bims-cesemi 2025-04-27 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2025–04–27
eight papers selected by
Julio Cesar Cardenas, Universidad Mayor

Healthy diets for healthy aging.
Temozolomide promotes glioblastoma stemness expression through senescence-associated reprogramming via HIF1α/HIF2α regulation.
Therapy-induced senescent glioblastoma cells sustain a procancer immune microenvironment by activating DDX58-mediated STAT1 signaling.
Targeting Senescence with Apigenin Improves Chemotherapeutic Efficacy and Ameliorates Age-Related Conditions in Mice.
At the Nexus Between Epigenetics and Senescence: The Effects of Senolytic (BI01) Administration on DNA Methylation Clock Age and the Methylome in Aged and Regenerated Skeletal Muscle.
Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism.
Age-associated reduction in ER-Mitochondrial contacts impairs mitochondrial lipid metabolism and autophagosome formation in the heart.
Combined inhibition of de novo glutathione and nucleotide biosynthesis is synthetically lethal in glioblastoma.

Nat Aging. 2025 Apr 24.

Healthy diets for healthy aging.

Hannah Walters.

DOI: https://doi.org/10.1038/s43587-025-00871-9
Cell Death Dis. 2025 Apr 19. 16(1): 317

Temozolomide promotes glioblastoma stemness expression through senescence-associated reprogramming via HIF1α/HIF2α regulation.

Pan Wang, Bin Liao, Sheng Gong, HaiYan Guo, Lu Zhao, Jie Liu, Nan Wu.

A critical challenge in glioblastoma multiforme (GBM) treatment is that tumors recurring after temozolomide (TMZ) therapy become more malignant, exhibiting increased invasiveness and stemness compared to the primary tumor. However, the underlying mechanisms remain unclear. While the majority of GBM cells are eradicated by TMZ, a subset enters cell cycle arrest, adopts a senescence-associated secretory phenotype (SASP), and activates senescence-related signaling pathways. These cells eventually escape senescence, re-enter the cell cycle, and form aggregates exhibiting stem-like characteristics such as elevated stemness marker expression, enhanced colony formation, increased invasiveness, and resistance to chemotherapy. Furthermore, these aggregates promote the invasion and chemotherapy resistance of surrounding cells. Gene Set Enrichment Analysis (GSEA) and KEGG pathway analysis of miRNA and mRNA sequences revealed activation of hallmark hypoxia and HIF1 signaling pathways. The study demonstrated that HIF1α and HIF2α expression fluctuates during and after TMZ treatment. Knockout of HIF1α and HIF2α in GBM cells exposed to TMZ reduced the formation of senescent cells and stem-like aggregates. These findings challenge the efficacy of TMZ therapy by highlighting its role in inducing the process of cellular senescence, thereby contributing to the enhanced stemness and malignancy of recurrent GBM. The regulatory roles of HIF1α and HIF2α are emphasized, underscoring the necessity of preventing senescent cell formation and inhibiting HIF1α/HIF2α expression to improve therapeutic outcomes.

DOI: https://doi.org/10.1038/s41419-025-07617-w
Neuro Oncol. 2025 Apr 22. pii: noaf107. [Epub ahead of print]

Therapy-induced senescent glioblastoma cells sustain a procancer immune microenvironment by activating DDX58-mediated STAT1 signaling.

Zhixing Wang, Yuxin Zhang, Fan Wu, Bojun Qiu, Yiyun Yin, Xinrun Wang, Ruoyu Huang, Xin Zhang, Zhiyan Sun, Wanjun Tang, Zefan Jing, Wei Han, Tao Jiang, Xiaozhong Peng.

