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Mehran YZ, Weber HM, Hoseinzade F, Harandi NT, Ayazi M, Mirzadeh S. Longevity concept by regenerative medicine methods synergy: exosome therapy, functional medicine, and advanced multi-wavelengths laser therapy. Eur J Transl Myol 2025. [PMID: 40341289 DOI: 10.4081/ejtm.2025.13540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Accepted: 01/20/2025] [Indexed: 05/10/2025] Open
Abstract
Regenerative medicine is one of the most important branches of medicine today and in the future and brings together all the methods to stop or even reverse the aging process. Regenerative medicine may include cellular therapies such as stem cell therapy or extracellular vesicle therapies such as exosomes and growth factor therapy. It may also involve the use of Photobiomodulation (PBM) and functional medicine treatments targets on mitochondrial medicine, to control the aging process. In this article, we have discussed the role, importance, rationale, overlap, and synergy of the joint application of these methods. Combining these regenerative medicine approaches can achieve better results in various medical indications. For longevity, any autoimmune disease, chronic disease, especially in elderly patients, this recommended combination seems to be very critical, for a higher survival rate in cell therapy methods. It is like a plant growing process that requires good quality seeds (cell therapy), light (targeted laser therapy) and good soil (functional medicine).
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Affiliation(s)
| | - Hans Michael Weber
- Head of International Society of Medical LASER Applications, Lauenfoerde.
| | - Fateme Hoseinzade
- Physical Medicine and Rehabilitation Specialist, Isfahan University of Medical Science, Isfahan.
| | | | | | - Shila Mirzadeh
- Dermatologist, Dr Shila Mirzadeh Ghomsheh Clinic, Shariati, Tehran.
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2
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Jing Y, Zheng W, Zhou Z, Yao H, Zhang W, Wu Y, Guo Z, Huang C, Wang X. Recent research advances of c-fos in regulating cell senescence. Arch Biochem Biophys 2025; 769:110423. [PMID: 40246221 DOI: 10.1016/j.abb.2025.110423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 10/25/2024] [Accepted: 04/14/2025] [Indexed: 04/19/2025]
Abstract
c-fos is an immediate early gene (IEG) that forms a heterodimeric activator protein-1 (AP-1) complex with c-Jun. Following stimulation by a variety of factors, it changes the expression of genes and participates in cellular growth, proliferation, differentiation, and apoptosis. Previous studies have reported that c-fos is linked to cellular senescence and is involved in aging-related signaling pathways or damage repair processes. However, there are limited studies related to this topic. This review summarizes the findings of the connection between c-fos and cellular senescence, including the regulatory role of c-fos in the senescence of stem cells and various kinds of somatic cells. In addition, we discussed the involvement of c-fos in the cellular senescence process and related signaling pathways, as well as the importance of regulating DNA damage repair. The current studies have demonstrated that c-fos has important roles in inhibiting stem cell senescence. They can pave the way for a more thorough examination of the aging process and the regeneration of stem cells and provide new therapeutic strategies for aging-related diseases.
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Affiliation(s)
- Yuxin Jing
- Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Wei Zheng
- Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Zhou Zhou
- Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Haiyang Yao
- Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Wenchuan Zhang
- Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yilun Wu
- Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Zimo Guo
- Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Chenxuan Huang
- Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xianli Wang
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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3
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Komleva Y, Shpiliukova K, Bondar N, Salmina A, Khilazheva E, Illarioshkin S, Piradov M. Decoding brain aging trajectory: predictive discrepancies, genetic susceptibilities, and emerging therapeutic strategies. Front Aging Neurosci 2025; 17:1562453. [PMID: 40177249 PMCID: PMC11962000 DOI: 10.3389/fnagi.2025.1562453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Accepted: 02/28/2025] [Indexed: 04/05/2025] Open
Abstract
The global extension of human lifespan has intensified the focus on aging, yet its underlying mechanisms remain inadequately understood. The article highlights aspects of genetic susceptibility to impaired brain bioenergetics, trends in age-related gene expression related to neuroinflammation and brain senescence, and the impact of stem cell exhaustion and quiescence on accelerated brain aging. We also review the accumulation of senescent cells, mitochondrial dysfunction, and metabolic disturbances as central pathological processes in aging, emphasizing how these factors contribute to inflammation and disrupt cellular competition defining the aging trajectory. Furthermore, we discuss emerging therapeutic strategies and the future potential of integrating advanced technologies to refine aging assessments. The combination of several methods including genetic analysis, neuroimaging techniques, cognitive tests and digital twins, offer a novel approach by simulating and monitoring individual health and aging trajectories, thereby providing more accurate and personalized insights. Conclusively, the accurate estimation of brain aging trajectories is crucial for understanding and managing aging processes, potentially transforming preventive and therapeutic strategies to improve health outcomes in aging populations.
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Affiliation(s)
| | | | - Nikolai Bondar
- Research Center of Neurology, Moscow, Russia
- Laboratory of Molecular Virology, First Moscow State Medical University (Sechenov University), Moscow, Russia
| | | | - Elena Khilazheva
- Department of Biological Chemistry with Courses in Medical, Research Institute of Molecular Medicine and Pathobiochemistry, Pharmaceutical and Toxicological Chemistry Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University of the Ministry of Healthcare of the Russian Federation, Krasnoyarsk, Russia
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4
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Even-Ros D, Huertas-Romero J, Marín-Menguiano M, Nusspaumer G, Borge M, Irimia M, Zurita F, González-Reyes A. Drosophila ovarian stem cell niche ageing involves coordinated changes in transcription and alternative splicing. Nat Commun 2025; 16:2596. [PMID: 40091053 PMCID: PMC11911433 DOI: 10.1038/s41467-025-57901-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 03/06/2025] [Indexed: 03/19/2025] Open
Abstract
Gene expression (GE) and alternative splicing (AS) contribute to the formation of new interaction networks with potentially significant cellular functions. Here, we investigate ageing in the Drosophila female germline stem cell (GSC) niche and describe functional changes in both GE and AS. The GSC niche comprises three types of support cells, whose ageing transcriptomes reveal differential GE and AS variations related to cell adhesion, cytoskeleton and neural signalling. Because each population show distinctive GE and AS changes, niche cell types possess unique ageing signatures. Depending on the cell population, groups of genes display changes in both GE and AS, revealing a coordinated regulation of transcription and splicing during niche ageing. One such gene is Fasciclin 2, a neural adhesion molecule that we find is essential for niche functioning. Furthermore, genes involved in AS undergo changes in GE and/or AS themselves, providing a mechanistic explanation for the coordination of these two processes during niche ageing. This is the case of the splicing factor Smu1, described here as a key element necessary for ovarian niche homeostasis.
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Affiliation(s)
- Dilamm Even-Ros
- Centro Andaluz de Biología del Desarrollo (CABD), CSIC-Junta de Andalucía-UPO, Carretera de Utrera km 1, 41013, Seville, Spain
| | - Judit Huertas-Romero
- Centro Andaluz de Biología del Desarrollo (CABD), CSIC-Junta de Andalucía-UPO, Carretera de Utrera km 1, 41013, Seville, Spain
| | - Miriam Marín-Menguiano
- Centro Andaluz de Biología del Desarrollo (CABD), CSIC-Junta de Andalucía-UPO, Carretera de Utrera km 1, 41013, Seville, Spain
| | - Gretel Nusspaumer
- Centro Andaluz de Biología del Desarrollo (CABD), CSIC-Junta de Andalucía-UPO, Carretera de Utrera km 1, 41013, Seville, Spain
| | - Miguel Borge
- Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Manuel Irimia
- Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- ICREA, Barcelona, Spain
| | - Federico Zurita
- Departamento de Genética e Instituto de Biotecnología, Universidad de Granada, Centro de Investigación Biomédica, 18071, Granada, Spain.
| | - Acaimo González-Reyes
- Centro Andaluz de Biología del Desarrollo (CABD), CSIC-Junta de Andalucía-UPO, Carretera de Utrera km 1, 41013, Seville, Spain.
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5
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Zhuang X, Wang Q, Joost S, Ferrena A, Humphreys DT, Li Z, Blum M, Krause K, Ding S, Landais Y, Zhan Y, Zhao Y, Chaligne R, Lee JH, Carrasco SE, Bhanot UK, Koche RP, Bott MJ, Katajisto P, Soto-Feliciano YM, Pisanic T, Thomas T, Zheng D, Wong ES, Tammela T. Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis. Nature 2025; 637:184-194. [PMID: 39633048 DOI: 10.1038/s41586-024-08285-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 10/24/2024] [Indexed: 12/07/2024]
Abstract
Ageing is associated with a decline in the number and fitness of adult stem cells1,2. Ageing-associated loss of stemness is posited to suppress tumorigenesis3,4, but this hypothesis has not been tested in vivo. Here we use physiologically aged autochthonous genetically engineered5,6 mouse models and primary cells5,6 to demonstrate that ageing suppresses lung cancer initiation and progression by degrading the stemness of the alveolar cell of origin. This phenotype is underpinned by the ageing-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, which leads to functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1-lipocalin-2 axis or iron supplementation rescues stemness and promotes the tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1-lipocalin-2 axis is detrimental to young alveolar cells through ferroptosis induction. Ageing-associated DNA hypomethylation at specific enhancer sites is associated with increased NUPR1 expression, which is recapitulated in young alveolar cells through DNA methylation inhibition. We uncover that ageing drives functional iron insufficiency that leads to loss of stemness and tumorigenesis but promotes resistance to ferroptosis. These findings have implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate at a young age, thereby highlighting the importance of directing cancer prevention efforts towards young individuals.
