bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023‒08‒06
twenty-one papers selected by
Ayesh Seneviratne
Western University
  1. Clonal hematopoiesis of indeterminate potential: Overmedicalization or context dependant relevance?
  2. How the cGAS-STING system links inflammation and cognitive decline.
  3. Blockade of IL-6 signaling alleviates atherosclerosis in Tet2-deficient clonal hematopoiesis.
  4. Mitochondrial epigenetics in aging and cardiovascular diseases.
  5. Multiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton.
  6. Composition of healthy diets for older persons.
  7. Complex interventions for independent living: good news for complex patients.
  8. cGAS-STING drives ageing-related inflammation and neurodegeneration.
  9. The theory of orchid and dandelion offers a new subtyping framework for cognitive aging.
  10. Modulation of DNA methylation by one-carbon metabolism: a milestone for healthy aging.
  11. Environmental Enrichment Improves Motor Function and Muscle Transcriptome of Aged Mice.
  12. Anti-aging mechanism of different age donor-matched adipose-derived stem cells.
  13. Etiological relationship between lipid metabolism and endometrial carcinoma.
  14. Progressive disruption of hematopoietic architecture from clonal hematopoiesis to MDS.
  15. Systemic taurine decline drives aging.
  16. Fatty acid synthesis and oxidation regulate human endoderm differentiation by mediating SMAD3 nuclear localization via acetylation.
  17. Phospholipids can regulate complex I assembly independent of their role in maintaining mitochondrial membrane integrity.
  18. Colchicine for cardiovascular prevention: the dawn of a new era has finally come.
  19. The impact of age-related syndromes on ICU process and outcomes in very old patients.
  20. Anti-inflammatory therapeutic biomarkers identified of human bone marrow mesenchymal stem cell therapy on aging mice by serum proteomics and peptidomics study.
  21. TET2-mediated mRNA demethylation regulates leukemia stem cell homing and self-renewal.
  1. Leuk Res. 2023 Jul 18. pii: S0145-2126(23)00621-5. [Epub ahead of print]133 107356
    Clonal hematopoiesis of indeterminate potential: Overmedicalization or context dependant relevance?
    Mrinal M Patnaik.
      
    Keywords:  CHIP; Clonal hematopoiesis; Context dependant
    DOI:  https://doi.org/10.1016/j.leukres.2023.107356
  2. Nature. 2023 Aug;620(7973): 280-282
    How the cGAS-STING system links inflammation and cognitive decline.
    Bart J L Eggen.
      
    Keywords:  Ageing; Immunology; Neurodegeneration; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-023-02240-1
  3. Nat Cardiovasc Res. 2023 Jun;2(6): 572-586
    Blockade of IL-6 signaling alleviates atherosclerosis in Tet2-deficient clonal hematopoiesis.
    Wenli Liu, Mustafa Yalcinkaya, Inés Fernández Maestre, Malgorzata Olszewska, Patrick B Ampomah, J Brett Heimlich, Ranran Wang, Pablo Sánchez Vela, Tong Xiao, Alexander G Bick, Ross Levine, Eirini P Papapetrou, Peter Libby, Ira Tabas, Nan Wang, Alan R Tall.
      Clonal hematopoiesis (CH) increases the risk of atherosclerotic cardiovascular disease possibly due to increased plaque inflammation. Human studies suggest that limitation of interleukin-6 (IL-6) signaling could be beneficial in people with large CH clones, particularly in TET2 CH. Here we show that IL-6 receptor antibody treatment reverses the atherosclerosis promoted by Tet2 CH, with reduction of monocytosis, lesional macrophage burden and macrophage colony-stimulating factor 1 receptor (CSF1R) expression. IL-6 induces expression of Csf1r in Tet2-deficient macrophages through enhanced STAT3 binding to its promoter. In mouse and human Tet2-deficient macrophages, IL-6 increases CSF1R expression and enhances macrophage survival. Treatment with the CSF1R inhibitor PLX3397 reversed accelerated atherosclerosis in Tet2 CH mice. Our study demonstrates the causality of IL-6 signaling in Tet2 CH accelerated atherosclerosis, identifies IL-6-induced CSF1R expression as a critical mechanism and supports blockade of IL-6 signaling as a potential therapy for CH-driven cardiovascular disease.