   BACKGROUND: Depending on the context, therapy-induced cancer cell senescence promotes or inhibits tumor progression and recurrence, but the underlying mechanism and effects on the tumor immune microenvironment are poorly understood.
METHODS: Here, we developed senescent glioblastoma cell models in vitro via drug treatment. The protumor function of senescent cells was demonstrated by coinjection of chemotherapy-induced senescent cells with tumorigenic GL261 cells in C57BL/6J male mice. In addition, conditioned medium coculture experiments were used to explore the functions of senescent glioblastoma cells in vitro. Mechanistically, through a CRISPR-Cas9-based screen, we revealed that the RNA-binding protein DDX58 was induced in senescent glioblastoma cells. By combining RNA sequencing and protein mass spectrometry analysis, we observed that STAT1 signaling was activated. Immunoprecipitation experiments were subsequently performed to identify the interaction between DDX58 and STAT1.
RESULTS: We show that glioblastoma cells can enter a senescent state after chemotherapy. In vivo, senescent glioblastoma cells have a tumor-promoting function and reduce survival in male mice. Mechanistically, we found that the RNA-binding protein DDX58 plays an important role in therapy-induced senescent glioblastoma. Inhibition of DDX58 slowed therapy-induced senescence. The activation of DDX58 depends on the accumulation of mitochondrial double-stranded RNA (mtdsRNA) in the cytoplasm via the BAX protein. Moreover, DDX58 promotes the recruitment of tumor-associated macrophages (TAMs) and their M2-like polarization by activating the STAT1-mediated transcription of colony-stimulating factor 1 (CSF1). We also revealed that DDX58 regulates STAT1 at the post-translational level by inhibiting the ubiquitin E3 ligase TRIM21-mediated STAT1 ubiquitination. Compared with temozolomide (TMZ) treatment alone, treatment with fludarabine, which blocks STAT1 signaling, combined with TMZ can more effectively reduce the recruitment of TAMs and delay tumor growth in vivo. Moreover, knockdown of STAT1 enhances the therapeutic effect of TMZ in vivo and prolongs the survival of tumor-bearing male mice.
CONCLUSION: A critical mechanism for the protumor immune microenvironment mediated by therapy-induced senescent glioblastoma cells, the DDX58-STAT1-CSF1 axis, may be a potential therapeutic avenue for alleviating traditional therapy-induced glioblastoma cell senescence.

Keywords:  DDX58; Glioblastoma; Immune microenvironment; STAT1; Senescence; TAM

DOI:  https://doi.org/10.1093/neuonc/noaf107
Adv Sci (Weinh). 2025 Apr 23. e2412950

Targeting Senescence with Apigenin Improves Chemotherapeutic Efficacy and Ameliorates Age-Related Conditions in Mice.

Hongwei Zhang, Qixia Xu, Zhirui Jiang, Rong Sun, Qun Wang, Sanhong Liu, Xin Luan, Judith Campisi, James L Kirkland, Weidong Zhang, Yu Sun.

  Cellular senescence is a cell fate triggered by stressful stimuli and displays a hypersecretory feature, the senescence-associated secretory phenotype (SASP). Senescent cell burden increases with aging and contributes to age-related organ dysfunction and multiple chronic disorders. In this study, a large scale screening of a natural product library for senotherapeutic candidates is performed. Apigenin, a dietary flavonoid previously reported with antioxidant and anti-inflammatory activities, exhibits capacity for targeting senescent cells as a senomorphic agent. This compound blocks the interactions between ATM/p38MAPK and HSPA8, preventing the transition of an acute stress-associated phenotype (ASAP) toward the SASP. Mechanistically, apigenin targets peroxiredoxin 6 (PRDX6), an intracellular redox-active molecule, suppressing the iPLA2 activity of PRDX6 and disrupting downstream reactions underlying SASP development. Apigenin reduces the severity of cancer cell malignancy promoted by senescent stromal cells in culture, while restraining chemoresistance when combined with chemotherapy in anticancer regimens. In preclinical trials, apigenin improves the physical function of animals with a premature aging-like state, alleviating physical frailty and cognitive impairment. Together, the study demonstrates the feasibility of exploiting a natural compound with senomorphic capacity to achieve geroprotective effects by modulating the SASP, thus providing a baseline for future exploration of natural agents for alleviating age-related conditions.