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Affiliation(s)
- Xueqian Zhuang
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Qing Wang
- Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia
| | - Simon Joost
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alexander Ferrena
- Institute for Clinical and Translational Research, Albert Einstein College of Medicine, New York, NY, USA
| | - David T Humphreys
- Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia
| | - Zhuxuan Li
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Graduate School of Medical Science, Weill Cornell Medicine, New York, NY, USA
| | - Melissa Blum
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Klavdija Krause
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Selena Ding
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yuna Landais
- Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia
| | - Yingqian Zhan
- Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yang Zhao
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Ronan Chaligne
- Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Joo-Hyeon Lee
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Sebastian E Carrasco
- Laboratory of Comparative Pathology, Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center and Rockefeller University, New York, NY, USA
| | - Umeshkumar K Bhanot
- Pathology Core Facility, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Richard P Koche
- Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Matthew J Bott
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Pekka Katajisto
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
- Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
- Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Yadira M Soto-Feliciano
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Thomas Pisanic
- Institute for NanoBioTechnology, Department of Oncology-Cancer Genetics and Epigenetics, Johns Hopkins University, Baltimore, MD, USA
| | - Tiffany Thomas
- Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Deyou Zheng
- Institute for Clinical and Translational Research, Albert Einstein College of Medicine, New York, NY, USA
- Departments of Genetics, Neurology, and Neuroscience, Albert Einstein College of Medicine, New York, NY, USA
| | - Emily S Wong
- Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia
- School of Biotechnology and Biomolecular Sciences, UNSW, Sydney, New South Wales, Australia
| | - Tuomas Tammela
- Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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6
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Nogalska A, Eerdeng J, Akre S, Vergel-Rodriguez M, Lee Y, Bramlett C, Chowdhury AY, Wang B, Cess CG, Finley SD, Lu R. Age-associated imbalance in immune cell regeneration varies across individuals and arises from a distinct subset of stem cells. Cell Mol Immunol 2024; 21:1459-1473. [PMID: 39443746 PMCID: PMC11607082 DOI: 10.1038/s41423-024-01225-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 09/23/2024] [Indexed: 10/25/2024] Open
Abstract
The age-associated decline in immunity manifests as imbalanced adaptive and innate immune cells, which originate from the aging of the stem cells that sustain their regeneration. Aging variation across individuals is well recognized, but its mechanism remains unclear. Here, we used high-throughput single-cell technologies to compare mice of the same chronological age that exhibited early or delayed immune aging phenotypes. We found that some hematopoietic stem cells (HSCs) in early aging mice upregulated genes related to aging, myeloid differentiation, and stem cell proliferation. Delayed aging was instead associated with genes involved in stem cell regulation and the response to external signals. These molecular changes align with shifts in HSC function. We found that the lineage biases of 30% to 40% of the HSC clones shifted with age. Moreover, their lineage biases shifted in opposite directions in mice exhibiting an early or delayed aging phenotype. In early aging mice, the HSC lineage bias shifted toward the myeloid lineage, driving the aging phenotype. In delayed aging mice, HSC lineage bias shifted toward the lymphoid lineage, effectively counteracting aging progression. Furthermore, the anti-aging HSC clones did not increase lymphoid production but instead decreased myeloid production. Additionally, we systematically quantified the frequency of various changes in HSC differentiation and their roles in driving the immune aging phenotype. Taken together, our findings suggest that temporal variation in the aging of immune cell regeneration among individuals primarily arises from differences in the myelopoiesis of a distinct subset of HSCs. Therefore, interventions to delay aging may be possible by targeting a subset of stem cells.
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Affiliation(s)
- Anna Nogalska
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, Los Angeles, CA, 90033, USA
| | - Jiya Eerdeng
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, Los Angeles, CA, 90033, USA
| | - Samir Akre
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, Los Angeles, CA, 90033, USA
| | - Mary Vergel-Rodriguez
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, Los Angeles, CA, 90033, USA
| | - Yeachan Lee
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, Los Angeles, CA, 90033, USA
| | - Charles Bramlett
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, Los Angeles, CA, 90033, USA
| | - Adnan Y Chowdhury
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, Los Angeles, CA, 90033, USA
| | - Bowen Wang
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, Los Angeles, CA, 90033, USA
| | - Colin G Cess
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, 90089, USA
- Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, 90089, USA
| | - Stacey D Finley
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, 90089, USA
- Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, 90089, USA
| | - Rong Lu
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, Los Angeles, CA, 90033, USA.
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, 90089, USA.
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7
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Hirsch MS, Hildebrand CB, Geltinger F, Pich A, Mühlfeld C, Wedekind D, Brandenberger C. Senescence in Alveolar Epithelial Type II Cells Promotes Acute Lung Injury and Impairs Regeneration. Am J Respir Cell Mol Biol 2024; 71:688-701. [PMID: 39088755 DOI: 10.1165/rcmb.2024-0054oc] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 08/01/2024] [Indexed: 08/03/2024] Open
Abstract
The mortality associated with acute lung injury (ALI) increases with age. Alveolar epithelial type II (AEII) cells are the progenitor cells of the alveolar epithelium and are crucial for repair after injury. We hypothesize that telomere dysfunction-mediated AEII cell senescence impairs regeneration and promotes the development of ALI. To discriminate between the impact of old age and AEII cell senescence in ALI, young (3 mo) and old (18 mo) Sftpc-Ai9 mice with surfactant protein c mediated tdTomato expression, and young Sftpc-Ai9-Trf1 mice with additional telomeric repeat-binding factor 1 (Trf1) knockout-mediated senescence in AEII cells were treated with 1 μg LPS per gram body weight (n = 9-11). Control mice received saline solution (n = 7). Mice were killed 4 or 7 days later. Lung mechanics, pulmonary inflammation, and proteomes were analyzed, and parenchymal injury, AEII cell proliferation and AEI cell differentiation rate were quantified using stereology. Old mice showed 55% mortality by Day 4, whereas all young mice survived. Pulmonary inflammation was most severe in old Sftpc-Ai9 mice, followed by Sftpc-Ai9-Trf1 mice. Young Sftpc-Ai9 mice recovered almost completely by Day 7, whereas Sftpc-Ai9-Trf1 mice still showed mild signs of injury. An expansion of AEII cells was measured only in young Sftpc-Ai9 mice at Day 7. Aging and telomere dysfunction-mediated senescence had no impact on AEI differentiation rate in controls, but the reduced number of AEII cells in Sftpc-Ai9-Trf1 mice also affected de novo differentiation after injury. In conclusion, telomere dysfunction- mediated AEII cell senescence promoted parenchymal inflammation in ALI, but did not enhance mortality like old age. Although the differentiation rate remained functional with old age and AEII cell senescence, AEII cell proliferative capacity was impaired in ALI, affecting the regenerative ability.
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Affiliation(s)
- Merle S Hirsch
- Institute of Functional and Applied Anatomy
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany; and
| | - Christina B Hildebrand
- Institute of Functional and Applied Anatomy
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany; and
- Institute of Functional Anatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Florian Geltinger
- Institute of Functional Anatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Andreas Pich
- Institute of Toxicology, Core Facility Proteomics, and
| | - Christian Mühlfeld
- Institute of Functional and Applied Anatomy
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany; and
| | - Dirk Wedekind
- Institute of Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - Christina Brandenberger
- Institute of Functional and Applied Anatomy
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany; and
- Institute of Functional Anatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany
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8
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Jones SD, Miller JEB, Amos MM, Hernández JM, Piaszynski KM, Geyer PK. Emerin preserves stem cell survival through maintenance of centrosome and nuclear lamina structure. Development 2024; 151:dev204219. [PMID: 39465887 PMCID: PMC11586520 DOI: 10.1242/dev.204219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 10/04/2024] [Indexed: 10/29/2024]
Abstract
Drosophila female germline stem cells (GSCs) complete asymmetric mitosis in the presence of an intact, but permeable, nuclear envelope and nuclear lamina (NL). This asymmetric division requires a modified centrosome cycle, wherein mitotic centrosomes with mature pericentriolar material (PCM) embed in the NL and interphase centrosomes with reduced PCM leave the NL. This centrosome cycle requires Emerin, an NL protein required for GSC survival and germ cell differentiation. In emerin mutants, interphase GSC centrosomes retain excess PCM, remain embedded in the NL and nucleate microtubule asters at positions of NL distortion. Here, we investigate the contributions of abnormal interphase centrosomes to GSC loss. Remarkably, reducing interphase PCM in emerin mutants rescues GSC survival and partially restores germ cell differentiation. Direct tests of the effects of abnormal centrosomes were achieved by expression of constitutively active Polo kinase to drive enlargement of interphase centrosomes in wild-type GSCs. Notably, these conditions failed to alter NL structure or decrease GSC survival. However, coupling enlarged interphase centrosomes with nuclear distortion promoted GSC loss. These studies establish that Emerin maintains centrosome structure to preserve stem cell survival.
