bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–03–16
nineteen papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Mitochondrial Ca2+ uniporter b (MCUb) regulates neuronal Ca2+ dynamics and resistance to ischemic stroke.
  2. Cellular Senescence Is a Central Driver of Cognitive Disparities in Aging.
  3. Current Methodologies to Assess Cellular Senescence in Cancer.
  4. Disruption of ER-mitochondria contact sites induces autophagy-dependent loss of P-bodies through the Ca2+-CaMKK2-AMPK pathway.
  5. VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes.
  6. Accelerating the promise of geroscience through The Academy of Health & Lifespan Research.
  7. Senolytic treatment for low back pain.
  8. Detecting Senescence in T Cells by Flow Cytometry Using the SA-β-Galactosidase Assay.
  9. Detection and Characterization of Senescent Cells with Flow Cytometry.
  10. A Key Role of the EMC Complex for Mitochondrial Respiration and Quiescence in Fission Yeasts.
  11. Targeting metabolic reprogramming in glioblastoma as a new strategy to overcome therapy resistance.
  12. Electron Microscopy to Visualize and Quantify Mitochondrial Structure and Organellar Interactions in Cultured Cells During Senescence.
  13. Mitochondrial priming and response to BH3 mimetics in "one-two punch" senogenic-senolytic strategies.
  14. Young fibroblast-derived migrasomes alleviate keratinocyte senescence and enhance wound healing in aged skin.
  15. Cellular Senescence in the Regenerative Niche Hampers Skeletal Muscle Repair.
  16. The pro-inflammatory cytokine IL6 suppresses mitochondrial function via the gp130-JAK1/STAT1/3-HIF1α/ERRα axis.
  17. Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study.
  18. SUV39H1 maintains cancer stem cell chromatin state and properties in glioblastoma.
  19. Calciprotein particle-induced calcium overload triggers mitochondrial dysfunction in endothelial cells.
  1. Cell Calcium. 2025 Feb 27. pii: S0143-4160(25)00022-3. [Epub ahead of print]128 103013
    Mitochondrial Ca2+ uniporter b (MCUb) regulates neuronal Ca2+ dynamics and resistance to ischemic stroke.
    Tam Nguyen, Zhihong Lin, Nirav Dhanesha, Rakesh B Patel, Mallorie Lane, Grant C Walters, Leonid P Shutov, Stefan Strack, Anil K Chauhan, Yuriy M Usachev.
      Mitochondrial Ca2+ transport regulates many neuronal functions including synaptic transmission, ATP production, gene expression and neuronal survival. The mitochondrial Ca2+ uniporter (MCU) is the core molecular component of the mitochondrial Ca2+ uptake complex in the inner mitochondrial membrane. MCUb is a paralog of MCU that negatively regulates mitochondrial Ca2+ uptake in the heart and the cells of the immune system. However, the function of MCUb in the brain is largely unknown. Here, we report that MCUb knockout (KO) led to enhanced mitochondrial Ca2+ uptake in cortical neurons. By simultaneously monitoring changes in cytosolic and mitochondrial Ca2+ concentrations, [Ca2+]cyt and [Ca2+]mt, respectively, we also found that MCUb KO reduced the [Ca2+]cyt threshold required to induce mitochondrial uptake in cortical neurons during electrical stimulation. Exposure of cortical neurons to toxic concentrations of glutamate led to a collapse of mitochondrial membrane potential (ΔΨmt) and [Ca2+]cyt deregulation, and MCUb deletion accelerated the development of both events. Furthermore, using the middle cerebral artery occlusion (MCAO) as a model of transient ischemic stroke in mice, we found that MCUb KO significantly increased MCAO-induced brain damage in male, but not female mice. These results suggest that MCUb regulates neuronal Ca2+ dynamics and excitotoxicity and reveal a sex-dependent role of MCUb in controlling resistance to brain damage following ischemic stroke.
    Keywords:  Ischemia; MCAO; MCU; MCUb; Mitochondria; calcium; excitotoxicity; stroke
    DOI:  https://doi.org/10.1016/j.ceca.2025.103013
  2. Aging Cell. 2025 Mar 12. e70041
    Cellular Senescence Is a Central Driver of Cognitive Disparities in Aging.
    Matthew P Baier, Rojina Ranjit, Daniel B Owen, Jenna L Wilson, Megan A Stiles, Anthony M Masingale, Zachary Thomas, Anne Bredegaard, David M Sherry, Sreemathi Logan.
