bims-cesemi 2025-11-02 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2025–11–02
nine papers selected by
Julio Cesar Cardenas, Universidad Mayor

Integrative Omics Reveal Female-Specific Benefits of p16+ Cell Clearance in Aging Mice.
Distinct senotypes in p16- and p21-positive cells across human and mouse aging tissues.
Heterogenous mitochondrial ultrastructure and metabolism of human glioblastoma cells: differences between stem-like and differentiated cancer cells in response to chemotherapy.
Targeting Cellular Senescence in Dystrophin-/-/Utrophin-/-Double Knockout Mice Improves Musculoskeletal Health and Increases Lifespan.
Irradiation-induced brain senescence accelerates cardiac aging via systemic mechanisms: insights from transcriptomic profiling.
Cellular Senescence and Inter-Organ Communication in Health and Disease.
Super mitochondria-enriched extracellular vesicles enable enhanced mitochondria transfer.
Deficiency of 2-Oxoglutarate Carrier (Slc25a11) Drives RPE Epithelial-to-Mesenchymal Transition and Exacerbates Subretinal Fibrosis in Neovascular Age-Related Macular Degeneration.
Accumulation of succinate suppresses de novo purine synthesis through succinylation-mediated control of the mitochondrial folate cycle.

Adv Sci (Weinh). 2025 Oct 30. e09444

Integrative Omics Reveal Female-Specific Benefits of p16+ Cell Clearance in Aging Mice.

Yao Lin, Boshi Wang, Mengling Huang, Justina C Wolters, Marco Demaria.

  Aging is marked by the accumulation of cells expressing the cyclin-dependent kinase inhibitor p16Ink4a. These p16⁺ cells, largely senescent, contribute to inflammation and tissue dysfunction. While eliminating p16⁺ cells improves healthspan, sex-specific differences in their burden and clearance remain unclear. Through combined transcriptomic, proteomic, and functional analyses, we reveal distinct sex-dependent dynamics of p16⁺ cells during aging. Female mice accumulate significantly more p16⁺ cells across multiple tissues, particularly in the liver. In the p16-3MR model, selective ablation of these cells enhances grip strength, promotes skin regeneration, and reduces liver damage exclusively in females. Multi-omics profiling shows that p16⁺ cell removal shifts female liver expression toward youthful, health-associated profiles, marked by improved mitochondrial activity and reduced inflammatory signaling-molecular patterns resembling those induced by longevity interventions such as calorie restriction, rapamycin, and acarbose. Integrative analysis of our and independent datasets identifies a conserved transcriptional network involving Srm, Cd36, and Lrrfip1, suggesting shared mitochondrial-immune regulatory mechanisms. Overall, our findings establish p16⁺ cells as critical yet heterogeneous drivers of tissue aging, uncover sex-specific differences in their abundance and senolytic responsiveness, and support the development of precision senotherapeutics that consider sex as a key biological variable in aging and rejuvenation.

Keywords:  SASP; aging; cellular senescence; p16; senolytics

DOI:  https://doi.org/10.1002/advs.202509444
EMBO J. 2025 Oct 29.

Distinct senotypes in p16- and p21-positive cells across human and mouse aging tissues.

Dominik Saul, Diana Jurk, Madison L Doolittle, Robyn Laura Kosinsky, Yeaeun Han, Xu Zhang, Ana Catarina Franco, Sung Y Kim, Saranya P Wyles, Y S Prakash, David G Monroe, Luigi Ferrucci, Nathan K LeBrasseur, Paul D Robbins, Laura J Niedernhofer, Sundeep Khosla, João F Passos.