    DOI:  https://doi.org/10.1038/s44161-023-00281-3
  4. Front Cardiovasc Med. 2023 ;10 1204483
    Mitochondrial epigenetics in aging and cardiovascular diseases.
    Alessia Mongelli, Alessandro Mengozzi, Martin Geiger, Era Gorica, Shafeeq Ahmed Mohammed, Francesco Paneni, Frank Ruschitzka, Sarah Costantino.
      Mitochondria are cellular organelles which generate adenosine triphosphate (ATP) molecules for the maintenance of cellular energy through the oxidative phosphorylation. They also regulate a variety of cellular processes including apoptosis and metabolism. Of interest, the inner part of mitochondria-the mitochondrial matrix-contains a circular molecule of DNA (mtDNA) characterised by its own transcriptional machinery. As with genomic DNA, mtDNA may also undergo nucleotide mutations that have been shown to be responsible for mitochondrial dysfunction. During physiological aging, the mitochondrial membrane potential declines and associates with enhanced mitophagy to avoid the accumulation of damaged organelles. Moreover, if the dysfunctional mitochondria are not properly cleared, this could lead to cellular dysfunction and subsequent development of several comorbidities such as cardiovascular diseases (CVDs), diabetes, respiratory and cardiovascular diseases as well as inflammatory disorders and psychiatric diseases. As reported for genomic DNA, mtDNA is also amenable to chemical modifications, namely DNA methylation. Changes in mtDNA methylation have shown to be associated with altered transcriptional programs and mitochondrial dysfunction during aging. In addition, other epigenetic signals have been observed in mitochondria, in particular the interaction between mtDNA methylation and non-coding RNAs. Mitoepigenetic modifications are also involved in the pathogenesis of CVDs where oxygen chain disruption, mitochondrial fission, and ROS formation alter cardiac energy metabolism leading to hypertrophy, hypertension, heart failure and ischemia/reperfusion injury. In the present review, we summarize current evidence on the growing importance of epigenetic changes as modulator of mitochondrial function in aging. A better understanding of the mitochondrial epigenetic landscape may pave the way for personalized therapies to prevent age-related diseases.
    Keywords:  aging; cardiovascular diseases; methylation; mitochondria; mitoepigenetics; mtDNA; ncRNAs
    DOI:  https://doi.org/10.3389/fcvm.2023.1204483
  5. Nat Commun. 2023 07 31. 14(1): 4587
    Multiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton.
    Madison L Doolittle, Dominik Saul, Japneet Kaur, Jennifer L Rowsey, Stephanie J Vos, Kevin D Pavelko, Joshua N Farr, David G Monroe, Sundeep Khosla.
      Senescence drives organismal aging, yet the deep characterization of senescent cells in vivo remains incomplete. Here, we apply mass cytometry by time-of-flight using carefully validated antibodies to analyze senescent cells at single-cell resolution. We use multiple criteria to identify senescent mesenchymal cells that are growth-arrested and resistant to apoptosis. These p16 + Ki67-BCL-2+ cells are highly enriched for senescence-associated secretory phenotype and DNA damage markers, are strongly associated with age, and their percentages are increased in late osteoblasts/osteocytes and CD24high osteolineage cells. Moreover, both late osteoblasts/osteocytes and CD24high osteolineage cells are robustly cleared by genetic and pharmacologic senolytic therapies in aged mice. Following isolation, CD24+ skeletal cells exhibit growth arrest, senescence-associated β-galactosidase positivity, and impaired osteogenesis in vitro. These studies thus provide an approach using multiplexed protein profiling to define senescent mesenchymal cells in vivo and identify specific skeletal cell populations cleared by senolytics.
    DOI:  https://doi.org/10.1038/s41467-023-40393-9
  6. Curr Opin Clin Nutr Metab Care. 2023 Aug 01.
    Composition of healthy diets for older persons.