      Cognitive function in aging is heterogeneous: while some older individuals develop significant impairments and dementia, others remain resilient and retain cognitive function throughout their lifespan. The molecular mechanisms that underlie these divergent cognitive trajectories, however, remain largely unresolved. Here, we utilized a high-resolution home-cage-based cognitive testing paradigm to delineate mechanisms that contribute to age-related cognitive heterogeneity. We cognitively stratified aged C57Bl/6N male mice by cognitive performance into intact (resilient) or impaired subgroups based on young performance benchmarks. Cognitively impaired males exhibited marked reactive gliosis in the hippocampus, characterized by microglial activation, increased astrocyte arborization, and elevated transcriptional expression of reactivity markers. These changes were accompanied by increased markers of cellular senescence and the associated senescence-associated secretory phenotype (SASP) in impaired animals, including p16INK4a, SASP factors (e.g., Il-6, Il-1b, Mmp3), and SA-β-gal staining in the hippocampus. Notably, clearance of senescent cells using senolytic agents dasatinib and quercetin ameliorated the heterogeneity in cognitive performance observed with age and attenuated impairment-associated gliosis, senescence markers, and mitochondrial dysfunction. Aged female mice could not be stratified into subgroups yet showed increased neuroinflammation with age that was not resolved with senolytics. Collectively, our findings implicate cellular senescence as a central driver of sex-specific neuroinflammation that drives divergent cognitive trajectories in aging. Thus, we demonstrate that senolytic treatment is an effective therapeutic strategy to mitigate cognitive impairment by reducing neuroinflammation and associated metabolic disturbances.
    Keywords:  cellular senescence; cognitive heterogeneity; dementia; neuroinflammation; reactive gliosis; senolytic
    DOI:  https://doi.org/10.1111/acel.70041
  3. Methods Mol Biol. 2025 ;2906 21-44
    Current Methodologies to Assess Cellular Senescence in Cancer.
    Panayiotis Laouris, Daniel Muñoz-Espín.
      Cellular senescence plays a critical role in cancer, acting as both a tumor-suppressive and tumor-promoting mechanism. Senescent cells undergo stable cell-cycle arrest in response to various stressors, including DNA damage and oncogenic signaling, and exhibit a complex secretory phenotype known as the senescence-associated secretory phenotype (SASP), which can impact the tumor microenvironment. The hallmarks of senescence include cell-cycle arrest, secretion of pro-inflammatory factors, structural changes, and metabolic alterations. These features, while initially suppressing tumorigenesis, can later contribute to cancer progression under certain conditions. Methods for studying senescence in preclinical models include in vitro assays, ex vivo tissue analysis, and in vivo detection techniques. Emerging therapeutic strategies focus on exploiting senescence for cancer treatment, particularly through the use of senolytic agents that selectively eliminate senescent cells and senomorphic compounds that modulate SASP activity. However, the identification of reliable and universal biomarkers for senescence remains a challenge, necessitating a multimarker approach to accurately detect and characterize senescent cells in various contexts.
    Keywords:  Biomarkers; Cancer; Cellular senescence; Methodologies; Oncogene-induced-senescence
    DOI:  https://doi.org/10.1007/978-1-0716-4426-3_2
  4. J Cell Sci. 2025 Mar 01. pii: JCS263652. [Epub ahead of print]138(5):
    Disruption of ER-mitochondria contact sites induces autophagy-dependent loss of P-bodies through the Ca2+-CaMKK2-AMPK pathway.
    Nikhil More, Jomon Joseph.
      P-bodies (PBs) and stress granules (SGs) are conserved, non-membranous cytoplasmic condensates of RNA-protein complexes. PBs are implicated in post-transcriptional regulation of gene expression through mRNA decay, translational repression and/or storage. Although much is known about the de novo formation of PBs and SGs involving liquid-liquid phase separation through multiple protein-protein and protein-RNA interactions, their subcellular localization and turnover mechanisms are less understood. Here, we report the presence of a subpopulation of PBs and SGs that are in proximity to ER-mitochondria contact sites (ERMCSs) in mammalian cells. Disruption of ERMCSs, achieved through depletion of ER-mitochondria tethering proteins, leads to the disappearance of PBs but not SGs. This effect can be reversed by inhibiting autophagy through both genetic and pharmacological means. Additionally, we find that the disruption of ERMCSs leads to cytosolic Ca2+-induced activation of CaMKK2 and AMP-activated protein kinase (AMPK), ultimately resulting in an autophagy-dependent decrease in PB abundance. Collectively, our findings unveil a mechanism wherein disturbances in ERMCSs induce autophagy-dependent loss of PBs via activation of the Ca2+-CaMKK2-AMPK pathway, thus potentially linking the dynamics and functions of ERMCS with post-transcriptional gene regulation.
