bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2024‒07‒14
fourteen papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Reduced oxidative capacity of skeletal muscle mitochondria is a fundamental consequence of adult ageing.
  2. Senescent cell heterogeneity and responses to senolytic treatment are related to cell cycle status during cell growth arrest.
  3. Exosomes Released from Senescent Cells and Circulatory Exosomes Isolated from Human Plasma Reveal Aging-associated Proteomic and Lipid Signatures.
  4. Marcinek and Ferrucci response to Lanza et al.
  5. Lysosomal TRPML1 triggers global Ca2+ signals and nitric oxide release in human cerebrovascular endothelial cells.
  6. Long-term NMN treatment increases lifespan and healthspan in mice in a sex dependent manner.
  7. PKM2 aggregation drives metabolism reprograming during aging process.
  8. Mitochondrial Protein Density, Biomass, and Bioenergetics as Predictors for the Efficacy of Glioma Treatments.
  9. Reduced oxidative capacity of skeletal muscle IS NOT an inevitable consequence of adult ageing.
  10. The Changes of Mitochondria during Aging and Regeneration.
  11. Alpha-ketoglutarate ameliorates age-related and surgery induced temporomandibular joint osteoarthritis via regulating IKK/NF-κB signaling.
  12. Replicative senescence is ATM driven, reversible, and accelerated by hyperactivation of ATM at normoxia.
  13. Activatable Fluorescent Probe for Studying Drug-Induced Senescence In Vitro and In Vivo.
  14. Senescence-related signatures predict prognosis and response to immunotherapy in colon cancer.
  1. J Physiol. 2024 Jul 06.
    Reduced oxidative capacity of skeletal muscle mitochondria is a fundamental consequence of adult ageing.
    David J Marcinek, Luigi Ferrucci.
      
    Keywords:  ageing; magnetic resonance; mitochondria; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1113/JP285040
  2. bioRxiv. 2024 Jun 26. pii: 2024.06.22.600200. [Epub ahead of print]
    Senescent cell heterogeneity and responses to senolytic treatment are related to cell cycle status during cell growth arrest.
    Francesco Neri, Shuyuan Zheng, Mark Watson, Pierre-Yves Desprez, Akos A Gerencser, Judith Campisi, Denis Wirtz, Pei-Hsun Wu, Birgit Schilling.
      Cellular senescence has been strongly linked to aging and age-related diseases. It is well established that the phenotype of senescent cells is highly heterogeneous and influenced by their cell type and senescence-inducing stimulus. Recent single-cell RNA-sequencing studies identified heterogeneity within senescent cell populations. However, proof of functional differences between such subpopulations is lacking. To identify functionally distinct senescent cell subpopulations, we employed high-content image analysis to measure senescence marker expression in primary human endothelial cells and fibroblasts. We found that G2-arrested senescent cells feature higher senescence marker expression than G1-arrested senescent cells. To investigate functional differences, we compared IL-6 secretion and response to ABT263 senolytic treatment in G1 and G2 senescent cells. We determined that G2-arrested senescent cells secrete more IL-6 and are more sensitive to ABT263 than G1-arrested cells. We hypothesize that cell cycle dependent DNA content is a key contributor to the heterogeneity within senescent cell populations. This study demonstrates the existence of functionally distinct senescent subpopulations even in culture. This data provides the first evidence of selective cell response to senolytic treatment among senescent cell subpopulations. Overall, this study emphasizes the importance of considering the senescent cell heterogeneity in the development of future senolytic therapies.
    DOI:  https://doi.org/10.1101/2024.06.22.600200
  3. bioRxiv. 2024 Jun 24. pii: 2024.06.22.600215. [Epub ahead of print]
    Exosomes Released from Senescent Cells and Circulatory Exosomes Isolated from Human Plasma Reveal Aging-associated Proteomic and Lipid Signatures.
    Sandip Kumar Patel, Joanna Bons, Jacob P Rose, Jessie R Chappel, Rebecca L Beres, Mark A Watson, Corey Webster, Jordan B Burton, Roland Bruderer, Pierre-Yves Desprez, Lukas Reiter, Judith Campisi, Erin S Baker, Birgit Schilling.