    Suey S Y Yeung, Michelle Kwan, Jean Woo.
      PURPOSE OF REVIEW: This study aims to review recent evidence (2022-2023) on the role of diet in promoting healthy aging in older adults.RECENT FINDINGS: Current evidence of diet and healthy aging is limited to epidemiological studies. A healthy diet is beneficial for individual domains of intrinsic capacity, that is, cognition, locomotion, vitality, psychological, and/or sensory functions, with sex-specific differences reported. Only a few studies used the multidimensional concept of intrinsic capacity as an outcome. This review supports that a healthy diet for older adults consists of plenty of plant-based foods, adequate protein-rich foods, and healthy fats. Next to quantity, improving the quality and variety within food groups play a role in optimizing health. Data on the associations between adherence to national food-based dietary guidelines and intrinsic capacity are scarce.
    SUMMARY: A healthy diet, centered on plant-based foods, adequate protein-rich foods and healthy fats, potentially promotes healthy aging. Future studies may evaluate the association between adherence to healthy dietary patterns (particularly national food-based dietary guidelines) and the multidimensional concept of intrinsic capacity, with consideration of sex-specific differences. Clinical trials are warranted to inform the causal effects of diet and outcomes related to intrinsic capacity.
    DOI:  https://doi.org/10.1097/MCO.0000000000000972
  7. Age Ageing. 2023 Jul 01. pii: afad131. [Epub ahead of print]52(7):
    Complex interventions for independent living: good news for complex patients.
    Graham Ellis.
      
    Keywords:  community; complexity; comprehensive; coordinated care; frailty; older people
    DOI:  https://doi.org/10.1093/ageing/afad131
  8. Nature. 2023 Aug 02.
    cGAS-STING drives ageing-related inflammation and neurodegeneration.
    Muhammet F Gulen, Natasha Samson, Alexander Keller, Marius Schwabenland, Chong Liu, Selene Glück, Vivek V Thacker, Lucie Favre, Bastien Mangeat, Lona J Kroese, Paul Krimpenfort, Marco Prinz, Andrea Ablasser.
      Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease1. Multiple factors can contribute to ageing-associated inflammation2; however, the molecular pathways that transduce aberrant inflammatory signalling and their impact in natural ageing remain unclear. Here we show that the cGAS-STING signalling pathway, which mediates immune sensing of DNA3, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglial transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia, defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nucleus RNA-sequencing analysis of microglia and hippocampi of a cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglial states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt neurodegenerative processes during old age.
    DOI:  https://doi.org/10.1038/s41586-023-06373-1
  9. Aging (Albany NY). 2023 Jul 28. undefined
    The theory of orchid and dandelion offers a new subtyping framework for cognitive aging.
    Sylvain Moreno, Emma Rodrigues, Faranak Farzan.
      
    Keywords:  cognitive aging; healthy cognition; heterogeneity; subtyping; trajectories
    DOI:  https://doi.org/10.18632/aging.204955
  10. Nutr Res Pract. 2023 Aug;17(4): 597-615
    Modulation of DNA methylation by one-carbon metabolism: a milestone for healthy aging.
    Sang-Woon Choi, Simonetta Friso.
      Healthy aging can be defined as an extended lifespan and health span. Nutrition has been regarded as an important factor in healthy aging, because nutrients, bioactive food components, and diets have demonstrated beneficial effects on aging hallmarks such as oxidative stress, mitochondrial function, apoptosis and autophagy, genomic stability, and immune function. Nutrition also plays a role in epigenetic regulation of gene expression, and DNA methylation is the most extensively investigated epigenetic phenomenon in aging. Interestingly, age-associated DNA methylation can be modulated by one-carbon metabolism or inhibition of DNA methyltransferases. One-carbon metabolism ultimately controls the balance between the universal methyl donor S-adenosylmethionine and the methyltransferase inhibitor S-adenosylhomocysteine. Water-soluble B-vitamins such as folate, vitamin B6, and vitamin B12 serve as coenzymes for multiple steps in one-carbon metabolism, whereas methionine, choline, betaine, and serine act as methyl donors. Thus, these one-carbon nutrients can modify age-associated DNA methylation and subsequently alter the age-associated physiologic and pathologic processes. We cannot elude aging per se but we may at least change age-associated DNA methylation, which could mitigate age-associated diseases and disorders.