  Senescent cells drive age-related tissue dysfunction via the induction of a chronic senescence-associated secretory phenotype (SASP). The cyclin-dependent kinase inhibitors p21Cip1 and p16Ink4a have long served as markers of cellular senescence. However, their individual roles remain incompletely elucidated, particularly in vivo. Thus, we conducted a comprehensive examination of multiple single-cell RNA sequencing datasets spanning both murine and human tissues during aging. Our analysis revealed that p21Cip1 and p16Ink4a transcripts demonstrate significant heterogeneity across distinct cell types and tissues, frequently exhibiting a lack of co-expression. Moreover, we identified tissue-specific variations in SASP profiles linked to p21Cip1 or p16Ink4a expression. Using RNA velocity and pseudotime analyses, we discovered that p21+ and p16+ cells follow independent trajectory dynamics, with no evidence of direct transitions between these two states. Despite this heterogeneity, we identified a limited set of shared "core" SASP factors that may drive common senescence-related functions. Our study underscores the substantial diversity of cellular senescence and the SASP, emphasizing that these phenomena are inherently cell- and tissue-dependent.

Keywords:  Aging; Cellular Senescence; Heterogeneity; Senescence-Associated Secretory Phenotype (SASP); Single-Cell Mapping

DOI:  https://doi.org/10.1038/s44318-025-00601-2
Radiol Oncol. 2025 Oct 27.

Heterogenous mitochondrial ultrastructure and metabolism of human glioblastoma cells: differences between stem-like and differentiated cancer cells in response to chemotherapy.

Urban Bogataj, Metka Novak, Simona Katrin Galun, Klementina Fon Tacer, Milos Vittori, Cornelis J F Van Noorden, Barbara Breznik.

   BACKGROUND: Glioblastoma stem-like cells (GSCs) contribute to the resistance of glioblastoma (GBM) tumors to standard therapies. The background of the resistance of GSCs to the chemotherapeutic agent temozolomide is not yet fully understood in the context of cellular metabolism and the role of mitochondria. The aim of this study was to perform a detailed ultrastructural characterization of the mitochondria of GSCs prior and post temozolomide exposure and to compare it to differentiated GBM cells.
MATERIALS AND METHODS: Patient-derived and established GBM cell lines were used for the study. The ultrastructure of the mitochondria of the examined cell lines was assessed by transmission electron microscopy. The microscopic analysis was complemented and compared by an analysis of cell metabolism using Seahorse extracellular flux analysis.
RESULTS: We found that the metabolic profile of GSCs is quiescent and aerobic. Their elongated mitochondria with highly organized cristae are indicating increased biogenesis and mitochondrial fusion and corresponds to a more oxidative phosphorylation (OXPHOS)-dependent metabolism. The metabolism of GSCs is dependent on OXPHOS and there are no changes in defective mitochondria fraction after the treatment with temozolomide. In contrast, differentiated GBM cells with fragmented mitochondria, which have less organized cristae, are more energetic and glycolytic. Temozolomide treatment induced ultrastructural mitochondrial damage in differentiated GBM cells.
CONCLUSIONS: We demonstrated differences in mitochondrial ultrastructure and cellular metabolism between GSCs and differentiated GBM cells in response to temozolomide, suggesting that mitochondria play an important role in the resistance of GSCs to temozolomide. This study provides a basis for further studies addressing GSC chemotherapy resistance in the context of mitochondrial structure and function.

Keywords:  chemotherapy resistance; glioblastoma; metabolism; mitochondria ultrastructure; stem cells

DOI:  https://doi.org/10.2478/raon-2025-0056
Pharmacol Res. 2025 Oct 29. pii: S1043-6618(25)00441-4. [Epub ahead of print] 108016

Targeting Cellular Senescence in Dystrophin-/-/Utrophin-/-Double Knockout Mice Improves Musculoskeletal Health and Increases Lifespan.

Xueqin Gao, Joseph J Ruzbarsky, Matthieu Huard, S Amir H Sajedi, Peter T Shyu, Zuokui Xiao, Britney S Force, Sarah White, Jessica Ayers, Bing Wang, X Edward Guo, Johnny Huard.