      Senescence emerged as a significant mechanism of aging and age-related diseases, offering an attractive target for clinical interventions. Senescent cells release a senescence-associated secretory phenotype (SASP), including exosomes that may act as signal transducers between distal tissues, propagating secondary or bystander senescence and signaling throughout the body. However, the composition of exosome SASP remains underexplored, presenting an opportunity for novel unbiased discovery. Here, we present a detailed proteomic and lipidomic analysis of exosome SASP using mass spectrometry from human plasma from young and older individuals and from tissue culture of senescent primary human lung fibroblasts. We identified ~1,300 exosome proteins released by senescent fibroblasts induced by three different senescence inducers causing most exosome proteins to be differentially regulated with senescence. In parallel, a human plasma cohort from young and old individuals revealed over 1,350 exosome proteins and 171 plasma exosome proteins were regulated when comparing old vs young individuals. Of the age-regulated plasma exosome proteins, we observed 52 exosome SASP factors that were also regulated in exosomes from the senescent fibroblasts, including serine protease inhibitors (SERPINs), Prothrombin, Coagulation factor V, Plasminogen, and Reelin. In addition, 247 lipids were identified with high confidence in all exosome samples. Following the senescence inducers, a majority of the identified phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin species increased significantly indicating cellular membrane changes. The most notable categories of significantly changed proteins were related to extracellular matrix remodeling and inflammation, both potentially detrimental pathways that can damage surrounding tissues and even induce secondary or bystander senescence. Our findings reveal mechanistic insights and potential senescence biomarkers, enabling a better approach to surveilling the senescence burden in the aging population and offering promising therapeutic targets for interventions.
    DOI:  https://doi.org/10.1101/2024.06.22.600215
  4. J Physiol. 2024 Jul 06.
    Marcinek and Ferrucci response to Lanza et al.
    David J Marcinek, Luigi Ferrucci.
      
    Keywords:  ageing; mitochondria; mobility; muscle energetics
    DOI:  https://doi.org/10.1113/JP286696
  5. Front Physiol. 2024 ;15 1426783
    Lysosomal TRPML1 triggers global Ca2+ signals and nitric oxide release in human cerebrovascular endothelial cells.
    Valentina Brunetti, Roberto Berra-Romani, Filippo Conca, Teresa Soda, Gerardo Rosario Biella, Andrea Gerbino, Francesco Moccia, Giorgia Scarpellino.
      Lysosomal Ca2+ signaling is emerging as a crucial regulator of endothelial Ca2+ dynamics. Ca2+ release from the acidic vesicles in response to extracellular stimulation is usually promoted via Two Pore Channels (TPCs) and is amplified by endoplasmic reticulum (ER)-embedded inositol-1,3,4-trisphosphate (InsP3) receptors and ryanodine receptors. Emerging evidence suggests that sub-cellular Ca2+ signals in vascular endothelial cells can also be generated by the Transient Receptor Potential Mucolipin 1 channel (TRPML1) channel, which controls vesicle trafficking, autophagy and gene expression. Herein, we adopted a multidisciplinary approach, including live cell imaging, pharmacological manipulation, and gene targeting, revealing that TRPML1 protein is expressed and triggers global Ca2+ signals in the human brain microvascular endothelial cell line, hCMEC/D3. The direct stimulation of TRPML1 with both the synthetic agonist, ML-SA1, and the endogenous ligand phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) induced a significant increase in [Ca2+]i, that was reduced by pharmacological blockade and genetic silencing of TRPML1. In addition, TRPML1-mediated lysosomal Ca2+ release was sustained both by lysosomal Ca2+ release and ER Ca2+- release through inositol-1,4,5-trisphophate receptors and store-operated Ca2+ entry. Notably, interfering with TRPML1-mediated lysosomal Ca2+ mobilization led to a decrease in the free ER Ca2+ concentration. Imaging of DAF-FM fluorescence revealed that TRPML1 stimulation could also induce a significant Ca2+-dependent increase in nitric oxide concentration. Finally, the pharmacological and genetic blockade of TRPML1 impaired ATP-induced intracellular Ca2+ release and NO production. These findings, therefore, shed novel light on the mechanisms whereby the lysosomal Ca2+ store can shape endothelial Ca2+ signaling and Ca2+-dependent functions in vascular endothelial cells.
    Keywords:  Ca2+ signaling; InsP3 receptors; TRPML1; endothelial cells; lysosomes; nitric oxide; store-operated Ca2+ entry
    DOI:  https://doi.org/10.3389/fphys.2024.1426783
  6. bioRxiv. 2024 Jun 27. pii: 2024.06.21.599604. [Epub ahead of print]
    Long-term NMN treatment increases lifespan and healthspan in mice in a sex dependent manner.
    Alice E Kane, Karthikeyani Chellappa, Michael B Schultz, Matthew Arnold, Jien Li, Joao Amorim, Christian Diener, Dantong Zhu, Sarah J Mitchell, Patrick Griffin, Xiao Tian, Christopher Petty, Ryan Conway, Katie Walsh, Lukas Shelerud, Charlotte Duesing, Amber Mueller, Karlin Li, Maeve McNamara, Rafaella T Shima, James Mitchell, Michael S Bonkowski, Rafael de Cabo, Sean M Gibbons, Lindsay E Wu, Yuji Ikeno, Joseph A Baur, Luis Rajman, David A Sinclair.