    Keywords:  DNA methylation; Healthy aging; S-adenosylhomocysteine; S-adenosylmethionine; folate; homocysteine
    DOI:  https://doi.org/10.4162/nrp.2023.17.4.597
  11. Adv Biol (Weinh). 2023 Jul 30. e2300148
    Environmental Enrichment Improves Motor Function and Muscle Transcriptome of Aged Mice.
    Wei Huang, Rhiannon Bates, Xunchang Zou, Nicholas J Queen, Xiaokui Mo, W David Arnold, Alissa Ray, Gregory Owendoff, Lei Cao.
      Aging results in the progressive decline of muscle strength. Interventions to maintain muscle strength may mitigate the age-related loss of physical function, thus maximizing health span. The work on environmental enrichment (EE), an experimental paradigm recapitulating aspects of an active lifestyle, has revealed EE-induced metabolic benefits mediated by a brain-fat axis across the lifespan of mice. EE initiated at 18-month of age shows a trend toward an increased mean lifespan. While previous work described EE's influences on the aging dynamics of several central-peripheral processes, its influence on muscle remained understudied. Here, the impact of EE is investigated on motor function, neuromuscular physiology, and the skeletal muscle transcriptome. EE is initiated in 20-month-old mice for a five-month period. EE mice exhibit greater relative lean mass that is associated with improved mobility and hindlimb grip strength. Transcriptomic profiling of muscle tissue reveals an EE-associated enrichment of gene expression within several metabolic pathways related to oxidative phosphorylation and the TCA cycle. Many mitochondrial-related genes-several of which participate in the electron transport chain-are upregulated. Stress-responsive signaling pathways are downregulated because of EE. The results suggest that EE improves motor function-possibly through preservation of mitochondrial function-even late in life.
    Keywords:  aged mice; environment enrichment; mitochondrial genes; motor function; muscle transcriptomics; neuromuscular physiology
    DOI:  https://doi.org/10.1002/adbi.202300148
  12. Stem Cell Res Ther. 2023 Aug 02. 14(1): 192
    Anti-aging mechanism of different age donor-matched adipose-derived stem cells.
    Tao Wang, Yingyu Li, Yu Zhu, Zebiao Liu, Li Huang, Hongxia Zhao, Zuping Zhou, Qiong Wu.
      BACKGROUND: Adipose-derived stem cells (ASCs) have anti-aging and anti-obesity effects in aged animals, but the underlying molecular mechanism remains unknown.METHODS: In the present study, we evaluated the in vivo transplantation effects of different age donor-matched ASCs on natural aging and leptin knockout mice (ob-/ob- mice). The multi-omics expression profiles of young and aged mouse donor-derived ASCs were also analyzed.
    RESULTS: The results revealed that ASCs from young donors induced weight and abdominal fat loss for older recipients but not for young or ob-/ob-mice. The young and aged mouse donor ASCs displayed significant phenotypic differences, contributing to the distinguished weight loss and anti-aging effects in aged mice.
    CONCLUSIONS: Our data suggest an underlying molecular mechanism by which young-donor ASCs reduce immune cells and inflammation in aged mice via secreted immune factors. These findings point to a general anti-aging mechanism of stem cells, which may provide new insights into age-related disturbances of stem cell plasticity in healthy aging and age-related diseases.
    Keywords:  Adipose stem cells (ASCs); Aging; Multi-omics; Obesity
    DOI:  https://doi.org/10.1186/s13287-023-03415-3
  13. Lipids Health Dis. 2023 Aug 04. 22(1): 116
    Etiological relationship between lipid metabolism and endometrial carcinoma.