  Duchenne muscular dystrophy (DMD) is a severe genetic muscle disease caused by mutations of the dystrophin gene. Previous studies have detected senescent cells in the skeletal muscle of human DMD, dystrophin-deficient mice (Mdx), and rats. This study aimed to use a more severe dystrophin-/-/utrophin-/- (dKO-Hom) mouse model to identify which cells become senescent and if targeting cellular senescence can improve bone quality and muscle pathology in dKO-Hom mice. Immunohistochemistry of P21 and GLB1 revealed significantly more senescent cells in the skeletal muscle tissues of 4-week-old Mdx and dKO-Hom mice compared to WT mice, but not in the bone tissue. The senescent cells were predominantly macrophages (GLB1+/CD68+). Treatment of dKO-Hom mice with ruxolitinib improved spine L5 trabecular bone microarchitecture and ameliorated skeletal muscle histopathology by decreasing senescent macrophages (GLB1+CD68+, FUCA1+/CD68+ or P21+/CD68+) and senescent-associated phenotypes (SASP) such as macrophage migration inhibitory factor (MIF) in skeletal muscle. Ruxolitinib treatment also improved heart muscle pathology by decreasing senescent macrophages. Additionally, ruxolitinib treatment increased muscle grip strength and treadmill endurance of Mdx mice. Moreover, ruxolitinib significantly extended the lifespan of dKO-Hom mice after 12 days of treatment. Furthermore, treatment of dKO-Hom mice with ruxolitinib and deflazacort synergistically improved bone microarchitecture of the spine L5 vertebrate and the proximal tibia trabecular bone (BV/TV, Tb.N, Tb.Th) by increasing osteoblast cells and decreasing osteoclasts. Co-administration of ruxolitinib and deflazacort also synergistically ameliorated skeletal muscle and heart pathology. Therefore, targeting senescent cells with ruxolitinib represents a promising approach for treating DMD patients but warrants further studies in humans.

Keywords:  Muscular dystrophy; bone health; cellular senescence; deflazacort; dystrophin(-/-)/Utrophin(-/-) mice; ruxolitinib

DOI:  https://doi.org/10.1016/j.phrs.2025.108016
Geroscience. 2025 Oct 26.

Irradiation-induced brain senescence accelerates cardiac aging via systemic mechanisms: insights from transcriptomic profiling.

Rafal Gulej, Roland Patai, Tamas Kiss, Siva Sai Chandragiri, Shoba Ekambaram, Raghavendra Yelahanka Nagaraja, Dorina Nagy, Kiana Vali Kordestan, Tamas Lakat, Stefano Tarantini, Peter Mukli, Anna Ungvari, Andriy Yabluchanskiy, Zoltan Benyo, Anna Csiszar, Zoltan Ungvari.

  Aging is characterized by a coordinated functional decline across multiple organs. While cell-autonomous mechanisms contribute to local aging phenotypes, the systemic synchronicity of aging suggests a major role for cell non-autonomous drivers. Emerging evidence implicates the hypothalamus-a central regulator of neuroendocrine and homeostatic functions-as a potential source of circulating pro-geronic signals. A hallmark of brain aging is the accumulation of senescent cells, particularly in microglia and brain microvascular endothelial cells, including within the hypothalamus, which contributes to a heightened state of neuroinflammation and altered systemic signaling. Here, we tested the hypothesis that brain senescence and its associated inflammatory milieu promote peripheral aging by reshaping the systemic environment. To model this, we employed targeted whole-brain irradiation (WBI) in young mice-a well-established method to induce widespread brain cellular senescence and neuroinflammation, mimicking changes seen in natural aging. Two months after WBI, we performed transcriptomic profiling of the heart to evaluate remote, cell non-autonomous effects. Cardiac RNA sequencing revealed a striking overlap in gene expression changes between WBI-treated young mice and naturally aged controls. Notably, several gene sets associated with fundamental cellular and molecular mechanisms of aging were concordantly dysregulated in both groups, with strong enrichment for pathways related to mitochondrial metabolism, immune activation, interferon signaling, and extracellular matrix remodeling. These findings demonstrate that localized brain senescence is sufficient to induce aging-like transcriptomic remodeling in peripheral organs, likely mediated by circulating factors. Our findings establish brain senescence as a key orchestrator of systemic aging-a mechanism that may contribute to accelerated aging trajectories in individuals with lifestyle-associated increased brain senescence and neuroinflammation, as well as in cancer survivors exposed to senescence-inducing treatments such as whole-brain irradiation.