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Affiliation(s)
- Samuel D. Jones
- Department of Biochemistry and Molecular Biology, University of Iowa, Iowa City, IA 52242, USA
| | - Jack E. B. Miller
- Department of Biochemistry and Molecular Biology, University of Iowa, Iowa City, IA 52242, USA
| | - Madilynn M. Amos
- Department of Biochemistry and Molecular Biology, University of Iowa, Iowa City, IA 52242, USA
| | - Julianna M. Hernández
- Department of Biochemistry and Molecular Biology, University of Iowa, Iowa City, IA 52242, USA
| | - Katherine M. Piaszynski
- Department of Biochemistry and Molecular Biology, University of Iowa, Iowa City, IA 52242, USA
| | - Pamela K. Geyer
- Department of Biochemistry and Molecular Biology, University of Iowa, Iowa City, IA 52242, USA
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9
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Perales IE, Jones SD, Duan T, Geyer PK. Maintenance of germline stem cell homeostasis despite severe nuclear distortion. Dev Biol 2024; 515:139-150. [PMID: 39038593 PMCID: PMC11317214 DOI: 10.1016/j.ydbio.2024.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 07/17/2024] [Accepted: 07/19/2024] [Indexed: 07/24/2024]
Abstract
Stem cell loss in aging and disease is associated with nuclear deformation. Yet, how nuclear shape influences stem cell homeostasis is poorly understood. We investigated this connection using Drosophila germline stem cells, as survival of these stem cells is compromised by dysfunction of the nuclear lamina, the extensive protein network that lines the inner nuclear membrane and gives shape to the nucleus. To induce nuclear distortion in germline stem cells, we used the GAL4-UAS system to increase expression of the permanently farnesylated nuclear lamina protein, Kugelkern, a rate limiting factor for nuclear growth. We show that elevated Kugelkern levels cause severe nuclear distortion in germline stem cells, including extensive thickening and lobulation of the nuclear envelope and nuclear lamina, as well as alteration of internal nuclear compartments. Despite these changes, germline stem cell number, proliferation, and female fertility are preserved, even as females age. Collectively, these data demonstrate that disruption of nuclear architecture does not cause a failure of germline stem cell survival or homeostasis, revealing that nuclear deformation does not invariably promote stem cell loss.
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Affiliation(s)
- Isabella E Perales
- Department of Biochemistry and Molecular Biology, University of Iowa, Iowa City, IA, 52242, USA
| | - Samuel D Jones
- Department of Biochemistry and Molecular Biology, University of Iowa, Iowa City, IA, 52242, USA
| | - Tingting Duan
- Department of Biochemistry and Molecular Biology, University of Iowa, Iowa City, IA, 52242, USA
| | - Pamela K Geyer
- Department of Biochemistry and Molecular Biology, University of Iowa, Iowa City, IA, 52242, USA.
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10
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Chiappara G, Di Vincenzo S, Cascio C, Pace E. Stem cells, Notch-1 signaling, and oxidative stress: a hellish trio in cancer development and progression within the airways. Is there a role for natural compounds? Carcinogenesis 2024; 45:621-629. [PMID: 39046986 DOI: 10.1093/carcin/bgae049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 06/22/2024] [Accepted: 07/20/2024] [Indexed: 07/27/2024] Open
Abstract
Notch-1 signaling plays a crucial role in stem cell maintenance and in repair mechanisms in various mucosal surfaces, including airway mucosa. Persistent injury can induce an aberrant activation of Notch-1 signaling in stem cells leading to an increased risk of cancer initiation and progression. Chronic inflammatory respiratory disorders, including chronic obstructive pulmonary disease (COPD) is associated with both overactivation of Notch-1 signaling and increased lung cancer risk. Increased oxidative stress, also due to cigarette smoke, can further contribute to promote cancer initiation and progression by amplifying inflammatory responses, by activating the Notch-1 signaling, and by blocking regulatory mechanisms that inhibit the growth capacity of stem cells. This review offers a comprehensive overview of the effects of aberrant Notch-1 signaling activation in stem cells and of increased oxidative stress in lung cancer. The putative role of natural compounds with antioxidant properties is also described.
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Affiliation(s)
- Giuseppina Chiappara
- Institute of Translational Pharmacology (IFT), National Research Council (CNR), Palermo, via Ugo La Malfa 153, 90146, Italy
| | - Serena Di Vincenzo
- Institute of Translational Pharmacology (IFT), National Research Council (CNR), Palermo, via Ugo La Malfa 153, 90146, Italy
| | - Caterina Cascio
- Institute of Translational Pharmacology (IFT), National Research Council (CNR), Palermo, via Ugo La Malfa 153, 90146, Italy
| | - Elisabetta Pace
- Institute of Translational Pharmacology (IFT), National Research Council (CNR), Palermo, via Ugo La Malfa 153, 90146, Italy
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11
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Głowacka P, Oszajca K, Pudlarz A, Szemraj J, Witusik-Perkowska M. Postbiotics as Molecules Targeting Cellular Events of Aging Brain-The Role in Pathogenesis, Prophylaxis and Treatment of Neurodegenerative Diseases. Nutrients 2024; 16:2244. [PMID: 39064687 PMCID: PMC11279795 DOI: 10.3390/nu16142244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 07/01/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
Aging is the most prominent risk factor for neurodegeneration occurrence. The most common neurodegenerative diseases (NDs), Alzheimer's (AD) and Parkinson's (PD) diseases, are characterized by the incidence of proteinopathy, abnormal activation of glial cells, oxidative stress, neuroinflammation, impaired autophagy and cellular senescence excessive for the patient's age. Moreover, mitochondrial disfunction, epigenetic alterations and neurogenesis inhibition, together with increased blood-brain barrier permeability and gut dysbiosis, have been linked to ND pathogenesis. Since NDs still lack curative treatment, recent research has sought therapeutic options in restoring gut microbiota and supplementing probiotic bacteria-derived metabolites with beneficial action to the host-so called postbiotics. The current review focuses on literature explaining cellular mechanisms involved in ND pathogenesis and research addressing the impact that postbiotics as a whole mixture and particular metabolites, such as short-chain fatty acids (SCFAs), lactate, polyamines, polyphenols, tryptophan metabolites, exopolysaccharides and bacterial extracellular vesicles, have on the ageing-associated processes underlying ND occurrence. The review also discusses the issue of implementing postbiotics into ND prophylaxis and therapy, depicting them as compounds addressing senescence-triggered dysfunctions that are worth translating from bench to pharmaceutical market in response to "silver consumers" demands.
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Affiliation(s)
- Pola Głowacka
- Department of Medical Biochemistry, Medical University of Lodz, 6/8 Mazowiecka Str., 92-215 Lodz, Poland; (P.G.); (K.O.); (A.P.); (J.S.)
- International Doctoral School, Medical University of Lodz, 90-419 Lodz, Poland
| | - Katarzyna Oszajca
- Department of Medical Biochemistry, Medical University of Lodz, 6/8 Mazowiecka Str., 92-215 Lodz, Poland; (P.G.); (K.O.); (A.P.); (J.S.)
| | - Agnieszka Pudlarz
- Department of Medical Biochemistry, Medical University of Lodz, 6/8 Mazowiecka Str., 92-215 Lodz, Poland; (P.G.); (K.O.); (A.P.); (J.S.)
| | - Janusz Szemraj
- Department of Medical Biochemistry, Medical University of Lodz, 6/8 Mazowiecka Str., 92-215 Lodz, Poland; (P.G.); (K.O.); (A.P.); (J.S.)
| | - Monika Witusik-Perkowska
- Department of Medical Biochemistry, Medical University of Lodz, 6/8 Mazowiecka Str., 92-215 Lodz, Poland; (P.G.); (K.O.); (A.P.); (J.S.)