    Wenzhe Li, Yi Xu, Xinling Zeng, Jie Tan, Ya Wang, Hongyan Wu, Maokun Li, Cunjian Yi.
      Endometrial carcinoma (EC) has become one of the most common gynecological malignant neoplasms in developed countries worldwide. Studies have shown that this may be closely related to the abnormal metabolism of blood lipids, which was the most significant metabolic change in the human body in this cancer. In this review, we focus on the correlation between lipid metabolism and EC and discuss the evidence that abnormal lipid metabolism promotes an increase in EC growth and metabolism, as well as the regulatory mechanism and related signaling pathways involved in this relationship. In addition, we also discussed the research progress of targeted therapies and drug treatments for EC that act on lipid metabolism, and statins are expected to become adjuvant drugs for EC in the future. This review will provide a systematic view for a better understanding of the etiological relationship between lipid metabolism and EC and further open up new therapeutic possibilities and effective treatments for EC by targeting lipid metabolism.
    Keywords:  Biological mechanisms; Endometrial carcinoma; Etiological relationship; Lipid metabolism; Statins
    DOI:  https://doi.org/10.1186/s12944-023-01868-2
  14. iScience. 2023 Aug 18. 26(8): 107328
    Progressive disruption of hematopoietic architecture from clonal hematopoiesis to MDS.
    Michèle C Buck, Lisa Bast, Judith S Hecker, Jennifer Rivière, Maja Rothenberg-Thurley, Luisa Vogel, Dantong Wang, Immanuel Andrä, Fabian J Theis, Florian Bassermann, Klaus H Metzeler, Robert A J Oostendorp, Carsten Marr, Katharina S Götze.
      Clonal hematopoiesis of indeterminate potential (CHIP) describes the age-related acquisition of somatic mutations in hematopoietic stem/progenitor cells (HSPC) leading to clonal blood cell expansion. Although CHIP mutations drive myeloid malignancies like myelodysplastic syndromes (MDS) it is unknown if clonal expansion is attributable to changes in cell type kinetics, or involves reorganization of the hematopoietic hierarchy. Using computational modeling we analyzed differentiation and proliferation kinetics of cultured hematopoietic stem cells (HSC) from 8 healthy individuals, 7 CHIP, and 10 MDS patients. While the standard hematopoietic hierarchy explained HSPC kinetics in healthy samples, 57% of CHIP and 70% of MDS samples were best described with alternative hierarchies. Deregulated kinetics were found at various HSPC compartments with high inter-individual heterogeneity in CHIP and MDS, while altered HSC rates were most relevant in MDS. Quantifying kinetic heterogeneity in detail, we show that reorganization of the HSPC compartment is already detectable in the premalignant CHIP state.
    Keywords:  Computational molecular modelling; Disease; Experimental systems for structural biology
    DOI:  https://doi.org/10.1016/j.isci.2023.107328
  15. Lab Anim (NY). 2023 Aug;52(8): 175
    Systemic taurine decline drives aging.
    Jorge Ferreira.
      
    DOI:  https://doi.org/10.1038/s41684-023-01226-w
  16. Dev Cell. 2023 Jul 25. pii: S1534-5807(23)00335-0. [Epub ahead of print]
    Fatty acid synthesis and oxidation regulate human endoderm differentiation by mediating SMAD3 nuclear localization via acetylation.
    Ying Yi, Xianchun Lan, Yinglei Li, Chenchao Yan, Jing Lv, Tianzhe Zhang, Wei Jiang.
      Metabolic remodeling is one of the earliest events that occur during cell differentiation. Here, we define fatty acid metabolism as a key player in definitive endoderm differentiation from human embryonic stem cells. Fatty acid β-oxidation is enhanced while lipogenesis is decreased, and this is due to the phosphorylation of lipogenic enzyme acetyl-CoA carboxylase by AMPK. More importantly, inhibition of fatty acid synthesis by either its inhibitors or AMPK agonist significantly promotes human endoderm differentiation, while blockade of fatty acid oxidation impairs differentiation. Mechanistically, reduced de novo fatty acid synthesis and enhanced fatty acid β-oxidation both contribute to the accumulation of intracellular acetyl-CoA, which guarantees the acetylation of SMAD3 and further causes nuclear localization to promote endoderm differentiation. Thus, our current study identifies a fatty acid synthesis/oxidation shift during early differentiation and presents an instructive role for fatty acid metabolism in regulating human endoderm differentiation.