      Nicotinamide adenine dinucleotide (NAD) is essential for many enzymatic reactions, including those involved in energy metabolism, DNA repair and the activity of sirtuins, a family of defensive deacylases. During aging, levels of NAD + can decrease by up to 50% in some tissues, the repletion of which provides a range of health benefits in both mice and humans. Whether or not the NAD + precursor nicotinamide mononucleotide (NMN) extends lifespan in mammals is not known. Here we investigate the effect of long-term administration of NMN on the health, cancer burden, frailty and lifespan of male and female mice. Without increasing tumor counts or severity in any tissue, NMN treatment of males and females increased activity, maintained more youthful gene expression patterns, and reduced overall frailty. Reduced frailty with NMN treatment was associated with increases in levels of Anerotruncus colihominis, a gut bacterium associated with lower inflammation in mice and increased longevity in humans. NMN slowed the accumulation of adipose tissue later in life and improved metabolic health in male but not female mice, while in females but not males, NMN increased median lifespan by 8.5%, possible due to sex-specific effects of NMN on NAD + metabolism. Together, these data show that chronic NMN treatment delays frailty, alters the microbiome, improves male metabolic health, and increases female mouse lifespan, without increasing cancer burden. These results highlight the potential of NAD + boosters for treating age-related conditions and the importance of using both sexes for interventional lifespan studies.
    DOI:  https://doi.org/10.1101/2024.06.21.599604
  7. Nat Commun. 2024 Jul 09. 15(1): 5761
    PKM2 aggregation drives metabolism reprograming during aging process.
    Juntao Bie, Ridong Li, Yutong Li, Chen Song, Zhaoming Chen, Tianzhuo Zhang, Zhiheng Tang, Li Su, Liangyi Zhu, Jiaxin Wang, You Wan, Jun Chen, Xiaoyun Liu, Tingting Li, Jianyuan Luo.
      While protein aggregation's association with aging and age-related diseases is well-established, the specific proteins involved and whether dissolving them could alleviate aging remain unclear. Our research addresses this gap by uncovering the role of PKM2 aggregates in aging. We find that PKM2 forms aggregates in senescent cells and organs from aged mice, impairing its enzymatic activity and glycolytic flux, thereby driving cells into senescence. Through a rigorous two-step small molecule library screening, we identify two compounds, K35 and its analog K27, capable of dissolving PKM2 aggregates and alleviating senescence. Further experiments show that treatment with K35 and K27 not only alleviate aging-associated signatures but also extend the lifespan of naturally and prematurely aged mice. These findings provide compelling evidence for the involvement of PKM2 aggregates in inducing cellular senescence and aging phenotypes, and suggest that targeting these aggregates could be a promising strategy for anti-aging drug discovery.
    DOI:  https://doi.org/10.1038/s41467-024-50242-y
  8. Int J Mol Sci. 2024 Jun 27. pii: 7038. [Epub ahead of print]25(13):
    Mitochondrial Protein Density, Biomass, and Bioenergetics as Predictors for the Efficacy of Glioma Treatments.
    Gulnaz Sharapova, Sirina Sabirova, Marina Gomzikova, Anna Brichkina, Nick A Barlev, Natalia V Kalacheva, Albert Rizvanov, Nikita Markov, Hans-Uwe Simon.
      The metabolism of glioma cells exhibits significant heterogeneity and is partially responsible for treatment outcomes. Given this variability, we hypothesized that the effectiveness of treatments targeting various metabolic pathways depends on the bioenergetic profiles and mitochondrial status of glioma cells. To this end, we analyzed mitochondrial biomass, mitochondrial protein density, oxidative phosphorylation (OXPHOS), and glycolysis in a panel of eight glioma cell lines. Our findings revealed considerable variability: mitochondrial biomass varied by up to 3.2-fold, the density of mitochondrial proteins by up to 2.1-fold, and OXPHOS levels by up to 7.3-fold across the cell lines. Subsequently, we stratified glioma cell lines based on their mitochondrial status, OXPHOS, and bioenergetic fitness. Following this stratification, we utilized 16 compounds targeting key bioenergetic, mitochondrial, and related pathways to analyze the associations between induced changes in cell numbers, proliferation, and apoptosis with respect to their steady-state mitochondrial and bioenergetic metrics. Remarkably, a significant fraction of the treatments showed strong correlations with mitochondrial biomass and the density of mitochondrial proteins, suggesting that mitochondrial status may reflect glioma cell sensitivity to specific treatments. Overall, our results indicate that mitochondrial status and bioenergetics are linked to the efficacy of treatments targeting metabolic pathways in glioma.