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12
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Zhuang X, Wang Q, Joost S, Ferrena A, Humphreys DT, Li Z, Blum M, Bastl K, Ding S, Landais Y, Zhan Y, Zhao Y, Chaligne R, Lee JH, Carrasco SE, Bhanot UK, Koche RP, Bott MJ, Katajisto P, Soto-Feliciano YM, Pisanic T, Thomas T, Zheng D, Wong ES, Tammela T. Aging limits stemness and tumorigenesis in the lung by reprogramming iron homeostasis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.23.600305. [PMID: 38979280 PMCID: PMC11230188 DOI: 10.1101/2024.06.23.600305] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
Aging is associated with a decline in the number and fitness of adult stem cells 1-4 . Aging-associated loss of stemness is posited to suppress tumorigenesis 5,6 , but this hypothesis has not been tested in vivo . Here, using physiologically aged autochthonous genetically engineered mouse models and primary cells 7,8 , we demonstrate aging suppresses lung cancer initiation and progression by degrading stemness of the alveolar cell of origin. This phenotype is underpinned by aging-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, leading to a functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1-lipocalin-2 axis or iron supplementation rescue stemness and promote tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1- lipocalin-2 axis is detrimental to young alveolar cells via induction of ferroptosis. We find that aging-associated DNA hypomethylation at specific enhancer sites associates with elevated NUPR1 expression, which is recapitulated in young alveolar cells by inhibition of DNA methylation. We uncover that aging drives a functional iron insufficiency, which leads to loss of stemness and tumorigenesis, but promotes resistance to ferroptosis. These findings have significant implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate in young individuals, revealing a critical window for such cancer prevention efforts.
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13
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Siewe N, Friedman A. Osteoporosis induced by cellular senescence: A mathematical model. PLoS One 2024; 19:e0303978. [PMID: 38805428 PMCID: PMC11132490 DOI: 10.1371/journal.pone.0303978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 05/03/2024] [Indexed: 05/30/2024] Open
Abstract
Osteoporosis is a disease characterized by loss of bone mass, where bones become fragile and more likely to fracture. Bone density begins to decrease at age 50, and a state of osteoporosis is defined by loss of more than 25%. Cellular senescence is a permanent arrest of normal cell cycle, while maintaining cell viability. The number of senescent cells increase with age. Since osteoporosis is an aging disease, it is natural to consider the question to what extend senescent cells induce bone density loss and osteoporosis. In this paper we use a mathematical model to address this question. We determine the percent of bone loss for men and women during age 50 to 100 years, and the results depend on the rate η of net formation of senescent cell, with η = 1 being the average rate. In the case η = 1, the model simulations are in agreement with empirical data. We also consider senolytic drugs, like fisetin and quercetin, that selectively eliminate senescent cells, and assess their efficacy in terms of reducing bone loss. For example, at η = 1, with estrogen hormonal therapy and early treatment with fisetin, bone density loss for women by age 75 is 23.4% (below osteoporosis), while with no treatment with fisetin it is 25.8% (osteoporosis); without even a treatment with estrogen hormonal therapy, bone loss of 25.3% occurs already at age 65.
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Affiliation(s)
- Nourridine Siewe
- School of Mathematics and Statistics, College of Science, Rochester Institute of Technology, Rochester, New York, United States of America
| | - Avner Friedman
- Department of Mathematics, The Ohio State University, Columbus, Ohio, United States of America
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14
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Li Y, Tian X, Luo J, Bao T, Wang S, Wu X. Molecular mechanisms of aging and anti-aging strategies. Cell Commun Signal 2024; 22:285. [PMID: 38790068 PMCID: PMC11118732 DOI: 10.1186/s12964-024-01663-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024] Open
Abstract
Aging is a complex and multifaceted process involving a variety of interrelated molecular mechanisms and cellular systems. Phenotypically, the biological aging process is accompanied by a gradual loss of cellular function and the systemic deterioration of multiple tissues, resulting in susceptibility to aging-related diseases. Emerging evidence suggests that aging is closely associated with telomere attrition, DNA damage, mitochondrial dysfunction, loss of nicotinamide adenine dinucleotide levels, impaired macro-autophagy, stem cell exhaustion, inflammation, loss of protein balance, deregulated nutrient sensing, altered intercellular communication, and dysbiosis. These age-related changes may be alleviated by intervention strategies, such as calorie restriction, improved sleep quality, enhanced physical activity, and targeted longevity genes. In this review, we summarise the key historical progress in the exploration of important causes of aging and anti-aging strategies in recent decades, which provides a basis for further understanding of the reversibility of aging phenotypes, the application prospect of synthetic biotechnology in anti-aging therapy is also prospected.
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Affiliation(s)
- Yumeng Li
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences; National Center of Technology Innovation for Synthetic Biology, Tianjin, China
| | - Xutong Tian
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences; National Center of Technology Innovation for Synthetic Biology, Tianjin, China
| | - Juyue Luo
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences; National Center of Technology Innovation for Synthetic Biology, Tianjin, China
| | - Tongtong Bao
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences; National Center of Technology Innovation for Synthetic Biology, Tianjin, China
| | - Shujin Wang
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Xin Wu
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences; National Center of Technology Innovation for Synthetic Biology, Tianjin, China.
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15
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Reddien PW. The purpose and ubiquity of turnover. Cell 2024; 187:2657-2681. [PMID: 38788689 DOI: 10.1016/j.cell.2024.04.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/19/2024] [Accepted: 04/24/2024] [Indexed: 05/26/2024]
Abstract
Turnover-constant component production and destruction-is ubiquitous in biology. Turnover occurs across organisms and scales, including for RNAs, proteins, membranes, macromolecular structures, organelles, cells, hair, feathers, nails, antlers, and teeth. For many systems, turnover might seem wasteful when degraded components are often fully functional. Some components turn over with shockingly high rates and others do not turn over at all, further making this process enigmatic. However, turnover can address fundamental problems by yielding powerful properties, including regeneration, rapid repair onset, clearance of unpredictable damage and errors, maintenance of low constitutive levels of disrepair, prevention of stable hazards, and transitions. I argue that trade-offs between turnover benefits and metabolic costs, combined with constraints on turnover, determine its presence and rates across distinct contexts. I suggest that the limits of turnover help explain aging and that turnover properties and the basis for its levels underlie this fundamental component of life.
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Affiliation(s)
- Peter W Reddien
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, MIT, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA.
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16
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Matveeva D, Kashirina D, Ezdakova M, Larina I, Buravkova L, Ratushnyy A. Senescence-Associated Alterations in Matrisome of Mesenchymal Stem Cells. Int J Mol Sci 2024; 25:5332. [PMID: 38791371 PMCID: PMC11120844 DOI: 10.3390/ijms25105332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 04/26/2024] [Accepted: 04/30/2024] [Indexed: 05/26/2024] Open
Abstract
The process of aging is intimately linked to alterations at the tissue and cellular levels. Currently, the role of senescent cells in the tissue microenvironment is still being investigated. Despite common characteristics, different cell populations undergo distinctive morphofunctional changes during senescence. Mesenchymal stem cells (MSCs) play a pivotal role in maintaining tissue homeostasis. A multitude of studies have examined alterations in the cytokine profile that determine their regulatory function. The extracellular matrix (ECM) of MSCs is a less studied aspect of their biology. It has been shown to modulate the activity of neighboring cells. Therefore, investigating age-related changes in the MSC matrisome is crucial for understanding the mechanisms of tissue niche ageing. This study conducted a broad proteomic analysis of the matrisome of separated fractions of senescent MSCs, including the ECM, conditioned medium (CM), and cell lysate. This is the first time such an analysis has been conducted. It has been established that there is a shift in production towards regulatory molecules and a significant downregulation of the main structural and adhesion proteins of the ECM, particularly collagens, fibulins, and fibrilins. Additionally, a decrease in the levels of cathepsins, galectins, S100 proteins, and other proteins with cytoprotective, anti-inflammatory, and antifibrotic properties has been observed. However, the level of inflammatory proteins and regulators of profibrotic pathways increases. Additionally, there is an upregulation of proteins that can directly cause prosenescent effects on microenvironmental cells (SERPINE1, THBS1, and GDF15). These changes confirm that senescent MSCs can have a negative impact on other cells in the tissue niche, not only through cytokine signals but also through the remodeled ECM.
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Affiliation(s)
| | | | | | | | | | - Andrey Ratushnyy
- Institute of Biomedical Problems, Russian Academy of Sciences, Khoroshevskoye Shosse, 76a, 123007 Moscow, Russia; (D.M.); (D.K.); (M.E.); (I.L.); (L.B.)