Keywords:  SASP; aging; apigenin; cellular senescence; senomorphics

DOI:  https://doi.org/10.1002/advs.202412950
Aging Cell. 2025 Apr 21. e70068

At the Nexus Between Epigenetics and Senescence: The Effects of Senolytic (BI01) Administration on DNA Methylation Clock Age and the Methylome in Aged and Regenerated Skeletal Muscle.

Toby L Chambers, Jaden Wells, Pieter Jan Koopmans, Francielly Morena, Zain B Malik, Nicholas P Greene, Antonio Filareto, Michael Franti, Patrizia Sini, Harald Weinstabl, Robert T Brooke, Milda Milčiūtė, Juozas Gordevičius, Steve Horvath, Yuan Wen, Cory M Dungan, Kevin A Murach.

  Senescent cells emerge with aging and injury. The contribution of senescent cells to DNA methylation age (DNAmAGE) in vivo is uncertain. Furthermore, stem cell therapy can mediate "rejuvenation", but how tissue regeneration controlled by resident stem cells affects whole tissue DNAmAGE is unclear. We assessed DNAmAGE with or without senolytics (BI01) in aged male mice (24-25 months) 35 days following muscle healing (BaCl2-induced regeneration versus non-injured). Young injured mice (5-6 months) without senolytics were comparators. DNAmAGE was decelerated by up to 68% after injury in aged muscle. DNAmAGE was modestly but further significantly decelerated by injury recovery with senolytics. ~1/4 of measured CpGs were altered by injury then recovery regardless of senolytics in aged muscle. Specific methylation changes caused by senolytics included differential regulation of Col, Hdac, Hox, and Wnt genes, which likely contributed to improved regeneration. Altered extracellular matrix remodeling using histological analysis aligned with the methylomic findings with senolytics. Without senolytics, regeneration had a contrasting effect in young mice and tended not to influence or modestly accelerate DNAmAGE. Comparing young to old injury recovery without senolytics using methylome-transcriptome integration, we found a more coordinated molecular profile in young and differential regulation of genes implicated in muscle stem cell performance: Axin2, Egr1, Fzd4, Meg3, and Spry1. Muscle injury and senescent cells affect DNAmAGE and aging influences the transcriptomic-methylomic landscape after resident stem cell-driven tissue reformation. Our data have implications for understanding muscle plasticity with aging and developing therapies aimed at collagen remodeling and senescence.

Keywords:  DNAmAGE; aging; extracellular matrix; methylation clock; omics integration

DOI:  https://doi.org/10.1111/acel.70068
Nat Cell Biol. 2025 Apr 21.

Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism.

Dohun Kim, Rushendhiran Kesavan, Kevin Ryu, Trishna Dey, Austin Marckx, Cameron Menezes, Prakash P Praharaj, Stewart Morley, Bookyong Ko, Mona H Soflaee, Harrison J Tom, Harrison Brown, Hieu S Vu, Shih-Chia Tso, Chad A Brautigam, Andrew Lemoff, Marcel Mettlen, Prashant Mishra, Feng Cai, Doug K Allen, Gerta Hoxhaj.

Nicotinamide adenine dinucleotide phosphate (NADPH) is a vital electron donor essential for macromolecular biosynthesis and protection against oxidative stress. Although NADPH is compartmentalized within the cytosol and mitochondria, the specific functions of mitochondrial NADPH remain largely unexplored. Here we demonstrate that NAD+ kinase 2 (NADK2), the principal enzyme responsible for mitochondrial NADPH production, is critical for maintaining protein lipoylation, a conserved lipid modification necessary for the optimal activity of multiple mitochondrial enzyme complexes, including the pyruvate dehydrogenase complex. The mitochondrial fatty acid synthesis (mtFAS) pathway utilizes NADPH for generating protein-bound acyl groups, including lipoic acid. By developing a mass-spectrometry-based method to assess mammalian mtFAS, we reveal that NADK2 is crucial for mtFAS activity. NADK2 deficiency impairs mtFAS-associated processes, leading to reduced cellular respiration and mitochondrial translation. Our findings support a model in which mitochondrial NADPH fuels the mtFAS pathway, thereby sustaining protein lipoylation and mitochondrial oxidative metabolism.

