bims-cesemi 2025-01-19 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2025–01–19
twelve papers selected by
Julio Cesar Cardenas, Universidad Mayor

Exosomal miR-302b rejuvenates aging mice by reversing the proliferative arrest of senescent cells.
Gut microbial-derived phenylacetylglutamine accelerates host cellular senescence.
IP3 receptor depletion in a spontaneous canine model of Charcot-Marie-Tooth disease 1J with amelogenesis imperfecta.
Characterization of Human Senescent Cell Biomarkers for Clinical Trials.
Recommendations for mitochondria transfer and transplantation nomenclature and characterization.
Aging stem cells limit tumorigenesis.
Disease stage-specific role of the mitochondrial pyruvate carrier suppresses differentiation in temozolomide and radiation-treated glioblastoma.
Senescence in neural cell lines: comparative insights from SH-SY5Y and ReNcell VM.
Menopause-induced 17β-estradiol and progesterone loss increases senescence markers, matrix disassembly and degeneration in mouse cartilage.
Safe and Orally Bioavailable Inhibitor of Serine Palmitoyltransferase Improves Age-Related Sarcopenia.
Induction of age-related ocular disorders in a mouse model of pulmonary fibrosis.
Glutaminase-2 Expression Induces Metabolic Changes and Regulates Pyruvate Dehydrogenase Activity in Glioblastoma Cells.

Cell Metab. 2025 Jan 13. pii: S1550-4131(24)00481-9. [Epub ahead of print]

Exosomal miR-302b rejuvenates aging mice by reversing the proliferative arrest of senescent cells.

Youkun Bi, Xinlong Qiao, Zhaokui Cai, Hailian Zhao, Rong Ye, Qun Liu, Lin Gao, Yingqi Liu, Bo Liang, Yixuan Liu, Yaning Zhang, Zhiguang Yang, Yanyun Wu, Huiwen Wang, Wei Jia, Changqing Zeng, Ce Jia, Hongjin Wu, Yuanchao Xue, Guangju Ji.

  Cellular senescence, a hallmark of aging, involves a stable exit from the cell cycle. Senescent cells (SnCs) are closely associated with aging and aging-related disorders, making them potential targets for anti-aging interventions. In this study, we demonstrated that human embryonic stem cell-derived exosomes (hESC-Exos) reversed senescence by restoring the proliferative capacity of SnCs in vitro. In aging mice, hESC-Exos treatment remodeled the proliferative landscape of SnCs, leading to rejuvenation, as evidenced by extended lifespan, improved physical performance, and reduced aging markers. Ago2 Clip-seq analysis identified miR-302b enriched in hESC-Exos that specifically targeted the cell cycle inhibitors Cdkn1a and Ccng2. Furthermore, miR-302b treatment reversed the proliferative arrest of SnCs in vivo, resulting in rejuvenation without safety concerns over a 24-month observation period. These findings demonstrate that exosomal miR-302b has the potential to reverse cellular senescence, offering a promising approach to mitigate senescence-related pathologies and aging.

Keywords:  Ccng2; Cdkn1a; aging; cellular senescence; hESC-Exos; miR-302b; proliferative arrest; rejuvenation

DOI:  https://doi.org/10.1016/j.cmet.2024.11.013
Nat Aging. 2025 Jan 10.

Gut microbial-derived phenylacetylglutamine accelerates host cellular senescence.

Hao Yang, Tongyao Wang, Chenglang Qian, Huijing Wang, Dong Yu, Meifang Shi, Mengwei Fu, Xueguang Liu, Miaomiao Pan, Xingyu Rong, Zhenming Xiao, Xiejiu Chen, Anaguli Yeerken, Yonglin Wu, Yufan Zheng, Hui Yang, Ming Zhang, Tao Liu, Peng Qiao, Yifan Qu, Yong Lin, Yiqin Huang, Jianliang Jin, Nan Liu, Yumei Wen, Ning Sun, Chao Zhao.