    Keywords:  Autophagy; CaMKK2; ER–mitochondria contact sites; P-bodies; Stress granules
    DOI:  https://doi.org/10.1242/jcs.263652
  5. Nat Commun. 2025 Mar 11. 16(1): 2416
    VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes.
    Shamim Naghdi, Piyush Mishra, Soumya Sinha Roy, David Weaver, Ludivine Walter, Erika Davies, Anil Noronha Antony, Xuena Lin, Gisela Moehren, Mark A Feitelson, Christopher A Reed, Tullia Lindsten, Craig B Thompson, Hien T Dang, Jan B Hoek, Erik S Knudsen, György Hajnóczky.
      Differences between normal tissues and invading tumors that allow tumor targeting while saving normal tissue are much sought after. Here we show that scarcity of VDAC2, and the consequent lack of Bak recruitment to mitochondria, renders hepatocyte mitochondria resistant to permeabilization by truncated Bid (tBid), a Bcl-2 Homology 3 (BH3)-only, Bcl-2 family protein. Increased VDAC2 and Bak is found in most human liver cancers and mitochondria from tumors and hepatic cancer cell lines exhibit VDAC2- and Bak-dependent tBid sensitivity. Exploring potential therapeutic targeting, we find that combinations of activators of the tBid pathway with inhibitors of the Bcl-2 family proteins that suppress Bak activation enhance VDAC2-dependent death of hepatocarcinoma cells with little effect on normal hepatocytes. Furthermore, in vivo, combination of S63845, a selective Mcl-1 inhibitor, with tumor-nectrosis factor-related, apoptosis-induncing ligand (TRAIL) peptide reduces tumor growth, but only in tumors expressing VDAC2. Thus, we describe mitochondrial molecular fingerprint that discriminates liver from hepatocarcinoma and allows sparing normal tissue while targeting tumors.
    DOI:  https://doi.org/10.1038/s41467-025-56898-4
  6. Nat Aging. 2025 Mar 07.
    Accelerating the promise of geroscience through The Academy of Health & Lifespan Research.
    Academy of Health & Lifespan Research
      
    DOI:  https://doi.org/10.1038/s43587-025-00832-2
  7. Sci Adv. 2025 Mar 14. 11(11): eadr1719
    Senolytic treatment for low back pain.
    Matthew Mannarino, Hosni Cherif, Saber Ghazizadeh, Oliver Wu Martinez, Kai Sheng, Elsa Cousineau, Seunghwan Lee, Magali Millecamps, Chan Gao, Alice Gilbert, Cedric Peirs, Reza Sharif Naeini, Jean A Ouellet, Laura S Stone, Lisbet Haglund.
      Senescent cells (SnCs) accumulate because of aging and external cellular stress throughout the body. They adopt a senescence-associated secretory phenotype (SASP) and release inflammatory and degenerative factors that actively contribute to age-related diseases, such as low back pain (LBP). The senolytics, o-vanillin and RG-7112, remove SnCs in human intervertebral discs (IVDs) and reduce SASP release, but it is unknown whether they can treat LBP. sparc-/- mice, with LBP, were treated orally with o-vanillin and RG-7112 as single or combination treatments. Treatment reduced LBP and SASP factor release and removed SnCs from the IVD and spinal cord. Treatment also lowered degeneration scores in the IVDs, improved vertebral bone quality, and reduced the expression of pain markers in the spinal cord. Together, our data suggest RG-7112 and o-vanillin as potential disease-modifying drugs for LBP and other painful disorders linked to cell senescence.
    DOI:  https://doi.org/10.1126/sciadv.adr1719
  8. Methods Mol Biol. 2025 ;2906 73-81
    Detecting Senescence in T Cells by Flow Cytometry Using the SA-β-Galactosidase Assay.
    Luca Pangrazzi, Ines Martic, Maria Cavinato, Birgit Weinberger.
      Cellular senescence is a biological process where somatic cells undergo irreversible growth arrest. One key marker of cellular senescence is senescence-associated β-galactosidase (SA-β-gal), an enzyme whose activity can be detected at pH 6 in senescent cells. Traditional methods for SA-β-gal detection often rely on the substrate X-Gal, which requires fixed cells and offers limited sensitivity for quantitative analysis. This study introduces a refined method using the SPiDER β-gal substrate from the Cellular Senescence Detection Kit (Dojindo), designed to improve cell permeability and enable quantification through flow cytometry in both live and fixed cells. We employed this novel protocol to detect SA-β-gal in peripheral blood mononuclear cells (PBMCs) isolated from healthy donors of different ages. The results revealed a progressive increase in SA-β-gal+ CD8+ T cells with advancing age, suggesting that the accumulation of senescent immune cells is a feature of aging. To further validate this method, UVB-treated fibroblasts were analyzed, a well-established model for studying senescence. Overall, this method provides a powerful tool for studying cellular senescence across different cell types and experimental contexts, with broad applications for research on aging, immune function, and cancer biology.