    Keywords:  OXPHOS; bioenergetics; cancer treatment; drug response; glioblastoma; glioma; metabolic reprogramming; metabolism; mitochondria; mitochondria-targeting
    DOI:  https://doi.org/10.3390/ijms25137038
  9. J Physiol. 2024 Jul 06.
    Reduced oxidative capacity of skeletal muscle IS NOT an inevitable consequence of adult ageing.
    Ian R Lanza, Christopher W Sundberg, Jane A Kent.
      
    Keywords:  ageing; mitochondria; oxidative phosphorylation; skeletal muscle
    DOI:  https://doi.org/10.1113/JP285042
  10. Adv Biol (Weinh). 2024 Jul 09. e2300445
    The Changes of Mitochondria during Aging and Regeneration.
    Anqi Li, Yuan Qin, Guohua Gong.
      Aging and regeneration are opposite cellular processes. Aging refers to progressive dysfunction in most cells and tissues, and regeneration refers to the replacement of damaged or dysfunctional cells or tissues with existing adult or somatic stem cells. Various studies have shown that aging is accompanied by decreased regenerative abilities, indicating a link between them. The performance of any cellular process needs to be supported by the energy that is majorly produced by mitochondria. Thus, mitochondria may be a link between aging and regeneration. It should be interesting to discuss how mitochondria behave during aging and regeneration. The changes of mitochondria in aging and regeneration discussed in this review can provide a timely and necessary study of the causal roles of mitochondrial homeostasis in longevity and health.
    Keywords:  mitochondrial homeostasis; mitochondrial oxidative respiration; mtROS; regeneration; senescence
    DOI:  https://doi.org/10.1002/adbi.202300445
  11. Aging Cell. 2024 Jul 11. e14269
    Alpha-ketoglutarate ameliorates age-related and surgery induced temporomandibular joint osteoarthritis via regulating IKK/NF-κB signaling.
    Xiaoping Ye, Xinping Li, Jin Qiu, Yiwen Kuang, Bingqiang Hua, Xianwen Liu.
      Recent studies have shed light on the important role of aging in the pathogenesis of joint degenerative diseases and the anti-aging effect of alpha-ketoglutarate (αKG). However, whether αKG has any effect on temporomandibular joint osteoarthritis (TMJOA) is unknown. Here, we demonstrate that αKG administration improves condylar cartilage health of middle-aged/aged mice, and ameliorates pathological changes in a rat model of partial discectomy (PDE) induced TMJOA. In vitro, αKG reverses IL-1β-induced/H2O2-induced decrease of chondrogenic markers (Col2, Acan and Sox9), and inhibited IL-1β-induced/ H2O2-induced elevation of cartilage catabolic markers (ADAMTS5 and MMP13) in condylar chondrocytes. In addition, αKG downregulates senescence-associated (SA) hallmarks of aged chondrocytes, including the mRNA/protein level of SA genes (p16 and p53), markers of nuclear disorders (Lamin A/C) and SA-β-gal activities. Mechanically, αKG decreases the expressions of p-IKK and p-NF-κB, protecting TMJ from inflammation and senescence-related damage by regulating the NF-κB signaling. Collectively, our findings illuminate that αKG can ameliorate age-related TMJOA and PDE-induced TMJOA, maintain the homeostasis of cartilage matrix, and exert anti-aging effects in chondrocytes, with a promising therapeutic potential in TMJOA, especially age-related TMJOA.
    Keywords:  IkappaB kinase; age‐related TMJOA; alpha‐ketoglutarate; cartilage; chondrocytes; nuclear factor‐kappa B; osteoarthritis; senescence
    DOI:  https://doi.org/10.1111/acel.14269
  12. bioRxiv. 2024 Jun 26. pii: 2024.06.24.600514. [Epub ahead of print]
    Replicative senescence is ATM driven, reversible, and accelerated by hyperactivation of ATM at normoxia.
    Alexander Stuart, Titia de Lange.