DOI: https://doi.org/10.1038/s41556-025-01655-4
Cell Death Differ. 2025 Apr 20.

Age-associated reduction in ER-Mitochondrial contacts impairs mitochondrial lipid metabolism and autophagosome formation in the heart.

Weilong Hong, Xue Zeng, Ruiyan Ma, Yu Tian, Huimin Miu, Xiaoping Ran, Rui Song, Zhenchun Luo, Dapeng Ju, Daqing Ma, Milad Ashrafizadeh, Sujit Kumar Bhutia, João Conde, Gautam Sethi, He Huang, Chenyang Duan.

The accumulation of dysfunctional giant mitochondria is a hallmark of aged cardiomyocytes. This study investigated the core mechanism underlying this phenomenon, focusing on the disruption of mitochondrial lipid metabolism and its effects on mitochondrial dynamics and autophagy, using both naturally aging mouse models and etoposide-induced cellular senescence models. In aged cardiomyocytes, a reduction in endoplasmic reticulum-mitochondrial (ER-Mito) contacts impairs lipid transport and leads to insufficient synthesis of mitochondrial phosphatidylethanolamine (PE). A deficiency in phosphatidylserine decarboxylase (PISD) further hinders the conversion of phosphatidylserine to PE within mitochondria, exacerbating the deficit of PE production. This PE shortage disrupts autophagosomal membrane formation, leading to impaired autophagic flux and the accumulation of damaged mitochondria. Modulating LACTB expression to enhance PISD activity and PE production helps maintain mitochondrial homeostasis and the integrity of aging cardiomyocytes. These findings highlight the disruption of mitochondrial lipid metabolism as a central mechanism driving the accumulation of dysfunctional giant mitochondria in aged cardiomyocytes and suggest that inhibiting LACTB expression could serve as a potential therapeutic strategy for mitigating cardiac aging and preserving mitochondrial function.

DOI: https://doi.org/10.1038/s41418-025-01511-w
Cell Rep. 2025 Apr 19. pii: S2211-1247(25)00367-5. [Epub ahead of print]44(5): 115596

Combined inhibition of de novo glutathione and nucleotide biosynthesis is synthetically lethal in glioblastoma.

Suresh Udutha, Céline Taglang, Georgios Batsios, Anne Marie Gillespie, Meryssa Tran, Johanna Ten Hoeve, Thomas G Graeber, Pavithra Viswanath.

  Understanding the mechanisms by which oncogenic events alter metabolism will help identify metabolic weaknesses that can be targeted for therapy. Telomerase reverse transcriptase (TERT) is essential for telomere maintenance in most cancers. Here, we show that TERT acts via the transcription factor forkhead box O1 (FOXO1) to upregulate glutamate-cysteine ligase (GCLC), the rate-limiting enzyme for de novo biosynthesis of glutathione (GSH, reduced) in multiple cancer models, including glioblastoma (GBM). Genetic ablation of GCLC or pharmacological inhibition using buthionine sulfoximine (BSO) reduces GSH synthesis from [U-13C]-glutamine in GBMs. However, GCLC inhibition drives de novo pyrimidine nucleotide biosynthesis by upregulating the glutamine-utilizing enzymes glutaminase (GLS) and carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotatase (CAD) in an MYC-driven manner. Combining BSO with the glutamine antagonist JHU-083 is synthetically lethal in vitro and in vivo and significantly extends the survival of mice bearing intracranial GBM xenografts. Collectively, our studies advance our understanding of oncogene-induced metabolic vulnerabilities in GBMs.

Keywords:  CP: Cancer; CP: Metabolism; TERT; brain tumors; cancer; glioblastoma; glutamine metabolism; glutathione; in vivo stable isotope tracing; metabolic synthetic lethality; metabolomics; nucleotide biosynthesis; telomerase reverse transcriptase

DOI:  https://doi.org/10.1016/j.celrep.2025.115596