    Keywords:  Aging; Flow cytometry; Senescence; T cells; β-galactosidase
    DOI:  https://doi.org/10.1007/978-1-0716-4426-3_5
  9. Methods Mol Biol. 2025 ;2906 57-71
    Detection and Characterization of Senescent Cells with Flow Cytometry.
    Panagiotis Bakouros, Ariadni Archavli, Ioannis V Kostopoulos, Evangelos Terpos, Efstathios Kastritis, Meletios A Dimopoulos, Ourania Tsitsilonis, Pantelis Rousakis.
      Cellular senescence, a stable cell cycle arrest induced by various stressors or DNA damage, plays a critical role in various aspects of human physiology, including embryonic development, wound healing, and age-related diseases like cancer. Despite its discovery nearly 50 years ago, a universal marker for senescent cells remains elusive. Current identification methods, such as the detection of senescence-associated β-galactosidase activity (SA-β-Gal), immunohistochemistry, and qPCR, have limitations, including subjective assessment of the results and complex prerequisites. Flow cytometry (FC) has emerged as a reliable technique for detecting senescent phenotypes at single-cell level, traditionally based on proteins like Ki-67 and p16INK4a and, more recently, via the detection of lipofuscin with a novel Sudan Black-B analog, namely, GLF16. Here, we present detailed protocols using GLF16 in FC, to detect senescent cells and specifically, of the human myeloma cell lines NCI-H929 and L363. In the protocols, we describe the induction of cellular senescence using H2O2, the staining process, and the gating strategy to accurately identify senescent cells. Additionally, we provide a comprehensive method for detecting senescent cells in bone marrow clinical samples from patients with multiple myeloma, following red blood cell lysis and leukocyte staining. These techniques broaden the potential of FC applications in the field of senescence and could be utilized as surrogate tests in clinical diagnostics.
    Keywords:  Flow cytometry; GLF16; Multiple myeloma; Oxidative stress; Plasma cells; Senescence
    DOI:  https://doi.org/10.1007/978-1-0716-4426-3_4
  10. Yeast. 2025 Mar 14.
    A Key Role of the EMC Complex for Mitochondrial Respiration and Quiescence in Fission Yeasts.
    Modesto Berraquero, Víctor A Tallada, Juan Jimenez.
      In eukaryotes, oxygen consumption is mainly driven by the respiratory activity of mitochondria, which generates most of the cellular energy that sustains life. This parameter provides direct information about mitochondrial activity of all aerobic biological systems. Using the Seahorse analyzer instrument, we show here that deletion of the oca3/emc2 gene (oca3Δ) encoding the Emc2 subunit of the ER membrane complex (EMC), a conserved chaperone/insertase that aids membrane protein biogenesis in the ER, severely affects oxygen consumption rates and quiescence survival in Schizosaccharomyces pombe yeast cells. Remarkably, the respiratory defect of the oca3Δ mutation (EMC dysfunction) is rescued synergistically by disruption of ergosterol biosynthesis (erg5Δ) and the action of the membrane fluidizing agent tween 20, suggesting a direct role of membrane fluidity and sterol composition in mitochondrial respiration in the fission yeast.
    Keywords:  EMC complex; ergosterol; fission yeast; mitochondria; oxygen consumption; quiescence
    DOI:  https://doi.org/10.1002/yea.3998
  11. Front Cell Dev Biol. 2025 ;13 1535073
    Targeting metabolic reprogramming in glioblastoma as a new strategy to overcome therapy resistance.
    Simona D'Aprile, Simona Denaro, Anna Gervasi, Nunzio Vicario, Rosalba Parenti.
      Glioblastoma (GBM) is one of the deadliest tumors due to its high aggressiveness and resistance to standard therapies, resulting in a dismal prognosis. This lethal tumor carries out metabolic reprogramming in order to modulate specific pathways, providing metabolites that promote GBM cells proliferation and limit the efficacy of standard treatments. Indeed, GBM remodels glucose metabolism and undergoes Warburg effect, fuelling glycolysis even when oxygen is available. Moreover, recent evidence revealed a rewiring in nucleotide, lipid and iron metabolism, resulting not only in an increased tumor growth, but also in radio- and chemo-resistance. Thus, while on the one hand metabolic reprogramming is an advantage for GBM, on the other hand it may represent an exploitable target to hamper GBM progression. Lately, a number of studies focused on drugs targeting metabolism to uncover their effects on tumor proliferation and therapy resistance, demonstrating that some of these are effective, in combination with conventional treatments, sensitizing GBM to radiotherapy and chemotherapy. However, GBM heterogeneity could lead to a plethora of metabolic alterations among subtypes, hence a metabolic treatment might be effective for proneural tumors but not for mesenchymal ones, which are more aggressive and resistant to conventional approaches. This review explores key mechanisms of GBM metabolic reprogramming and their involvement in therapy resistance, highlighting how metabolism acts as a double-edged sword for GBM, taking into account metabolic pathways that seem to offer promising treatment options for GBM.