Gut microbiota plays a crucial role in the host health in the aging process. However, the mechanisms for how gut microbiota triggers cellular senescence and the consequent impact on human aging remain enigmatic. Here we show that phenylacetylglutamine (PAGln), a metabolite linked to gut microbiota, drives host cellular senescence. Our findings indicate that the gut microbiota alters with age, which leads to increased production of phenylacetic acid (PAA) and its downstream metabolite PAGln in older individuals. The PAGln-induced senescent phenotype was verified in both cellular models and mouse models. Further experiments revealed that PAGln induces mitochondrial dysfunction and DNA damage via adrenoreceptor (ADR)-AMP-activated protein kinase (AMPK) signaling. Blockade of ADRs as well as senolytics therapy impede PAGln-induced cellular senescence in vivo, implying potential anti-aging therapies. This combined evidence reveals that PAGln, a naturally occurring metabolite of human gut microbiota, mechanistically accelerates host cellular senescence.

DOI: https://doi.org/10.1038/s43587-024-00795-w
PLoS Genet. 2025 Jan 13. 21(1): e1011328

IP3 receptor depletion in a spontaneous canine model of Charcot-Marie-Tooth disease 1J with amelogenesis imperfecta.

Marjo K Hytönen, Julius Rönkkö, Sruthi Hundi, Tarja S Jokinen, Emilia Suonto, Eeva Teräväinen, Jonas Donner, Rita La Rovere, Geert Bultynck, Emil Ylikallio, Henna Tyynismaa, Hannes Lohi.

Inositol 1,4,5-trisphosphate receptors (IP3R) mediate Ca2+ release from intracellular stores, contributing to complex regulation of numerous physiological responses. The involvement of the three IP3R genes (ITPR1, ITPR2 and ITPR3) in inherited human diseases has started to shed light on the essential roles of each receptor in different human tissues and cell types. Variants in the ITPR3 gene, which encodes IP3R3, have recently been found to cause demyelinating sensorimotor Charcot-Marie-Tooth neuropathy type 1J (CMT1J). In addition to peripheral neuropathy, immunodeficiency and tooth abnormalities are occasionally present. Here, we report the identification of a homozygous nonsense variant in the ITPR3 gene in Lancashire Heeler dogs, presenting with a severe developmental enamel defect and reduced nerve conduction velocity. We studied the primary skin fibroblasts of the affected dogs and observed that the nonsense variant in ITPR3 led to a complete absence of full-length IP3R3 protein. Unexpectedly, the protein levels of IP3R1 and IP3R2 were also markedly decreased, suggesting co-regulation. Functional Ca2+ measurements revealed reduced IP3R-mediated Ca2+ flux upon stimulation of G-protein-coupled-receptors in the affected dog fibroblasts. These findings highlight the first spontaneous mammalian phenotype caused by a nonsense variant in ITPR3, leading to the loss of IP3R3. The human and canine IP3R3 proteins are highly similar, and our study suggests that the tissue involvement resulting from the receptor's dysfunction is also conserved. In summary, IP3R3 is critical for enamel formation and peripheral nerve maintenance.

DOI: https://doi.org/10.1371/journal.pgen.1011328
Aging Cell. 2025 Jan 17. e14489

Characterization of Human Senescent Cell Biomarkers for Clinical Trials.

Joshua N Farr, David G Monroe, Elizabeth J Atkinson, Mitchell N Froemming, Ming Ruan, Nathan K LeBrasseur, Sundeep Khosla.

  There is an increasing need for biomarkers of senescent cell burden to facilitate the selection of participants for clinical trials. p16Ink4a is encoded by the CDKN2A locus, which produces five variant transcripts in humans, two of which encode homologous p16 proteins: p16Inka4a, encoded by p16_variant 1, and p16ɣ, encoded by p16_variant 5. While distinct quantitative polymerase chain reaction primers can be designed for p16_variant 5, primers for p16_variant 1 also measure p16_variant 5 (p16_variant 1 + 5). In a recent clinical trial evaluating the effects of the senolytic combination, dasatinib + quercetin (D + Q), on bone metabolism in postmenopausal women, we found that women in the highest tertile for T-cell expression of p16_variant 5 had the most robust skeletal responses to D + Q. Importantly, the assessment of p16_variant 5 was more predictive of these responses than p16_variant 1 + 5. Here, we demonstrate that in vitro, p16_variant 1 + 5 increased rapidly (Week 1) following the induction of DNA damage, whereas p16_variant 5 increased later (Week 4), suggesting that p16_variant 5 becomes detectable only when the abundance of senescent cells reaches some threshold. Further analysis identified a SASP panel in plasma that performed as well in identifying postmenopausal women with a positive skeletal response to D + Q. Collectively, our findings provide further support for the T-cell p16_variant 5 assay as a biomarker for selecting participants in clinical trials of senolytic interventions. In addition, our data indicate that correlated plasma SASP markers could be used in lieu of the more technically challenging T-cell p16 assay. Trial Registration: ClinicalTrials.gov identifier: NCT04313634.