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17
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Jing X, Jia S, Teng M, Day BW, Afolayan AJ, Jarzembowski JA, Lin CW, Hessner MJ, Pritchard KA, Naylor S, Konduri GG, Teng RJ. Cellular Senescence Contributes to the Progression of Hyperoxic Bronchopulmonary Dysplasia. Am J Respir Cell Mol Biol 2024; 70:94-109. [PMID: 37874230 PMCID: PMC12042139 DOI: 10.1165/rcmb.2023-0038oc] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 10/23/2023] [Indexed: 10/25/2023] Open
Abstract
Oxidative stress, inflammation, and endoplasmic reticulum (ER) stress sequentially occur in bronchopulmonary dysplasia (BPD), and all result in DNA damage. When DNA damage becomes irreparable, tumor suppressors increase, followed by apoptosis or senescence. Although cellular senescence contributes to wound healing, its persistence inhibits growth. Therefore, we hypothesized that cellular senescence contributes to BPD progression. Human autopsy lungs were obtained. Sprague-Dawley rat pups exposed to 95% oxygen between Postnatal Day 1 (P1) and P10 were used as the BPD phenotype. N-acetyl-lysyltyrosylcysteine-amide (KYC), tauroursodeoxycholic acid (TUDCA), and Foxo4 dri were administered intraperitoneally to mitigate myeloperoxidase oxidant generation, ER stress, and cellular senescence, respectively. Lungs were examined by histology, transcriptomics, and immunoblotting. Cellular senescence increased in rat and human BPD lungs, as evidenced by increased oxidative DNA damage, tumor suppressors, GL-13 stain, and inflammatory cytokines with decreased cell proliferation and lamin B expression. Cellular senescence-related transcripts in BPD rat lungs were enriched at P10 and P21. Single-cell RNA sequencing showed increased cellular senescence in several cell types, including type 2 alveolar cells. In addition, Foxo4-p53 binding increased in BPD rat lungs. Daily TUDCA or KYC, administered intraperitoneally, effectively decreased cellular senescence, improved alveolar complexity, and partially maintained the numbers of type 2 alveolar cells. Foxo4 dri administered at P4, P6, P8, and P10 led to outcomes similar to TUDCA and KYC. Our data suggest that cellular senescence plays an essential role in BPD after initial inducement by hyperoxia. Reducing myeloperoxidase toxic oxidant production, ER stress, and attenuating cellular senescence are potential therapeutic strategies for halting BPD progression.
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Affiliation(s)
- Xigang Jing
- Department of Pediatrics
- Children's Research Institute
| | - Shuang Jia
- Department of Pediatrics
- Children's Research Institute
| | - Maggie Teng
- Department of Anthropology, Washington University in St. Louis, St. Louis, Missouri; and
| | | | | | | | - Chien-Wei Lin
- Division of Biostatistics, Institute for Health and Equity, and
| | | | - Kirkwood A Pritchard
- Children's Research Institute
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
- ReNeuroGen LLC, Milwaukee, Wisconsin
| | | | | | - Ru-Jeng Teng
- Department of Pediatrics
- Children's Research Institute
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18
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Zhao H, Fan S, Sun J. Delayed Wound Healing in the Elderly and a New Therapeutic Target: CD271. Curr Stem Cell Res Ther 2024; 19:316-323. [PMID: 37016526 DOI: 10.2174/1574888x18666230403083603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 11/21/2022] [Accepted: 12/29/2022] [Indexed: 04/06/2023]
Abstract
With the development of society, the global population is showing a trend of aging. It is well known that age is one of the factors affecting wound healing. Aging compromises the normal physiological process of wound healing, such as the change of skin structure, the decrease of growth factors, the deceleration of cell proliferation, and the weakening of migration ability, hence delaying wound healing. At present, research in adult stem cell-related technology and its derived regenerative medicine provides a novel idea for the treatment of senile wounds. Studies have confirmed that CD271 (P75 neurotropism receptor/P75NTR)-positive cells (CD271+ cells) are a kind of stem cells with a stronger ability of proliferation, differentiation, migration and secretion than CD271 negative (CD271- cells). Meanwhile, the total amount and distribution of CD271 positive cells in different ages of skin are also different, which may be related to the delayed wound healing of aging skin. Therefore, this article reviews the relationship between CD271+ cells and senile wounds and discusses a new scheme for the treatment of senile wounds.
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Affiliation(s)
- Hongqing Zhao
- Department of Plastic Surgery, Jinzhou Medical University, Jinzhou, 121001, Liaoning Province, China
- Department of Burns and Plastic Surgery, The Fourth Medical Center of Chinese PLA General Hospital, Beijing, 100048, China
| | - Sirui Fan
- Department of Plastic Surgery, Jinzhou Medical University, Jinzhou, 121001, Liaoning Province, China
| | - Jiachen Sun
- Department of Burns and Plastic Surgery, The Fourth Medical Center of Chinese PLA General Hospital, Beijing, 100048, China
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19
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Rodriguez-Colman MJ, Dansen TB, Burgering BMT. FOXO transcription factors as mediators of stress adaptation. Nat Rev Mol Cell Biol 2024; 25:46-64. [PMID: 37710009 DOI: 10.1038/s41580-023-00649-0] [Citation(s) in RCA: 51] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/01/2023] [Indexed: 09/16/2023]
Abstract
The forkhead box protein O (FOXO, consisting of FOXO1, FOXO3, FOXO4 and FOXO6) transcription factors are the mammalian orthologues of Caenorhabditis elegans DAF-16, which gained notoriety for its capability to double lifespan in the absence of daf-2 (the gene encoding the worm insulin receptor homologue). Since then, research has provided many mechanistic details on FOXO regulation and FOXO activity. Furthermore, conditional knockout experiments have provided a wealth of data as to how FOXOs control development and homeostasis at the organ and organism levels. The lifespan-extending capabilities of DAF-16/FOXO are highly correlated with their ability to induce stress response pathways. Exogenous and endogenous stress, such as cellular redox stress, are considered the main drivers of the functional decline that characterizes ageing. Functional decline often manifests as disease, and decrease in FOXO activity indeed negatively impacts on major age-related diseases such as cancer and diabetes. In this context, the main function of FOXOs is considered to preserve cellular and organismal homeostasis, through regulation of stress response pathways. Paradoxically, the same FOXO-mediated responses can also aid the survival of dysfunctional cells once these eventually emerge. This general property to control stress responses may underlie the complex and less-evident roles of FOXOs in human lifespan as opposed to model organisms such as C. elegans.
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Affiliation(s)
| | - Tobias B Dansen
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
| | - Boudewijn M T Burgering
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands.
- Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands.
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20
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Rowbotham SP, Pessina P, Garcia-de-Alba C, Jensen J, Nguyen Y, Yoon J, Li J, Wong IG, Fahey C, Moye AL, Chongsaritsinsuk J, Bronson R, Ho Sui SJ, Kim CF. Age-associated H3K9me2 loss alters the regenerative equilibrium between murine lung alveolar and bronchiolar progenitors. Dev Cell 2023; 58:2974-2991.e6. [PMID: 37977149 PMCID: PMC10873032 DOI: 10.1016/j.devcel.2023.10.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 04/18/2023] [Accepted: 10/24/2023] [Indexed: 11/19/2023]
Abstract
The lung contains multiple progenitor cell types, but how their responses are choreographed during injury repair and whether this changes with age is poorly understood. We report that histone H3 lysine 9 di-methylation (H3K9me2), mediated by the methyltransferase G9a, regulates the dynamics of distal lung epithelial progenitor cells and that this regulation deteriorates with age. In aged mouse lungs, H3K9me2 loss coincided with fewer alveolar type 2 (AT2) cell progenitors and reduced alveolar regeneration but increased the frequency and activity of multipotent bronchioalveolar stem cells (BASCs) and bronchiolar progenitor club cells. H3K9me2 depletion in young mice decreased AT2 progenitor activity and impaired alveolar injury repair. Conversely, H3K9me2 depletion increased chromatin accessibility of bronchiolar cell genes, increased BASC frequency, and accelerated bronchiolar cell injury repair. These findings indicate that during aging, the epigenetic regulation that coordinates lung progenitor cells' regenerative responses becomes dysregulated, aiding our understanding of age-related susceptibility to lung disease.