    Keywords:  Warburg effect; chemotherapy; iron; lipids; metabolism; nucleotides; radiotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2025.1535073
  12. Methods Mol Biol. 2025 ;2906 229-242
    Electron Microscopy to Visualize and Quantify Mitochondrial Structure and Organellar Interactions in Cultured Cells During Senescence.
    Christina Glytsou.
      Mitochondria are multifunctional organelles that play a crucial role in numerous cellular processes, including oncogene-induced senescence. Recent studies have demonstrated that mitochondria undergo notable morphological and functional changes during senescence, with mitochondria dysregulation being a critical factor contributing to the induction of this state. To elucidate the intricate and dynamic structure of these organelles, high-resolution visualization techniques are imperative. Electron microscopy offers nanometer-scale resolution images, enabling the comprehensive study of organelles' architecture. This chapter provides a detailed guide for preparing fixed samples from cultured cells for electron microscopy imaging. It also describes various quantification methods to accurately assess organellar parameters, including morphometric measurements of mitochondrial shape, cristae structure, and mitochondria-endoplasmic reticulum contact sites. These analyses yield valuable insights into the status of subcellular organelles, advancing our understanding of their involvement in cellular senescence and disease.
    Keywords:  EM sample preparation; Electron microscopy; MERCs; Mitochondria visualization; Mitochondrial structure
    DOI:  https://doi.org/10.1007/978-1-0716-4426-3_13
  13. Cell Death Discov. 2025 Mar 07. 11(1): 91
    Mitochondrial priming and response to BH3 mimetics in "one-two punch" senogenic-senolytic strategies.
    Júlia López, Àngela Llop-Hernández, Sara Verdura, Eila Serrano-Hervás, Eva Martinez-Balibrea, Joaquim Bosch-Barrera, Eduard Teixidor, Eugeni López-Bonet, Begoña Martin-Castillo, Josep Sardanyés, Tomás Alarcón, Ruth Lupu, Elisabet Cuyàs, Javier A Menendez.
      A one-two punch sequential regimen of senescence-inducing agents followed by senolytic drugs has emerged as a novel therapeutic strategy in cancer. Unfortunately, cancer cells undergoing therapy-induced senescence (TIS) vary widely in their sensitivity to senotherapeutics, and companion diagnostics to predict the response of TIS cancer cells to a specific senolytic drug are lacking. Here, we hypothesized that the ability of the BH3 profiling assay to functionally measure the mitochondrial priming state-the proximity to the apoptotic threshold-and the dependencies on pro-survival BCL-2 family proteins can be exploited to inform the sensitivity of TIS cancer cells to BH3-mimetics. Replicative, mitotic, oxidative, and genotoxic forms of TIS were induced in p16-null/p53-proficient, BAX-deficient, and BRCA1-mutant cancer cells using mechanistically distinct TIS-inducing cancer therapeutics, including palbociclib, alisertib, doxorubicin, bleomycin, and olaparib. When the overall state of mitochondrial priming and competence was determined using activator peptides, the expected increase in overall mitochondrial priming was an exception rather than a generalizable feature across TIS phenotypes. A higher level of overall priming paralleled a higher sensitivity of competent TIS cancer cells to BCL-2/BCL-xL- and BCL-xL-targeted inhibitors when comparing TIS phenotypes among themselves. Unexpectedly, however, TIS cancer cells remained equally or even less overally primed than their proliferative counterparts. When sensitizing peptides were used to map dependencies on anti-apoptotic BCL-2 family proteins, competent TIS cancer cells appeared to share a dependency on BCL-xL. Furthermore, regardless of senescence-inducing therapeutic, stable/transient senescence acquisition, or genetic context, all TIS phenotypes shared a variable but significant senolytic response to the BCL-xL-selective BH3 mimetic A1331852. These findings may help to rethink the traditional assumption of the primed apoptotic landscape of TIS cancer cells. BCL-xL is a conserved anti-apoptotic effector of the TIS BCL2/BH3 interactome that can be exploited to maximize the efficacy of "one-two punch" senogenic-senolytic strategies.