Keywords:  SASP; biomarkers; p16; senescence

DOI:  https://doi.org/10.1111/acel.14489
Nat Metab. 2025 Jan 16.

Recommendations for mitochondria transfer and transplantation nomenclature and characterization.

Jonathan R Brestoff, Keshav K Singh, Katia Aquilano, Lance B Becker, Michael V Berridge, Eric Boilard, Andrés Caicedo, Clair Crewe, José Antonio Enríquez, Jianqing Gao, Åsa B Gustafsson, Kazuhide Hayakawa, Maroun Khoury, Yun-Sil Lee, Daniele Lettieri-Barbato, Patricia Luz-Crawford, Heidi M McBride, James D McCully, Ritsuko Nakai, Jiri Neuzil, Martin Picard, Alexander G Rabchevsky, Anne-Marie Rodriguez, Shiladitya Sengupta, Alexander J Sercel, Toshio Suda, Michael A Teitell, Alain R Thierry, Rong Tian, Melanie Walker, Minghao Zheng.

Intercellular mitochondria transfer is an evolutionarily conserved process in which one cell delivers some of their mitochondria to another cell in the absence of cell division. This process has diverse functions depending on the cell types involved and physiological or disease context. Although mitochondria transfer was first shown to provide metabolic support to acceptor cells, recent studies have revealed diverse functions of mitochondria transfer, including, but not limited to, the maintenance of mitochondria quality of the donor cell and the regulation of tissue homeostasis and remodelling. Many mitochondria-transfer mechanisms have been described using a variety of names, generating confusion about mitochondria transfer biology. Furthermore, several therapeutic approaches involving mitochondria-transfer biology have emerged, including mitochondria transplantation and cellular engineering using isolated mitochondria. In this Consensus Statement, we define relevant terminology and propose a nomenclature framework to describe mitochondria transfer and transplantation as a foundation for further development by the community as this dynamic field of research continues to evolve.

DOI: https://doi.org/10.1038/s42255-024-01200-x
Nat Aging. 2025 Jan 15.

Aging stem cells limit tumorigenesis.

Yahyah Aman.

DOI: https://doi.org/10.1038/s43587-025-00805-5
Neuro Oncol. 2025 Jan 11. pii: noaf008. [Epub ahead of print]

Disease stage-specific role of the mitochondrial pyruvate carrier suppresses differentiation in temozolomide and radiation-treated glioblastoma.

Emma Martell, Helgi Kuzmychova, Harshal Senthil, Ujala Chawla, Esha Kaul, Akaljot Grewal, Versha Banerji, Christopher M Anderson, Chitra Venugopal, Donald Miller, Tamra E Werbowetski-Ogilvie, Sheila K Singh, Tanveer Sharif.

   BACKGROUND: The mitochondrial pyruvate carrier (MPC), a central metabolic conduit linking glycolysis and mitochondrial metabolism, is instrumental in energy production. However, the role of the MPC in cancer is controversial. In particular, the importance of the MPC in glioblastoma (GBM) disease progression following standard temozolomide (TMZ) and radiation therapy (RT) remains unexplored.
METHODS: Leveraging in vitro and in vivo patient-derived models of TMZ-RT treatment in GBM, we characterize the temporal dynamics of MPC abundance and downstream metabolic consequences using state-of-the-art molecular, metabolic, and functional assays.
RESULTS: Our findings unveil a disease stage-specific role for the MPC, where in post-treatment GBM, but not therapy-naïve tumors, the MPC acts as a central metabolic regulator that suppresses differentiation. Temporal profiling reveals a dynamic metabolic rewiring where a steady increase in MPC abundance favors a shift towards enhanced mitochondrial metabolic activity across patient GBM samples. Intriguingly, while overall mitochondrial metabolism is increased, acetyl-CoA production is reduced in post-treatment GBM cells, hindering histone acetylation and silencing neural differentiation genes in an MPC-dependent manner. Finally, the therapeutic translations of these findings are highlighted by the successful pre-clinical patient-derived orthotopic xenograft (PDOX) trials utilizing a blood-brain-barrier (BBB) permeable MPC inhibitor, MSDC-0160, which augments standard TMZ-RT therapy to mitigate disease relapse and prolong animal survival.
CONCLUSION: Our findings demonstrate the critical role of the MPC in mediating GBM aggressiveness and molecular evolution following standard TMZ-RT treatment, illuminating a therapeutically-relevant metabolic vulnerability to potentially improve survival outcomes for GBM patients.