      Programmed telomere shortening limits tumorigenesis through the induction of replicative senescence. Here we address three long-standing questions concerning senescence. First, we show that the ATM kinase is solely responsible for the induction of replicative senescence. Senescence was delayed by ATM inhibition (ATMi) or overexpression of TRF2, the shelterin subunit dedicated to ATM repression. In contrast, there was no evidence for ATR signaling contributing to replicative senescence even when ATMi was combined with ATR inhibition. Second, we show ATMi can induce apparently normal cell divisions in a subset of senescent cells, indicating that senescence can be reversed. Third, we show that the extended replicative life span at low (physiological) oxygen is due to diminished ATM activity. At low oxygen, cells show a decreased ATM response to dysfunctional telomeres and genome-wide DSBs compared to 20% oxygen. As this effect could be reversed by NAC, the attenuated response of ATM to critically short telomeres and the resulting extended life span at low oxygen is likely due to ROS-induced formation of cysteine disulfide-bridges that crosslink ATM dimers into a form that is not activated by DSBs. These findings show how primary human cells detect shortened telomeres and reveal the molecular mechanism underlying the telomere tumor suppressor pathway.
    DOI:  https://doi.org/10.1101/2024.06.24.600514
  13. Anal Chem. 2024 Jul 08.
    Activatable Fluorescent Probe for Studying Drug-Induced Senescence In Vitro and In Vivo.
    Zihong Li, Ping Huang, Guoliang Wu, Weiying Lin.
      Aging represents a significant risk factor for compromised tissue function and the development of chronic diseases in the human body. This process is intricately linked to oxidative stress, with HClO serving as a vital reactive oxygen species (ROS) within biological systems due to its strong oxidative properties. Hence, conducting a thorough examination of HClO in the context of aging is crucial for advancing the field of aging biology. In this work, we successfully developed a fluorescent probe, OPD, tailored specifically for detecting HClO in senescent cells and in vivo. Impressively, OPD exhibited a robust reaction with HClO, showcasing outstanding selectivity, sensitivity, and photostability. Notably, OPD effectively identified HClO in senescent cells for the first time, confirming that DOX- and ROS-induced senescent cells exhibited higher HClO levels compared to uninduced normal cells. Additionally, in vivo imaging of zebrafish demonstrated that d-galactose- and ROS-stimulated senescent zebrafish displayed elevated HClO levels compared to normal zebrafish. Furthermore, when applied to mouse tissues and organs, OPD revealed increased fluorescence in the organs of senescent mice compared to their nonsenescent counterparts. Our findings also illustrated the probe's potential for detecting changes in HClO content pre- and post-aging in living mice. Overall, this probe holds immense promise as a valuable tool for in vivo detection of HClO and for studying aging biology in live organisms.
    DOI:  https://doi.org/10.1021/acs.analchem.4c02423
  14. J Gastrointest Oncol. 2024 Jun 30. 15(3): 1020-1034
    Senescence-related signatures predict prognosis and response to immunotherapy in colon cancer.
    Xiaoshan Hu, Xiongjie Zhu, Yifan Chen, Wenkai Zhang, Laiqing Li, Huankun Liang, Bekzod B Usmanov, Matteo Donadon, Abrorjon A Yusupbekov, Yanfang Zheng.
      Background: Colorectal cancer (CRC) is one of the most common cancers. Cellular senescence plays a vital role in carcinogenesis by activating many pathways. In this study, we aimed to identify biomarkers for predicting the survival and recurrence of CRC through cellular senescence-related genes.Methods: Utilizing The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, RNA-sequencing data and clinical information for CRC were collected. A risk model for predicting overall survival was established based on five differentially expressed genes using least absolute shrinkage and selection operator-Cox regression (LASSO-Cox regression), receiver operating characteristic (ROC), and Kaplan-Meier analyses. The study also delved into both the tumor microenvironment and the response to immunotherapy. Moreover, we gathered clinical sample data from our center in order to confirm the findings of public database analysis.
    Results: Through ROC and Kaplan-Meier analyses, a risk model was developed using five cellular senescence-related genes [i.e., CDKN2A, SERPINE1, SNAI1, CXCL1, and ETS2] to categorize patients into high- and low-risk groups. In the TCGA-colon adenocarcinoma (COAD) and GEO-COAD cohorts, the high-risk group was associated with a bleaker forecast (P<0.05), immune cell inactivation, and insensitivity to immunotherapy in IMvigor210 database (http://research-pub.gene.com/IMvigor210CoreBiologies/). Clinical samples were then used to confirm that ETS2 and CDKN2A could serve as independent prognostic biomarkers in CRC.
    Conclusions: Gene signatures related to cellular senescence, specifically involving CDKN2A and ETS2, are emerging as promising biomarkers for predicting CRC prognosis and guiding immunotherapy.
    Keywords:  Colorectal cancer (CRC); cell senescence; immunotherapy; tumor microenvironment (TME)
    DOI:  https://doi.org/10.21037/jgo-24-339
This page is being maintained by Thomas Krichel. It was last updated on 2024‒07‒14 at 18:48.