    DOI:  https://doi.org/10.1038/s41420-025-02379-y
  14. J Nanobiotechnology. 2025 Mar 11. 23(1): 200
    Young fibroblast-derived migrasomes alleviate keratinocyte senescence and enhance wound healing in aged skin.
    Hanlin Tu, Yingliang Shi, Yi Guo, Zhongyang Zou, Yuyan He, Jing Zhou, Sangang He, Guoliang Sa.
       BACKGROUND: Alterations in intercellular communication driven by cellular senescence constitute an important factor in skin aging. Migrasome, a newly discovered vesicular organelle, efficiently participates in intercellular communication; however, the relationship between cellular senescence and migrasomes remains unreported.
    OBJECTIVE: This study aims to explore the possible relationship between cellular senescence and migrasomes formation, and investigate the effects of young fibroblast-derived migrasomes on senescent keratinocytes and wound healing in aged skin.
    RESULT: Single-cell RNA sequencing (scRNA-seq) data analysis revealed that fibroblasts exhibited the highest level of transcriptional variability during skin aging, and the degree of fibroblast senescence negatively correlated with the expression level of migrasome-associated markers. Further multiplex Immunohistochemistry (mIHC) results suggested that younger mouse skin contained more migrasomes than older mouse skin. Transmission electron microscopy (TEM) observations demonstrated abundant migrasomes in the skin from young individuals. In vitro experiments indicated that young fibroblasts produced significantly more migrasomes than senescent fibroblasts, as confirmed by wheat germ agglutinin (WGA) staining and scanning electron microscopy (SEM). Importantly, purified migrasomes from young fibroblasts were found to reduce the expression of senescence-associated markers in HaCaT cells. In vivo, using a wound healing model in naturally aged mice, we observed that migrasomes derived from young fibroblasts not only accelerated wound healing but also reduced senescence-associated marker expression in the skin.
    CONCLUSION: Migrasomes formation ability reduced during skin aging progress, and young fibroblast-derived migrasomes rejuvenated senescent keratinocytes and promoted wound healing in aged skin. These findings offer new ideas for alleviating skin aging and enhancing wound healing in aged skin.
    Keywords:  Aging; Fibroblast; Migrasomes; Senescence; Skin wound healing
    DOI:  https://doi.org/10.1186/s12951-025-03293-2
  15. Aging Dis. 2025 Mar 06.
    Cellular Senescence in the Regenerative Niche Hampers Skeletal Muscle Repair.
    MingYu Qiu, YangYang Li, QiSen Wang, XiaoTing Jian, JingWen Huang, WeiChao Gui, Jijie Hu, Hua Liao.
      With the growing interest in skeletal muscle diseases, understanding the processes, factors, and treatments associated with muscle regeneration is crucial. Skeletal muscle regeneration is a complex process that largely depends on the niche composed of cell populations, such as satellite cells, and their microenvironment. Cellular senescence is associated with various physiological processes and age-related diseases and plays a significant role in the muscle regeneration niche. Deciphering senescence-associated alterations within this niche provides critical insights for developing targeted anti-aging therapies. This review synthesizes recent studies to elucidate the composition of the niche and its cell-cell interactions and outlines the effects of aging on muscle regeneration and corresponding therapeutic strategies. This review summarizes emerging findings and technologies in muscle regeneration, analyzing therapeutic potential and limitations of current approaches for age-related conditions to support research advancement.
    DOI:  https://doi.org/10.14336/AD.2024.1501
  16. Cell Rep. 2025 Mar 06. pii: S2211-1247(25)00174-3. [Epub ahead of print]44(3): 115403
    The pro-inflammatory cytokine IL6 suppresses mitochondrial function via the gp130-JAK1/STAT1/3-HIF1α/ERRα axis.
    Jianing Xu, Matthew Wakai, Kun Xiong, Yanfeng Yang, Adithya Prabakaran, Sophia Wu, Diana Ahrens, Maria Del Pilar Molina-Portela, Min Ni, Yu Bai, Tea Shavlakadze, David J Glass.
      Chronic inflammation and a decline in mitochondrial function are hallmarks of aging. Here, we show that the two mechanisms may be linked. We found that interleukin-6 (IL6) suppresses mitochondrial function in settings where PGC1 (both PGC1α and PGC1β) expression is low. This suppression is mediated by the JAK1/STAT1/3 axis, which activates HIF1α through non-canonical mechanisms involving upregulation of HIF1A and ERRα transcription, and subsequent stabilization of the HIF1A protein by ERRα. HIF1α, in turn, inhibits ERRα, which is a master regulator of mitochondrial biogenesis, thus contributing to the inhibition of mitochondrial function. When expressed at higher levels, PGC1 rescues ERRα to boost baseline mitochondrial respiration, including under IL6-treated conditions. Our study suggests that inhibition of the IL6 signaling axis could be a potential treatment for those inflammatory settings where mitochondrial function is compromised.