Keywords:  Brain senescence; Cardiac aging; Cardiovascular aging; Cell non-autonomous aging; Circulating factors; DNA damage; Endocrine; Hypothalamus; Neuroendocrine; Neuroinflammation; SASP; Senescence-associated secretory phenotype; Systemic aging; Transcriptomics

DOI:  https://doi.org/10.1007/s11357-025-01953-7
Physiology (Bethesda). 2025 Oct 25.

Cellular Senescence and Inter-Organ Communication in Health and Disease.

Yang Zhang, Xinyue Chi, Qiulian Zhou, Shengyuan Huang, Hou-Zao Chen, Anthony Rosenzweig.

  As populations age worldwide, understanding the biology of aging and its contribution to disease becomes increasingly important. Cellular senescence, a hallmark of aging, plays a pivotal role in shaping inter-organ communication and systemic health. Once viewed primarily as a local mechanism to prevent the proliferation of damaged cells, senescence is now recognized as a dynamic, multifaceted process that influences physiology across the lifespan. Through senescence-associated secretory phenotype (SASP) proteins and other signaling modalities, including metabolites, extracellular vesicles, immune cells, and neural circuits, senescent cells contribute to both homeostatic regulation and the propagation of chronic inflammation, fibrosis, and age-related disease. These effects are often context-dependent, and senescence in one organ can influence distant tissues, driving asynchronous aging and disease vulnerability. This review examines the mechanisms by which senescent cells facilitate inter-organ communication, including emerging roles for blood-borne factors, immune cell dynamics, and neuroendocrine signals. We highlight illustrative examples of organ crosstalk and emphasize the potential translational relevance of these pathways. We also examine therapeutic strategies aimed at modulating senescence, including senolytics, senomorphics, and interventions targeting specific SASP components, as well as the potential of lifestyle modifications to mitigate biological aging. Understanding senescence and the associated inter-organ communication offers new insights into aging biology and opens promising avenues for addressing age-related diseases in an integrated, organ-spanning framework.

Keywords:  Aging; Cellular Senescence; SASP; Senolytics; Senomorphics

DOI:  https://doi.org/10.1152/physiol.00017.2025
Nat Commun. 2025 Oct 27. 16(1): 9448

Super mitochondria-enriched extracellular vesicles enable enhanced mitochondria transfer.

Yi Wang, Hao-Yuan Yu, Zi-Juan Yi, Lian-Yu Qi, Jing-Song Yang, Hai-Xin Xie, Min Zhao, Na-Hui Liu, Jia-Qi Chen, Tian-Jiao Zhou, Lei Xing, Xian-Wu Cheng, Hu-Lin Jiang.

Mitochondria transfer is a spontaneous process that releases functional mitochondria to damaged cells via different mechanisms including extracellular vesicle containing mitochondria (EV-Mito) to restore mitochondrial functions. However, the limited EV-Mito yield makes it challenging to supply a sufficient quantity of functional mitochondria to damaged cells, hindering their application in mitochondrial diseases. Here, we show that the release of EV-Mito from mesenchymal stem cells (MSCs) is regulated by a calcium-dependent mechanism involving CD38 and IP3R signaling (CD38/IP3R/Ca2+ pathway). Activating this pathway through our non-viral gene engineering approach generates super donor MSCs which produce Super-EV-Mito with a threefold increase in yield compared to Ctrl-EV-Mito from normal MSCs. Leber's hereditary optic neuropathy (LHON), a classic mitochondrial disease caused by mtDNA mutations, is used as a proof-of-concept model. Super-EV-Mito rescues mtDNA defects and alleviates LHON-associated symptoms in LHON male mice. This strategy offers a promising avenue for enhancing mitochondria transfer efficiency and advancing its clinical application in mitochondrial disorders.

DOI: https://doi.org/10.1038/s41467-025-64486-9
Aging Cell. 2025 Oct 28. e70271

Deficiency of 2-Oxoglutarate Carrier (Slc25a11) Drives RPE Epithelial-to-Mesenchymal Transition and Exacerbates Subretinal Fibrosis in Neovascular Age-Related Macular Degeneration.