    Keywords:  SMAD3 acetylation; embryonic stem cell; fatty acid metabolism; fatty acid synthesis; human endoderm differentiation
    DOI:  https://doi.org/10.1016/j.devcel.2023.07.005
  17. Cell Rep. 2023 Jul 29. pii: S2211-1247(23)00857-4. [Epub ahead of print]42(8): 112846
    Phospholipids can regulate complex I assembly independent of their role in maintaining mitochondrial membrane integrity.
    Anjaneyulu Murari, Shauna-Kay Rhooms, Divya Vimal, Kaniz Fatima Binte Hossain, Sanjay Saini, Maximino Villanueva, Michael Schlame, Edward Owusu-Ansah.
      Several phospholipid (PL) molecules are intertwined with some mitochondrial complex I (CI) subunits in the membrane domain of CI, but their function is unclear. We report that when the Drosophila melanogaster ortholog of the intramitochondrial PL transporter, STARD7, is severely disrupted, assembly of the oxidative phosphorylation (OXPHOS) system is impaired, and the biogenesis of several CI subcomplexes is hampered. However, intriguingly, a restrained knockdown of STARD7 impairs the incorporation of NDUFS5 and NDUFA1 into the proximal part of the CI membrane domain without directly affecting the incorporation of subunits in the distal part of the membrane domain, OXPHOS complexes already assembled, or mitochondrial cristae integrity. Importantly, the restrained knockdown of STARD7 appears to induce a modest amount of cardiolipin remodeling, indicating that there could be some alteration in the composition of the mitochondrial phospholipidome. We conclude that PLs can regulate CI biogenesis independent of their role in maintaining mitochondrial membrane integrity.
    Keywords:  CP: Molecular biology; Drosophila; NDUFA1; NDUFS5; OXPHOS; STARD7; complex I; mitochondria; phospholipid
    DOI:  https://doi.org/10.1016/j.celrep.2023.112846
  18. Eur Heart J. 2023 Aug 02. pii: ehad453. [Epub ahead of print]
    Colchicine for cardiovascular prevention: the dawn of a new era has finally come.
    Aldo Bonaventura, Antonio Abbate.
      
    DOI:  https://doi.org/10.1093/eurheartj/ehad453
  19. Ann Intensive Care. 2023 Aug 04. 13(1): 68
    The impact of age-related syndromes on ICU process and outcomes in very old patients.
    Hélène Vallet, Bertrand Guidet, Ariane Boumendil, Dylan W De Lange, Susannah Leaver, Wojciech Szczeklik, Christian Jung, Sigal Sviri, Michael Beil, Hans Flaatten.
      In this narrative review, we describe the most important age-related "syndromes" found in the old ICU patients. The syndromes are frailty, comorbidity, cognitive decline, malnutrition, sarcopenia, loss of functional autonomy, immunosenescence and inflam-ageing. The underlying geriatric condition, together with the admission diagnosis and the acute severity contribute to the short-term, but also to the long-term prognosis. Besides mortality, functional status and quality of life are major outcome variables. The geriatric assessment is a key tool for long-term qualitative outcome, while immediate severity accounts for acute mortality. A poor functional baseline reduces the chances of a successful outcome following ICU. This review emphasises the importance of using a geriatric assessment and considering the older patient as a whole, rather than the acute illness in isolation, when making decisions regarding intensive care treatment.
    Keywords:  Comprehensive geriatric assessment; Critical care; Intensive care unit; Old patients
    DOI:  https://doi.org/10.1186/s13613-023-01160-7
  20. J Proteomics. 2023 Jul 29. pii: S1874-3919(23)00168-9. [Epub ahead of print] 104979
    Anti-inflammatory therapeutic biomarkers identified of human bone marrow mesenchymal stem cell therapy on aging mice by serum proteomics and peptidomics study.