    Keywords:  ATP; CP: Immunology; ERRα; ESRRA; HIF1A; HIF1α; IL6; PGC1α; PGC1β; PPARGC1A; PPARGC1B; aging; gp130; inflammation; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2025.115403
  17. J Nutr Health Aging. 2025 Mar 07. pii: S1279-7707(25)00052-1. [Epub ahead of print]29(5): 100529
    Biomarkers of cellular senescence predict risk of mild cognitive impairment: Results from the lifestyle interventions for elders (LIFE) study.
    Michelle M Mielke, Roger A Fielding, Elizabeth J Atkinson, Zaira Aversa, Marissa J Schafer, Steven R Cummings, Marco Pahor, Christiaan Leeuwenburgh, Nathan K LeBrasseur.
       OBJECTIVES: Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability.
    DESIGN: The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a "successful aging" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013.
    SETTING: Recruitment occurred at eight centers in the United States.
    PARTICIPANTS: We included 1,373 participants enrolled in the study with baseline measures of 27 biomarkers of cellular senescence and adjudication of mild cognitive impairment (MCI) and dementia at baseline and 24-month follow-up. At baseline, participants were aged 70-80, sedentary, and at high risk of mobility disability.
    MEASUREMENTS: A neuropsychological assessment was administered at baseline and 24 months post-randomization. At both timepoints, a clinical adjudication committee determined whether individuals had a diagnosis of cognitively normal, MCI, or dementia; individuals with dementia at baseline were excluded. The concentrations of 26 of the 27 plasma proteins identified as components of the SASP were measured with commercially available Luminex xMAP multiplex magnetic bead-based immunoassays analyzed on the MAGPIX System while 1 protein (Activin A) was measured using an enzyme-linked immunosorbent assay.
    RESULTS: Logistic regression models were used to examine the associations of each senescence biomarker, in quartiles, with baseline or incident MCI. Models stratified by clinical site and adjusted for intervention assignment, age, gender, race, and education. Among 1,373 participants, 117 (8.5%) were diagnosed with MCI at baseline. Increasing quartiles of myeloperoxidase (MPO) was associated with higher odds of MCI compared to quartile 1 (Q2: OR = 1.34, 95% CI: 0.74-2.45; Q3: OR = 1.43, 95% CI: 0.80-2.59; Q4: OR = 1.79, 95% CI: 1.02-3.22). Additionally, matrix metalloproteinase 1 (MMP1) quartiles 2-4 had lower odds of MCI compared to quartile 1 (Q2: OR = 0.61, 95% CI: 0.35-1.02; Q3: OR = 0.58, 95% CI: 0.33-0.98; Q4: OR = 0.64, 95% CI: 0.37-1.08). Of the 1,256 cognitively unimpaired participants at baseline, 141 (11.2%) were diagnosed with incident MCI or dementia at the 24-month follow-up. Compared to quartile 1, increasing baseline quartiles of MPO (Q2: OR = 1.10, 95% CI: 0.63-1.92; Q3: OR = 1.36, 95% CI: 0.80-2.33; Q4: OR = 1.92, 95% CI: 1.16-3.25) and matrix metalloproteinase 7 (MMP7, Q2: OR = 0.88, 95% CI: 0.47-1.62; Q3: OR = 1.46, 95% CI: 0.85-2.55; Q4: OR = 2.14, 95% CI: 1.28-3.65) were associated with increased odds of MCI or dementia at 24 months.
    CONCLUSIONS: Among older adults at high risk of mobility disability, high plasma MPO was cross-sectionally and, along with MMP7, longitudinally associated with increased odds of MCI and dementia. In contrast, high MMP1 was cross-sectionally associated with reduced odds of MCI.
    Keywords:  Cognition; Matrix metalloproteinase 7; Mobility disability; Myeloperoxidase; SASP
    DOI:  https://doi.org/10.1016/j.jnha.2025.100529
  18. JCI Insight. 2025 Mar 10. pii: e186344. [Epub ahead of print]10(5):
    SUV39H1 maintains cancer stem cell chromatin state and properties in glioblastoma.
    Chunying Li, Qiqi Xie, Sugata Ghosh, Bihui Cao, Yuanning Du, Giau V Vo, Timothy Y Huang, Charles Spruck, Richard L Carpenter, Y Alan Wang, Q Richard Lu, Kenneth P Nephew, Jia Shen.