Mo Wang, Feng-Juan Gao, Wenyi Tang, Boya Lei, Fangyuan Hu, Jun Ma, Srinivas R Sadda, Ram Kannan, Parameswaran G Sreekumar, Gezhi Xu.

  Subretinal fibrosis significantly contributes to vision loss in neovascular age-related macular degeneration (nAMD). Epithelial-to-mesenchymal transition (EMT) in RPE cells is a key early step in subretinal fibrosis. While mitochondrial dysfunction in RPE is involved, the metabolic and molecular connections between EMT and mitochondria are not well understood. This study explores the role of oxoglutarate carrier (OGC; Slc25a11) on EMT and investigates the molecular mechanisms, focusing on its role in mitochondrial metabolism and GSH transport. OGC-silenced or overexpressed ARPE-19 cells were treated with TGF-β2 (10 ng/mL) for 48 h. EMT markers, cell migration, mtGSH, and mitochondrial bioenergetics and signaling pathways were assessed. In vivo, subretinal fibrosis was induced in wild-type and OGC+/- mice via laser photocoagulation. Fibrosis volume was measured using optical coherence tomography and immunostaining in RPE-choroid flat mounts. OGC silencing aggravated EMT, while overexpression attenuated TGF-β2-induced EMT, cell proliferation, and migration. OGC knockdown significantly enhanced RPE EMT, as evidenced by upregulated expression of α-SMA, fibronectin, collagen type I, and Slug, while E-cadherin was downregulated. OGC overexpression improved mitochondrial bioenergetics, whereas its inhibition reduced mitochondrial respiration, which was further aggravated by co-treatment with TGF-β2. Loss of OGC promoted cell proliferation and migration through Slug-mediated EMT. OGC depletion stimulated EMT via pSmad2/3 upregulation, dependent on the PI3K/AKT signaling pathway activation. In vivo studies further demonstrate that subretinal fibrosis was significantly augmented in OGC+/- mice via TGF-β2-dependent PI3K signaling. In conclusion, modulating OGC expression in RPE affects EMT and mitochondrial function, making OGC a potential therapeutic target for subretinal fibrosis in nAMD.

Keywords:  OGC; RPE‐EMT; mitochondrial dysfunction; neovascular AMD; subretinal fibrosis

DOI:  https://doi.org/10.1111/acel.70271
Mol Cell. 2025 Oct 28. pii: S1097-2765(25)00819-6. [Epub ahead of print]

Accumulation of succinate suppresses de novo purine synthesis through succinylation-mediated control of the mitochondrial folate cycle.

Mushtaq A Nengroo, Austin T Klein, Heather S Carr, Olivia Vidal-Cruchez, Umakant Sahu, Daniel J McGrail, Nidhi Sahni, Niklas B Thompson, Peter A Faull, Peng Gao, John M Asara, Hardik Shah, Marc L Mendillo, Issam Ben-Sahra.

  The de novo purine synthesis pathway is fundamental for nucleotide production, yet the role of mitochondrial metabolism in modulating this process remains underexplored. Here, we identify that succinate dehydrogenase (SDH) is essential for maintaining de novo purine synthesis. Genetic or pharmacological inhibition of SDH suppresses purine synthesis, contributing to a decrease in cell proliferation. Mechanistically, SDH inhibition elevates succinate, which in turn promotes the succinylation of serine hydroxymethyltransferase 2 (SHMT2) within the mitochondrial tetrahydrofolate (THF) cycle. This post-translational modification lowers formate output, depriving cells of one-carbon units needed for purine assembly. In turn, cancer cells activate the purine salvage pathway, a metabolic compensatory adaptation that represents a therapeutic vulnerability. Notably, co-inhibition of SDH and purine salvage induces pronounced antiproliferative and antitumoral effects in preclinical models. These findings reveal a signaling role for mitochondrial succinate in tuning nucleotide metabolism and highlight a dual-targeted strategy to exploit metabolic dependencies in cancer.

Keywords:  TCA cycle; cancer; formate; mitochondrial metabolism; nucleotide metabolism; succinate

DOI:  https://doi.org/10.1016/j.molcel.2025.10.002