Keywords:  Glioblastoma; differentiation; metabolism; mitochondrial pyruvate carrier; tumor recurrence

DOI:  https://doi.org/10.1093/neuonc/noaf008
Gen Physiol Biophys. 2025 Jan;44(1): 39-49

Senescence in neural cell lines: comparative insights from SH-SY5Y and ReNcell VM.

Kristina Macova, Diana Mjartinova, Lubica Fialova, Dalibor Nakladal, Dominika Fricova.

Senescence, a crucial yet paradoxical phenomenon in cellular biology, acts as a barrier against cancer progression while simultaneously promoting aging and age-related pathologies. This duality underlines the importance of precise monitoring of senescence response, especially with regard to the proposed use of drugs selectively removing senescent cells. In particular, little is known about the role of senescence in neurons and in neurodegenerative diseases. Our study investigates the senescence response in neuroblastoma SH-SY5Y cells and human neural progenitor ReNcell VM cells exposed to doxorubicin, a chemotherapeutic agent known to induce DNA damage and subsequent senescence. Through a comprehensive analysis employing the most robust senescence markers, we characterized the senescence-associated patterns in these neural cell lines including cellular morphological changes, SA-beta-gal, γH2A.X, p21Waf1/Cip1 and p16Ink4a. Our findings indicate that ReNcell VM cells exhibit greater senescence-associated response at lower doxorubicin concentrations compared to SH-SY5Y cells. Additionally, we observed cell-type-specific differences in timing and levels of the expression of key cell cycle regulators during senescence. Our results emphasize the necessity of cell-type-specific strategies in senescence research with regard to implications as well as limitations for translation into aging and neurodegenerative disorders.

DOI: https://doi.org/10.4149/gpb_2024028
Nat Aging. 2025 Jan 16.

Menopause-induced 17β-estradiol and progesterone loss increases senescence markers, matrix disassembly and degeneration in mouse cartilage.

Gabrielle Gilmer, Hirotaka Iijima, Zachary R Hettinger, Natalie Jackson, Juliana Bergmann, Allison C Bean, Nafiseh Shahshahan, Ekaterina Creed, Rylee Kopchak, Kai Wang, Hannah Houston, Jonathan M Franks, Michael J Calderon, Claudette St Croix, Rebecca C Thurston, Christopher H Evans, Fabrisia Ambrosio.

Female individuals who are post-menopausal present with higher incidence of knee osteoarthritis (KOA) than male counterparts; however, the mechanisms underlying this disparity are unknown. The most commonly used preclinical models lack human-relevant menopausal phenotypes, which may contribute to our incomplete understanding of sex-specific differences in KOA pathogenesis. Here we chemically induced menopause in middle-aged (14-16 months) C57/BL6N female mice. When we mapped the trajectory of KOA over time, we found that menopause aggravated cartilage degeneration relative to non-menopause controls. Network medicine analyses revealed that loss of 17β-estradiol and progesterone with menopause enhanced susceptibility to senescence and extracellular matrix disassembly. In vivo, restoration of 17β-estradiol and progesterone in menopausal mice protected against cartilage degeneration compared to untreated menopausal controls. Accordingly, post-menopausal human chondrocytes displayed decreased markers of senescence and increased markers of chondrogenicity when cultured with 17β-estradiol and progesterone. These findings implicate menopause-associated senescence and extracellular matrix disassembly in the sex-specific pathogenesis of KOA.

DOI: https://doi.org/10.1038/s43587-024-00773-2
ACS Pharmacol Transl Sci. 2025 Jan 10. 8(1): 203-215

Safe and Orally Bioavailable Inhibitor of Serine Palmitoyltransferase Improves Age-Related Sarcopenia.

Johanne Poisson, Ioanna Daskalaki, Vijay Potluri, Jean-David Morel, Sandra Rodriguez-Lopez, Alessia De Masi, Giorgia Benegiamo, Suresh Jain, Tanes Lima, Johan Auwerx.