    Huan Niu, Bo-Yan Wang, Xiao-Yue Wei, Yan-Nan Wang, Wen-Hui Zhu, Wei-Jie Li, Ying Zhang, Jian-Cheng Wang.
      Aging is accompanied by deterioration in physical condition, and creates high risks of diseases and disorders. Stem cell therapy exhibited promising potential for anti-aging. However, the unelucidated treatment mechanism limits its further clinical application. Herein, to systematically understand at a molecular level the response to stem cells transfusion, we performed quantitative serum proteomic and peptidomics analyses in the 24-month-old aging mice model with or without mesenchymal stem cells (MSC) treatment. As a result, a total of 560 proteins and 2131 endogenous peptides were identified, among which, 6 proteins and 9 endogenous peptides derived from 6 precursor proteins were finally identified as therapeutic biomarkers after MSC transfusion on aging mice both by untargeted label-free quantification and targeted parallel reaction monitoring (PRM) quantification. Amazingly, the biological function of these differential proteins was mainly related to inflammation, which is not only the important hallmark of aging, but also the main cause of inducing aging. The reduction of these inflammatory protein content after MSC treatment further suggests the anti-inflammatory effect of MSC therapy reported elsewhere. Therefore, our study provides new evidence for the anti-inflammatory effect of MSC therapy for anti-aging and offers abundant data to support deeper investigations of the therapeutic mechanism of MSC for anti-aging.
    Keywords:  Aging; Mesenchymal stem cells; Peptidomics; Proteomics
    DOI:  https://doi.org/10.1016/j.jprot.2023.104979
  21. Cell Stem Cell. 2023 Aug 03. pii: S1934-5909(23)00246-1. [Epub ahead of print]30(8): 1072-1090.e10
    TET2-mediated mRNA demethylation regulates leukemia stem cell homing and self-renewal.
    Yangchan Li, Meilin Xue, Xiaolan Deng, Lei Dong, Le Xuan Truong Nguyen, Lili Ren, Li Han, Chenying Li, Jianhuang Xue, Zhicong Zhao, Wei Li, Ying Qing, Chao Shen, Brandon Tan, Zhenhua Chen, Keith Leung, Kitty Wang, Srividya Swaminathan, Ling Li, Mark Wunderlich, James C Mulloy, Xiaobo Li, Hao Chen, Bin Zhang, David Horne, Steven T Rosen, Guido Marcucci, Mingjiang Xu, Zejuan Li, Minjie Wei, Jingyan Tian, Baiyong Shen, Rui Su, Jianjun Chen.
      TET2 is recurrently mutated in acute myeloid leukemia (AML) and its deficiency promotes leukemogenesis (driven by aggressive oncogenic mutations) and enhances leukemia stem cell (LSC) self-renewal. However, the underlying cellular/molecular mechanisms have yet to be fully understood. Here, we show that Tet2 deficiency significantly facilitates leukemogenesis in various AML models (mediated by aggressive or less aggressive mutations) through promoting homing of LSCs into bone marrow (BM) niche to increase their self-renewal/proliferation. TET2 deficiency in AML blast cells increases expression of Tetraspanin 13 (TSPAN13) and thereby activates the CXCR4/CXCL12 signaling, leading to increased homing/migration of LSCs into BM niche. Mechanistically, TET2 deficiency results in the accumulation of methyl-5-cytosine (m5C) modification in TSPAN13 mRNA; YBX1 specifically recognizes the m5C modification and increases the stability and expression of TSPAN13 transcripts. Collectively, our studies reveal the functional importance of TET2 in leukemogenesis, leukemic blast cell migration/homing, and LSC self-renewal as an mRNA m5C demethylase.
    Keywords:  CXCR4; RNA 5-methylcytosine methylation; TET2; TSPAN13; YBX1; bone marrow microenvironment; homing; leukemia stem cell; migration; self-renewal
    DOI:  https://doi.org/10.1016/j.stem.2023.07.001
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