      Glioblastoma (GBM) is the most lethal brain cancer, with GBM stem cells (GSCs) driving therapeutic resistance and recurrence. Targeting GSCs offers a promising strategy for preventing tumor relapse and improving outcomes. We identify SUV39H1, a histone-3, lysine-9 methyltransferase, as critical for GSC maintenance and GBM progression. SUV39H1 is upregulated in GBM compared with normal brain tissues, with single-cell RNA-seq showing its expression predominantly in GSCs due to super-enhancer-mediated activation. Knockdown of SUV39H1 in GSCs impaired their proliferation and stemness. Whole-cell RNA-seq analysis revealed that SUV39H1 regulates G2/M cell cycle progression, stem cell maintenance, and cell death pathways in GSCs. By integrating the RNA-seq data with ATAC-seq data, we further demonstrated that knockdown of SUV39H1 altered chromatin accessibility in key genes associated with these pathways. Chaetocin, an SUV39H1 inhibitor, mimics the effects of SUV39H1 knockdown, reducing GSC stemness and sensitizing cells to temozolomide, a standard GBM chemotherapy. In a patient-derived xenograft model, targeting SUV39H1 inhibits GSC-driven tumor growth. Clinically, high SUV39H1 expression correlates with poor glioma prognosis, supporting its relevance as a therapeutic target. This study identifies SUV39H1 as a crucial regulator of GSC maintenance and a promising therapeutic target to improve GBM treatment and patient outcomes.
    Keywords:  Cancer; Cell biology; Oncology; Stem cells
    DOI:  https://doi.org/10.1172/jci.insight.186344
  19. J Physiol. 2025 Mar 09.
    Calciprotein particle-induced calcium overload triggers mitochondrial dysfunction in endothelial cells.
    Lian Feenstra, Laurent Chatre, Benoit Bernay, Julien Pontin, Mirjam F Mastik, Azuwerus van Buiten, Dalibor Nakládal, Bastiaan S Star, Jan-Luuk Hillebrands, Guido Krenning.
      Calciprotein particles (CPPs) are calcium- and phosphate-containing nanoparticles numbers of which are increased in patients with chronic kidney disease (CKD). CPPs have been associated with the development of vascular disease, although the underlying mechanisms are unknown. We previously showed that CPPs induce endothelial cell (EC) dysfunction by reducing nitric oxide (NO) bioavailability and generating superoxide (O2 .-). Here, we tested the hypothesis that CPPs induce mitochondrial calcium (Ca2+) overload, which may trigger mitochondrial dysfunction and, consequently, EC activation. Exposure of human umbilical vein ECs to CPPs resulted in significantly increased cytosolic and mitochondrial Ca2+ levels compared to vehicle-treated ECs. Proteome analysis demonstrated impaired endoplasmic reticulum calcium signalling, and decreased enrichment of proteins in the mitochondrial OXPHOS complexes I-III in CPP-exposed ECs. Respirometry data confirmed these findings and demonstrated decreased basal and maximal respiration in CPP-exposed ECs. This was accompanied by reduced mitochondrial membrane potential, reduced antioxidant capacity and loss of mitochondria. In the presence of cyclosporin A, a potent mitochondrial permeability transition pore inhibitor, CPP-induced EC activation and cell death were attenuated. Taken together, our data indicate that CPP-induced Ca2+ overload is an important trigger of mitochondrial dysfunction, and EC activation and cell loss, which eventually may contribute to the development of vascular diseases in CKD. Interventions that target CPP-induced mitochondrial dysfunction might preserve EC function and possibly alleviate the development of vascular diseases in CKD. KEY POINTS: Calciprotein particles (CPPs) are calcium- and phosphate-containing nanoparticles numbers of which are increased in patients with chronic kidney disease and which have been associated with the development of vascular disease. In this study, we tested the hypothesis that CPPs induce mitochondrial calcium (Ca2+) overload in endothelial cells, thereby triggering mitochondrial dysfunction and endothelial activation. We show that exposure of HUVECs (human umbilical vein endothelial cells) to CPPs results in increased cytosolic and mitochondrial Ca2+ levels, which is associated with alterations in mitochondrial processes (proteome analysis), cellular respiration, mitochondrial integrity and number. CPP-induced EC activation and cell death were attenuated in the presence of cyclosporin A, a potent mitochondrial permeability transition pore inhibitor. Our data indicate that CPP-induced Ca2+ overload triggers mitochondrial dysfunction, endothelial activation and cell loss. Interventions that target CPP-induced mitochondrial dysfunction might preserve EC function in chronic kidney disease.
    Keywords:  calciprotein particle (CPP); calcium ion; chronic kidney disease (CKD); endothelial cell; mitochondrial dysfunction; mitochondrion; vascular calcification
    DOI:  https://doi.org/10.1113/JP287656
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