The accumulation of ceramides and related metabolites has emerged as a pivotal mechanism contributing to the onset of age-related diseases. However, small molecule inhibitors targeting the ceramide de novo synthesis pathway for clinical use are currently unavailable. We synthesized a safe and orally bioavailable inhibitor, termed ALT-007, targeting the rate-limiting enzyme of ceramide de novo synthesis, serine palmitoyltransferase (SPT). In a mouse model of age-related sarcopenia, ALT-007, administered through the diet, effectively restored muscle mass and function compromised by aging. Mechanistic studies revealed that ALT-007 enhances protein homeostasis in Caenorhabditis elegans and mouse models of aging and age-related diseases, such as sarcopenia and inclusion body myositis (IBM); this effect is mediated by a specific reduction in very-long chain 1-deoxy-sphingolipid species, which accumulate in both muscle and brain tissues of aged mice and in muscle cells from IBM patients. These findings unveil a promising therapeutic avenue for developing safe ceramide inhibitors to address age-related neuromuscular diseases.

DOI: https://doi.org/10.1021/acsptsci.4c00587
Exp Eye Res. 2025 Jan 10. pii: S0014-4835(25)00009-0. [Epub ahead of print] 110238

Induction of age-related ocular disorders in a mouse model of pulmonary fibrosis.

Chao Wang, Xue Li, Qi Tang, Jialu Wu, Jie-Guang Chen.

  Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease linked to aging. This study investigates potential connections between IPF and age-related eye problems using a bleomycin-induced IPF mouse model. Intratracheal administration of bleomycin induces rapid lung injury in mice, followed by IPF with characteristics of cellular senescence. IPF-injured mice had reduced amplitudes of scotopic ERG and immunostaining of visual arrestin, suggesting declined rod-related visual function. Interestingly, the mice's eyes also showed increased susceptibility to Staphylococcus aureus infections, reminiscent of the aging eyes. To determine whether an early onset of aging contributes to the eye disorders, we examined complement and senescence markers in the retina. In bleomycin-injury IPF mice, DNA damage-related senescence marker γH2AX was found in the retinal out nuclear layer where photoreceptors are located. Additionally, IPF mice displayed elevated levels of C3b, a complement fragment resulting from C3 activation that occurs frequently in aging eyes. These findings underscore the potential of IPF as a valuable mouse model for investigating early-onset age-related ocular disorders.

Keywords:  age-related eye disorders; endophthalmitis; pulmonary fibrosis; senescence; visual arrestin

DOI:  https://doi.org/10.1016/j.exer.2025.110238
Int J Mol Sci. 2025 Jan 06. pii: 427. [Epub ahead of print]26(1):

Glutaminase-2 Expression Induces Metabolic Changes and Regulates Pyruvate Dehydrogenase Activity in Glioblastoma Cells.

Juan De Los Santos-Jiménez, José A Campos-Sandoval, Tracy Rosales, Bookyung Ko, Francisco J Alonso, Javier Márquez, Ralph J DeBerardinis, José M Matés.

  Glutaminase controls the first step in glutaminolysis, impacting bioenergetics, biosynthesis and oxidative stress. Two isoenzymes exist in humans, GLS and GLS2. GLS is considered prooncogenic and overexpressed in many tumours, while GLS2 may act as prooncogenic or as a tumour suppressor. Glioblastoma cells usually lack GLS2 while they express high GLS. We investigated how GLS2 expression modifies the metabolism of glioblastoma cells, looking for changes that may explain GLS2's potential tumour suppressive role. We developed LN-229 glioblastoma cells stably expressing GLS2 and performed isotope tracing using U-13C-glutamine and metabolomic quantification to analyze metabolic changes. Treatment with GLS inhibitor CB-839 was also included to concomitantly inhibit endogenous GLS. GLS2 overexpression resulted in extensive metabolic changes, altering the TCA cycle by upregulating part of the cycle but blocking the synthesis of the 6-carbon intermediates from acetyl-CoA. Expression of GLS2 caused downregulation of PDH activity through phosphorylation of S293 of PDHA1. GLS2 also altered nucleotide levels and induced the accumulation of methylated metabolites and S-adenosyl methionine. These changes suggest that GLS2 may be a key regulator linking glutamine and glucose metabolism, also impacting nucleotides and epigenetics. Future research should ascertain the mechanisms involved and the generalizability of these findings in cancer or physiological conditions.

Keywords:  cancer; glioblastoma; glutaminase; glutaminase-2; glutamine; metabolomics; pyruvate dehydrogenase

DOI:  https://doi.org/10.3390/ijms26010427