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Affiliation(s)
- Samuel P Rowbotham
- Stem Cell Program, Division of Hematology/Oncology and Pulmonary & Respiratory Diseases, Children's Hospital Boston, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
| | - Patrizia Pessina
- Stem Cell Program, Division of Hematology/Oncology and Pulmonary & Respiratory Diseases, Children's Hospital Boston, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Carolina Garcia-de-Alba
- Stem Cell Program, Division of Hematology/Oncology and Pulmonary & Respiratory Diseases, Children's Hospital Boston, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Jake Jensen
- Stem Cell Program, Division of Hematology/Oncology and Pulmonary & Respiratory Diseases, Children's Hospital Boston, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Yvonne Nguyen
- Stem Cell Program, Division of Hematology/Oncology and Pulmonary & Respiratory Diseases, Children's Hospital Boston, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Joon Yoon
- Harvard Chan Bioinformatics Core, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115
| | - Jingyun Li
- Stem Cell Program, Division of Hematology/Oncology and Pulmonary & Respiratory Diseases, Children's Hospital Boston, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Irene G Wong
- Stem Cell Program, Division of Hematology/Oncology and Pulmonary & Respiratory Diseases, Children's Hospital Boston, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Caroline Fahey
- Stem Cell Program, Division of Hematology/Oncology and Pulmonary & Respiratory Diseases, Children's Hospital Boston, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Aaron L Moye
- Stem Cell Program, Division of Hematology/Oncology and Pulmonary & Respiratory Diseases, Children's Hospital Boston, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Joann Chongsaritsinsuk
- Stem Cell Program, Division of Hematology/Oncology and Pulmonary & Respiratory Diseases, Children's Hospital Boston, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Roderick Bronson
- Rodent Histopathology Core, Harvard Medical School, Boston, MA 02115, USA
| | - Shannan J Ho Sui
- Harvard Chan Bioinformatics Core, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115
| | - Carla F Kim
- Stem Cell Program, Division of Hematology/Oncology and Pulmonary & Respiratory Diseases, Children's Hospital Boston, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
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21
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Cai Y, Xiong M, Xin Z, Liu C, Ren J, Yang X, Lei J, Li W, Liu F, Chu Q, Zhang Y, Yin J, Ye Y, Liu D, Fan Y, Sun S, Jing Y, Zhao Q, Zhao L, Che S, Zheng Y, Yan H, Ma S, Wang S, Izpisua Belmonte JC, Qu J, Zhang W, Liu GH. Decoding aging-dependent regenerative decline across tissues at single-cell resolution. Cell Stem Cell 2023; 30:1674-1691.e8. [PMID: 37898124 DOI: 10.1016/j.stem.2023.09.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 08/28/2023] [Accepted: 09/27/2023] [Indexed: 10/30/2023]
Abstract
Regeneration across tissues and organs exhibits significant variation throughout the body and undergoes a progressive decline with age. To decode the relationships between aging and regenerative capacity, we conducted a comprehensive single-cell transcriptome analysis of regeneration in eight tissues from young and aged mice. We employed diverse analytical models to study tissue regeneration and unveiled the intricate cellular and molecular mechanisms underlying the attenuated regenerative processes observed in aged tissues. Specifically, we identified compromised stem cell mobility and inadequate angiogenesis as prominent contributors to this age-associated decline in regenerative capacity. Moreover, we discovered a unique subset of Arg1+ macrophages that were activated in young tissues but suppressed in aged regenerating tissues, suggesting their important role in age-related immune response disparities during regeneration. This study provides a comprehensive single-cell resource for identifying potential targets for interventions aimed at enhancing regenerative outcomes in the aging population.
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Affiliation(s)
- Yusheng Cai
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Muzhao Xiong
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zijuan Xin
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Chengyu Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Jie Ren
- Key Laboratory of RNA Science and Engineering, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; Aging Biomarker Consortium, China
| | - Xiying Yang
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Weifang Medical University, Weifang 261053, China
| | - Jinghui Lei
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Wei Li
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Feifei Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Qun Chu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Yiyuan Zhang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Jian Yin
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Yanxia Ye
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Dingyi Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Yanling Fan
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China
| | - Shuhui Sun
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Yaobin Jing
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Qian Zhao
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Liyun Zhao
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Shanshan Che
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yandong Zheng
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Haoteng Yan
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Shuai Ma
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; Aging Biomarker Consortium, China
| | - Si Wang
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; Aging Biomarker Consortium, China
| | | | - Jing Qu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; Aging Biomarker Consortium, China.
| | - Weiqi Zhang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Aging Biomarker Consortium, China.
| | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; Aging Biomarker Consortium, China.
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22
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Gabarró‐Solanas R, Davaatseren A, Kleifeld J, Kepčija T, Köcher T, Giralt A, Crespo‐Enríquez I, Urbán N. Adult neural stem cells and neurogenesis are resilient to intermittent fasting. EMBO Rep 2023; 24:e57268. [PMID: 37987220 PMCID: PMC10702802 DOI: 10.15252/embr.202357268] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 09/13/2023] [Accepted: 10/30/2023] [Indexed: 11/22/2023] Open
Abstract
Intermittent fasting (IF) is a promising strategy to counteract ageing shown to increase the number of adult-born neurons in the dentate gyrus of mice. However, it is unclear which steps of the adult neurogenesis process are regulated by IF. The number of adult neural stem cells (NSCs) decreases with age in an activation-dependent manner and, to counteract this loss, adult NSCs are found in a quiescent state which ensures their long-term maintenance. We aimed to determine if and how IF affects adult NSCs in the hippocampus. To identify the effects of every-other-day IF on NSCs and all following steps in the neurogenic lineage, we combined fasting with lineage tracing and label retention assays. We show here that IF does not affect NSC activation or maintenance and, that contrary to previous reports, IF does not increase neurogenesis. The same results are obtained regardless of strain, sex, diet length, tamoxifen administration or new-born neuron identification method. Our data suggest that NSCs maintain homeostasis upon IF and that this intervention is not a reliable strategy to increase adult neurogenesis.
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Affiliation(s)
- Rut Gabarró‐Solanas
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)Vienna BioCenter (VBC)ViennaAustria
- Vienna BioCenter PhD ProgramDoctoral School of the University of Vienna and Medical University of ViennaViennaAustria
| | - Amarbayasgalan Davaatseren
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)Vienna BioCenter (VBC)ViennaAustria
| | - Justus Kleifeld
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)Vienna BioCenter (VBC)ViennaAustria
- Vienna BioCenter PhD ProgramDoctoral School of the University of Vienna and Medical University of ViennaViennaAustria
| | - Tatjana Kepčija
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)Vienna BioCenter (VBC)ViennaAustria
| | | | - Albert Giralt
- Departament de Biomedicina, Facultat de Medicina, Institut de NeurociènciesUniversitat de BarcelonaBarcelonaSpain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)BarcelonaSpain
- Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED)BarcelonaSpain
- Production and Validation Center of Advanced Therapies (Creatio), Faculty of Medicine and Health ScienceUniversity of BarcelonaBarcelonaSpain
| | - Iván Crespo‐Enríquez
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)Vienna BioCenter (VBC)ViennaAustria
| | - Noelia Urbán
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)Vienna BioCenter (VBC)ViennaAustria
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23
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Santos BF, Grenho I, Martel PJ, Ferreira BI, Link W. FOXO family isoforms. Cell Death Dis 2023; 14:702. [PMID: 37891184 PMCID: PMC10611805 DOI: 10.1038/s41419-023-06177-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 06/30/2023] [Accepted: 09/26/2023] [Indexed: 10/29/2023]
Abstract
FOXO family of proteins are transcription factors involved in many physiological and pathological processes including cellular homeostasis, stem cell maintenance, cancer, metabolic, and cardiovascular diseases. Genetic evidence has been accumulating to suggest a prominent role of FOXOs in lifespan regulation in animal systems from hydra, C elegans, Drosophila, and mice. Together with the observation that FOXO3 is the second most replicated gene associated with extreme human longevity suggests that pharmacological targeting of FOXO proteins can be a promising approach to treat cancer and other age-related diseases and extend life and health span. However, due to the broad range of cellular functions of the FOXO family members FOXO1, 3, 4, and 6, isoform-specific targeting of FOXOs might lead to greater benefits and cause fewer side effects. Therefore, a deeper understanding of the common and specific features of these proteins as well as their redundant and specific functions in our cells represents the basis of specific targeting strategies. In this review, we provide an overview of the evolution, structure, function, and disease-relevance of each of the FOXO family members.
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Affiliation(s)
- Bruno F Santos
- Algarve Biomedical Center Research Institute-ABC-RI, University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal
- Faculty of Medicine and Biomedical Sciences, University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal
- Centro Hospitalar Universitário do Algarve (CHUA). Rua Leão Penedo, 8000-386, Faro, Portugal
| | - Inês Grenho
- Algarve Biomedical Center Research Institute-ABC-RI, University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal
- Faculty of Medicine and Biomedical Sciences, University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal
| | - Paulo J Martel
- Center for Health Technology and Services Research (CINTESIS)@RISE, University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal
| | - Bibiana I Ferreira
- Algarve Biomedical Center Research Institute-ABC-RI, University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal.
- Algarve Biomedical Center (ABC), University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal.
- Faculty of Medicine and Biomedical Sciences, University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal.
| | - Wolfgang Link
- Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM). Arturo Duperier 4, 28029, Madrid, Spain.
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24
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Martin DE, Cadar AN, Bartley JM. Old drug, new tricks: the utility of metformin in infection and vaccination responses to influenza and SARS-CoV-2 in older adults. FRONTIERS IN AGING 2023; 4:1272336. [PMID: 37886013 PMCID: PMC10598609 DOI: 10.3389/fragi.2023.1272336] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 10/02/2023] [Indexed: 10/28/2023]
Abstract
In the face of global pathogens such as influenza (flu) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), strategies beyond standard vaccines and virus-specific treatments are critically needed for older populations who are more susceptible to severe disease and death from these infections due to age-related immune dysregulation. Thus, complimentary therapeutics are needed to address the increased risk of complications and death in older adults. Metformin, an FDA approved diabetes drug, is an attractive therapeutic candidate to improve immune defenses and resilience in older adults facing viral challenge. Metformin is already a candidate anti-aging drug, but its benefits have potential to span beyond this and improve specific immune responses. Metformin can target multiple aging hallmarks as well as directly impact innate and adaptive immune cell subsets. Both retrospective and prospective studies have demonstrated metformin's efficacy in improving outcomes after SARS-CoV-2 or flu infections. Moreover, evidence from clinical trials has also suggested that metformin treatment can improve vaccination responses. In totality, these findings suggest that metformin can improve age-related declines in immunological resilience. Strategies to improve outcomes after infection or improve vaccine-induced protection are invaluable for older adults. Moreover, the ability to repurpose an already FDA approved drug has significant advantages in terms of necessary time and resources. Thus, metformin has great potential as a therapeutic to improve age-related immune dysregulation during flu and SARS-CoV-2 infections and should be further explored to confirm its ability to improve overall immunological resilience in older adults.
