skin, ovarian, immune, senescent and mesenchymal-senescent cells; (2) No significant atavistic over-representation of the differential gene expression during aging of brain cells and mesenchymal stem cells; (3) overall age-dependent increase of heterogeneity in the direction of the phylogenetic position of tissues' transcriptional profiles; (4) and an overall negative evolutionary age mean shift toward the most ancient genes. Our analyses suggest that aging involves uncoordinated and tissue-specific phylogenetic changes in gene expression. Understanding aging as a structured, heterogeneous atavistic process opens new avenues for rejuvenation, focusing on restoring multicellular coherence in evolutionarily youthful gene expression.

Keywords:  aging; longevity; phylostratigraphy

DOI:  https://doi.org/10.1111/acel.70305
J Mol Cell Biol. 2025 Dec 08. pii: mjaf053. [Epub ahead of print]

Tumorigenic p53N236S balances aging and tumorigenesis via regulating DREAM/MMB and downstream telomere DNA replication pathways.

Qianqian Wang, Haili Li, Quan Zheng, Jun Yang, Kailong Hou, Liangxia Jiang, Shuting Jia, Xiaoming Wu, Juhua Dan, Ying Luo.

  The Werner syndrome (WS) is characterized with both premature aging and tumorigenic phenotypes. In this study, we introduced a tumorigenic mutation p53N236S (referred as p53S later), which is found in immortalized WS mouse embryo fibroblasts, back into WS mice to investigate its impact on the telomere dysfunction-induced aging process. Intriguingly, the introduction of p53S rescued the aging phenotypes of WS mice, showing the extension of the lifespan and the delay in organ degeneration. Further studies revealed that the introduction of p53S transcriptionally upregulated the DREAM/MMB pathway and downstream DNA helicases and telomere maintenance proteins, facilitated the recruitment of these proteins to G-quadruplex (G4) DNA structures proximal to DNA replication forks, and promoted the unwinding of G4. By comparing the cellular responses to pyridostatin and hydroxyurea, respectively, we confirmed that p53S specifically regulates G4-related DNA replication stress. Thus, p53S compensates the loss of Wrn and telomerase function, solves the DNA replication, telomere lengthening, and cell proliferation problems in WS cells, and ultimately, rescues the aging phenotypes of WS. Together, our data indicate that certain tumorigenic features can be applied to balance with premature aging, rescuing the aging phenotype without tumor risk. This study suggests a new mechanism in aging regulation and provides the possibility of developing a tumor-free longevity strategy and targeting G4 and DNA replication in aging-related tumor therapy.

Keywords:  DNA replication; DREAM/MMB pathway; Werner syndrome; p53 mutation; telomere

DOI:  https://doi.org/10.1093/jmcb/mjaf053
Nat Commun. 2025 Dec 11.

NRF1-mediated innate immune response drives inflammaging.

Hong Lei, Tian Zhao, Jiaojiao Zhang, Yijia Long, Yongze Chen, Yixuan Zhu, Yuanyuan Meng, Yinmei Tang, Xin Liu, Jiaxing Sun, Zhuoya Li, Jingyi Su, Fengcongzhe Gong, Guo Chen, Baofa Sun, Yanfang Chen, Quan Chen, Yanjun Li, Yushan Zhu.

Aberrant innate immune responses contribute significantly to cellular senescence, yet the precise interplay between innate immunity and senescence remains poorly characterized. Here, we elucidate the pivotal role of nuclear respiratory factor 1 (NRF1) in orchestrating innate immune responses that drive senescence and the senescence-associated secretory phenotype (SASP). NRF1 deficiency delayed cellular senescence and ameliorated age-related deterioration in multiple organs. Mechanistically, NRF1 enhanced SASP by transcriptionally regulating TBK1 and IRF3, critical nodes in innate immunity essential for senescence induction. Conversely, NRF1 deficiency suppressed innate immune activation, thereby attenuating inflammation associated with senescence and aging. Additionally, DNA damage activated ATM kinase, which phosphorylated NRF1 at Ser393, augmenting the NRF1-TBK1/IRF3-type I interferon axis and exacerbating cellular senescence. Furthermore, NRF1 knockdown treatment effectively mitigated aging phenotypes and extended lifespan in aged mice. Collectively, our findings underscore the essential role of the ATM-NRF1-TBK1/IRF3-type I interferon axis in DNA damage-induced senescence, suggesting that targeted NRF1 modulation holds therapeutic promise for improving inflammaging.