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25
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Sharma R, Diwan B. Lipids and the hallmarks of ageing: From pathology to interventions. Mech Ageing Dev 2023; 215:111858. [PMID: 37652278 DOI: 10.1016/j.mad.2023.111858] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 08/21/2023] [Accepted: 08/28/2023] [Indexed: 09/02/2023]
Abstract
Lipids are critical structural and functional architects of cellular homeostasis. Change in systemic lipid profile is a clinical indicator of underlying metabolic pathologies, and emerging evidence is now defining novel roles of lipids in modulating organismal ageing. Characteristic alterations in lipid metabolism correlate with age, and impaired systemic lipid profile can also accelerate the development of ageing phenotype. The present work provides a comprehensive review of the extent of lipids as regulators of the modern hallmarks of ageing viz., cellular senescence, chronic inflammation, gut dysbiosis, telomere attrition, genome instability, proteostasis and autophagy, epigenetic alterations, and stem cells dysfunctions. Current evidence on the modulation of each of these hallmarks has been discussed with emphasis on inherent age-dependent deficiencies in lipid metabolism as well as exogenous lipid changes. There appears to be sufficient evidence to consider impaired lipid metabolism as key driver of the ageing process although much of knowledge is yet fragmented. Considering dietary lipids, the type and quantity of lipids in the diet is a significant, but often overlooked determinant that governs the effects of lipids on ageing. Further research using integrative approaches amidst the known aging hallmarks is highly desirable for understanding the therapeutics of lipids associated with ageing.
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Affiliation(s)
- Rohit Sharma
- Nutrigerontology Laboratory, Faculty of Applied Sciences & Biotechnology, Shoolini University, Solan 173229, India.
| | - Bhawna Diwan
- Nutrigerontology Laboratory, Faculty of Applied Sciences & Biotechnology, Shoolini University, Solan 173229, India
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26
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Reece AS, Hulse GK. Perturbation of 3D nuclear architecture, epigenomic dysregulation and aging, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 1-aging and epigenomics. Front Psychiatry 2023; 14:1182535. [PMID: 37732074 PMCID: PMC10507876 DOI: 10.3389/fpsyt.2023.1182535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 08/07/2023] [Indexed: 09/22/2023] Open
Abstract
Much recent attention has been directed toward the spatial organization of the cell nucleus and the manner in which three-dimensional topologically associated domains and transcription factories are epigenetically coordinated to precisely bring enhancers into close proximity with promoters to control gene expression. Twenty lines of evidence robustly implicate cannabinoid exposure with accelerated organismal and cellular aging. Aging has recently been shown to be caused by increased DNA breaks. These breaks rearrange and maldistribute the epigenomic machinery to weaken and reverse cellular differentiation, cause genome-wide DNA demethylation, reduce gene transcription, and lead to the inhibition of developmental pathways, which contribute to the progressive loss of function and chronic immune stimulation that characterize cellular aging. Both cell lineage-defining superenhancers and the superanchors that control them are weakened. Cannabis exposure phenocopies the elements of this process and reproduces DNA and chromatin breakages, reduces the DNA, RNA protein and histone synthesis, interferes with the epigenomic machinery controlling both DNA and histone modifications, induces general DNA hypomethylation, and epigenomically disrupts both the critical boundary elements and the cohesin motors that create chromatin loops. This pattern of widespread interference with developmental programs and relative cellular dedifferentiation (which is pro-oncogenic) is reinforced by cannabinoid impairment of intermediate metabolism (which locks in the stem cell-like hyper-replicative state) and cannabinoid immune stimulation (which perpetuates and increases aging and senescence programs, DNA damage, DNA hypomethylation, genomic instability, and oncogenesis), which together account for the diverse pattern of teratologic and carcinogenic outcomes reported in recent large epidemiologic studies in Europe, the USA, and elsewhere. It also accounts for the prominent aging phenotype observed clinically in long-term cannabis use disorder and the 20 characteristics of aging that it manifests. Increasing daily cannabis use, increasing use in pregnancy, and exponential dose-response effects heighten the epidemiologic and clinical urgency of these findings. Together, these findings indicate that cannabinoid genotoxicity and epigenotoxicity are prominent features of cannabis dependence and strongly indicate coordinated multiomics investigations of cannabinoid genome-epigenome-transcriptome-metabolome, chromatin conformation, and 3D nuclear architecture. Considering the well-established exponential dose-response relationships, the diversity of cannabinoids, and the multigenerational nature of the implications, great caution is warranted in community cannabinoid penetration.
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Affiliation(s)
- Albert Stuart Reece
- Division of Psychiatry, University of Western Australia, Crawley, WA, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
| | - Gary Kenneth Hulse
- Division of Psychiatry, University of Western Australia, Crawley, WA, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
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27
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Vun J, Iqbal N, Jones E, Ganguly P. Anti-Aging Potential of Platelet Rich Plasma (PRP): Evidence from Osteoarthritis (OA) and Applications in Senescence and Inflammaging. Bioengineering (Basel) 2023; 10:987. [PMID: 37627872 PMCID: PMC10451843 DOI: 10.3390/bioengineering10080987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 07/21/2023] [Accepted: 08/15/2023] [Indexed: 08/27/2023] Open
Abstract
Aging and age-related changes impact the quality of life (QOL) in elderly with a decline in movement, cognitive abilities and increased vulnerability towards age-related diseases (ARDs). One of the key contributing factors is cellular senescence, which is triggered majorly by DNA damage response (DDR). Accumulated senescent cells (SCs) release senescence-associated secretory phenotype (SASP), which includes pro-inflammatory cytokines, matrix metalloproteinases (MMPs), lipids and chemokines that are detrimental to the surrounding tissues. Chronic low-grade inflammation in the elderly or inflammaging is also associated with cellular senescence and contributes to ARDs. The literature from the last decade has recorded the use of platelet rich plasma (PRP) to combat senescence and inflammation, alleviate pain as an analgesic, promote tissue regeneration and repair via angiogenesis-all of which are essential in anti-aging and tissue regeneration strategies. In the last few decades, platelet-rich plasma (PRP) has been used as an anti-aging treatment option for dermatological applications and with great interest in tissue regeneration for orthopaedic applications, especially in osteoarthritis (OA). In this exploration, we connect the intricate relationship between aging, ARDs, senescence and inflammation and delve into PRP's properties and potential benefits. We conduct a comparative review of the current literature on PRP treatment strategies, paying particular attention to the instances strongly linked to ARDs. Finally, upon careful consideration of this interconnected information in the context of aging, we suggest a prospective role for PRP in developing anti-aging therapeutic strategies.
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Affiliation(s)
- James Vun
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds LS9 7TF, UK; (J.V.); (E.J.)
- Leeds Orthopaedic & Trauma Sciences, Leeds General Infirmary, University of Leeds, Leeds LS97TF, UK
| | - Neelam Iqbal
- School of Chemical and Process Engineering, University of Leeds, Leeds LS2 9JT, UK;
| | - Elena Jones
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds LS9 7TF, UK; (J.V.); (E.J.)
| | - Payal Ganguly
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds LS9 7TF, UK; (J.V.); (E.J.)
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28
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Ribarski-Chorev I, Schudy G, Strauss C, Schlesinger S. Short heat shock has a long-term effect on mesenchymal stem cells' transcriptome. iScience 2023; 26:107305. [PMID: 37529103 PMCID: PMC10387575 DOI: 10.1016/j.isci.2023.107305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 05/23/2023] [Accepted: 07/03/2023] [Indexed: 08/03/2023] Open
Abstract
The adverse effects of heat stress (HS) on physiological systems are well documented, yet the underlying molecular mechanisms behind it remain poorly understood. To address this knowledge gap, we conducted a comprehensive investigation into the impact of HS on mesenchymal stem cells (MSCs), focusing on their morphology, phenotype, proliferative capacity, and fate determination. Our in-depth analysis of the MSCs' transcriptome revealed a significant influence of HS on the transcriptional landscape. Notably, even after a short period of stress, we observed a persistent alteration in cell identity, potentially mediated by the activation of bivalent genes. Furthermore, by comparing the differentially expressed genes following short HS with their transcriptional state after recovery, we identified the transient upregulation of MLL and other histone modifiers, providing a potential mechanistic explanation for the stable activation of bivalent genes. This could be used to predict and modify the long-term effect of HS on cell identity.