DOI: https://doi.org/10.1038/s41467-025-66368-6
DNA Repair (Amst). 2025 Dec 04. pii: S1568-7864(25)00108-9. [Epub ahead of print]156 103912

Fueling for the finish line: Control of human telomerase activity by nucleotide metabolism.

William Mannherz, Suneet Agarwal.

  Telomeres are repetitive DNA sequences that preserve genome integrity. Human telomere length is kept in a tight window through a balance between telomere erosion during genome replication and telomere elongation by the telomerase reverse transcriptase. In humans, genetically determined telomere length is associated with lifespan, while inherited defects in telomere length maintenance genes predispose to a spectrum of lethal diseases termed telomere biology disorders (TBDs). Recently, dNTP metabolism has emerged as a previously underappreciated pathway that is critical for human telomerase regulation and telomere length control. Genome-wide association studies have implicated variation in several dNTP metabolism genes with human telomere length. Genetic variants at the TYMS locus, which encodes the rate limiting thymidine synthesis enzyme thymidylate synthase, have been shown to cause the TBD dyskeratosis congenita. Genome-wide CRISPR/Cas9 functional screening has linked telomere length control to multiple key dNTP metabolism genes. Remarkably, mechanistic studies emerging from these genetic data have revealed a profound, bidirectional sensitivity of human telomerase activity to cellular dNTP levels, that is readily manipulated through several metabolic control nodes. Here, we review the emerging genetic evidence and mechanistic studies supporting the relationship between dNTP metabolism and telomere length control. We present an integrated model for human telomerase regulation, wherein the levels of dNTP substrates govern telomerase reverse transcriptase activity and in turn human telomere length. We discuss the therapeutic prospects and recent trials for manipulating dNTP metabolism to treat TBDs and related degenerative diseases.

Keywords:  Metabolism; Nucleotide; SAMHD1; Telomerase; Telomere; dNTP

DOI:  https://doi.org/10.1016/j.dnarep.2025.103912
J Biochem. 2025 Dec 11. pii: mvaf080. [Epub ahead of print]

Breaking the pH Code: Acidification Triggers SASP and Inflammation in Cellular Senescence.

Akimitsu Konishi.

  Cellular senescence is a stress-induced, stable growth arrest accompanied by marked metabolic alterations and acquisition of the senescence-associated secretory phenotype (SASP). While enhanced glycolysis, mitochondrial dysfunction, and lysosomal abnormalities are well-established features, emerging evidence identifies progressive intracellular acidification as an important yet underappreciated regulator of cellular senescence. Acidification results from suppressed NHE1-mediated proton efflux, elevated glycolytic proton production, and lysosomal membrane permeabilization. This lowered pH alters redox balance, inhibits HDAC activity, and promotes transcription of senescence-associated genes. Recent work by Kawakami et al. demonstrates that acidification activates a glycolysis-linked inflammatory circuit through accumulation of glucose-6-phosphate and induction of the MondoA targets TXNIP and ARRDC4, which correlate with SASP induction and define a highly secretory subset of senescent cells. These findings suggest that intracellular pH functions as a key metabolic cue linking altered glycolysis to inflammatory output, offering a conceptual framework that may guide future efforts to modulate age-associated chronic inflammation.

Keywords:  Cellular senescence; Glycolysis; Inflammation; Intracellular acidification; Senescence-associated secretory phenotype (SASP)

DOI:  https://doi.org/10.1093/jb/mvaf080