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Affiliation(s)
- Ivana Ribarski-Chorev
- The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 7610001, Israel
| | - Gisele Schudy
- The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 7610001, Israel
| | - Carmit Strauss
- The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 7610001, Israel
| | - Sharon Schlesinger
- The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 7610001, Israel
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29
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Lathe R, St Clair D. Programmed ageing: decline of stem cell renewal, immunosenescence, and Alzheimer's disease. Biol Rev Camb Philos Soc 2023; 98:1424-1458. [PMID: 37068798 DOI: 10.1111/brv.12959] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 03/27/2023] [Accepted: 03/30/2023] [Indexed: 04/19/2023]
Abstract
The characteristic maximum lifespan varies enormously across animal species from a few hours to hundreds of years. This argues that maximum lifespan, and the ageing process that itself dictates lifespan, are to a large extent genetically determined. Although controversial, this is supported by firm evidence that semelparous species display evolutionarily programmed ageing in response to reproductive and environmental cues. Parabiosis experiments reveal that ageing is orchestrated systemically through the circulation, accompanied by programmed changes in hormone levels across a lifetime. This implies that, like the circadian and circannual clocks, there is a master 'clock of age' (circavital clock) located in the limbic brain of mammals that modulates systemic changes in growth factor and hormone secretion over the lifespan, as well as systemic alterations in gene expression as revealed by genomic methylation analysis. Studies on accelerated ageing in mice, as well as human longevity genes, converge on evolutionarily conserved fibroblast growth factors (FGFs) and their receptors, including KLOTHO, as well as insulin-like growth factors (IGFs) and steroid hormones, as key players mediating the systemic effects of ageing. Age-related changes in these and multiple other factors are inferred to cause a progressive decline in tissue maintenance through failure of stem cell replenishment. This most severely affects the immune system, which requires constant renewal from bone marrow stem cells. Age-related immune decline increases risk of infection whereas lifespan can be extended in germfree animals. This and other evidence suggests that infection is the major cause of death in higher organisms. Immune decline is also associated with age-related diseases. Taking the example of Alzheimer's disease (AD), we assess the evidence that AD is caused by immunosenescence and infection. The signature protein of AD brain, Aβ, is now known to be an antimicrobial peptide, and Aβ deposits in AD brain may be a response to infection rather than a cause of disease. Because some cognitively normal elderly individuals show extensive neuropathology, we argue that the location of the pathology is crucial - specifically, lesions to limbic brain are likely to accentuate immunosenescence, and could thus underlie a vicious cycle of accelerated immune decline and microbial proliferation that culminates in AD. This general model may extend to other age-related diseases, and we propose a general paradigm of organismal senescence in which declining stem cell proliferation leads to programmed immunosenescence and mortality.
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Affiliation(s)
- Richard Lathe
- Division of Infection Medicine, Chancellor's Building, University of Edinburgh Medical School, Little France, Edinburgh, EH16 4SB, UK
| | - David St Clair
- Institute of Medical Sciences, School of Medicine, University of Aberdeen, Aberdeen, AB25 2ZD, UK
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30
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Reece AS, Bennett K, Hulse GK. Cannabis- and Substance-Related Carcinogenesis in Europe: A Lagged Causal Inferential Panel Regression Study. J Xenobiot 2023; 13:323-385. [PMID: 37489337 PMCID: PMC10366890 DOI: 10.3390/jox13030024] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 07/10/2023] [Accepted: 07/10/2023] [Indexed: 07/26/2023] Open
Abstract
Recent European data facilitate an epidemiological investigation of the controversial cannabis-cancer relationship. Of particular concern were prior findings associating high-dose cannabis use with reproductive problems and potential genetic impacts. Cancer incidence data age-standardised to the world population was obtained from the European Cancer Information System 2000-2020 and many European national cancer registries. Drug use data were obtained from the European Monitoring Centre for Drugs and Drug Addiction. Alcohol and tobacco consumption was sourced from the WHO. Median household income was taken from the World bank. Cancer rates in high-cannabis-use countries were significantly higher than elsewhere (β-estimate = 0.4165, p = 3.54 × 10-115). Eighteen of forty-one cancers (42,675 individual rates) were significantly associated with cannabis exposure at bivariate analysis. Twenty-five cancers were linked in inverse-probability-weighted multivariate models. Temporal lagging in panel models intensified these effects. In multivariable models, cannabis was a more powerful correlate of cancer incidence than tobacco or alcohol. Reproductive toxicity was evidenced by the involvement of testis, ovary, prostate and breast cancers and because some of the myeloid and lymphoid leukaemias implicated occur in childhood, indicating inherited intergenerational genotoxicity. Cannabis is a more important carcinogen than tobacco and alcohol and fulfills epidemiological qualitative and quantitative criteria for causality for 25/41 cancers. Reproductive and transgenerational effects are prominent. These findings confirm the clinical and epidemiological salience of cannabis as a major multigenerational community carcinogen.
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Affiliation(s)
- Albert Stuart Reece
- Division of Psychiatry, University of Western Australia, Crawley, WA 6009, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia
| | - Kellie Bennett
- Division of Psychiatry, University of Western Australia, Crawley, WA 6009, Australia
- Faculty of Health Sciences, Curtin University, 208 Kent St., Bentley, Perth, WA 6102, Australia
| | - Gary Kenneth Hulse
- Division of Psychiatry, University of Western Australia, Crawley, WA 6009, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia
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31
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Ya J, Bayraktutan U. Vascular Ageing: Mechanisms, Risk Factors, and Treatment Strategies. Int J Mol Sci 2023; 24:11538. [PMID: 37511296 PMCID: PMC10380571 DOI: 10.3390/ijms241411538] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 07/10/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
Ageing constitutes the biggest risk factor for poor health and adversely affects the integrity and function of all the cells, tissues, and organs in the human body. Vascular ageing, characterised by vascular stiffness, endothelial dysfunction, increased oxidative stress, chronic low-grade inflammation, and early-stage atherosclerosis, may trigger or exacerbate the development of age-related vascular diseases, which each year contribute to more than 3.8 million deaths in Europe alone and necessitate a better understanding of the mechanisms involved. To this end, a large number of recent preclinical and clinical studies have focused on the exponential accumulation of senescent cells in the vascular system and paid particular attention to the specific roles of senescence-associated secretory phenotype, proteostasis dysfunction, age-mediated modulation of certain microRNA (miRNAs), and the contribution of other major vascular risk factors, notably diabetes, hypertension, or smoking, to vascular ageing in the elderly. The data generated paved the way for the development of various senotherapeutic interventions, ranging from the application of synthetic or natural senolytics and senomorphics to attempt to modify lifestyle, control diet, and restrict calorie intake. However, specific guidelines, considering the severity and characteristics of vascular ageing, need to be established before widespread use of these agents. This review briefly discusses the molecular and cellular mechanisms of vascular ageing and summarises the efficacy of widely studied senotherapeutics in the context of vascular ageing.
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Affiliation(s)
- Jingyuan Ya
- Academic Unit of Mental Health and Clinical Neuroscience, Nottingham University, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Ulvi Bayraktutan
- Academic Unit of Mental Health and Clinical Neuroscience, Nottingham University, Queen's Medical Centre, Nottingham NG7 2UH, UK
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32
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Molinaro C, Scalise M, Leo I, Salerno L, Sabatino J, Salerno N, De Rosa S, Torella D, Cianflone E, Marino F. Polarizing Macrophage Functional Phenotype to Foster Cardiac Regeneration. Int J Mol Sci 2023; 24:10747. [PMID: 37445929 DOI: 10.3390/ijms241310747] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/22/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
There is an increasing interest in understanding the connection between the immune and cardiovascular systems, which are highly integrated and communicate through finely regulated cross-talking mechanisms. Recent evidence has demonstrated that the immune system does indeed have a key role in the response to cardiac injury and in cardiac regeneration. Among the immune cells, macrophages appear to have a prominent role in this context, with different subtypes described so far that each have a specific influence on cardiac remodeling and repair. Similarly, there are significant differences in how the innate and adaptive immune systems affect the response to cardiac damage. Understanding all these mechanisms may have relevant clinical implications. Several studies have already demonstrated that stem cell-based therapies support myocardial repair. However, the exact role that cardiac macrophages and their modulation may have in this setting is still unclear. The current need to decipher the dual role of immunity in boosting both heart injury and repair is due, at least for a significant part, to unresolved questions related to the complexity of cardiac macrophage phenotypes. The aim of this review is to provide an overview on the role of the immune system, and of macrophages in particular, in the response to cardiac injury and to outline, through the modulation of the immune response, potential novel therapeutic strategies for cardiac regeneration.
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Affiliation(s)
- Claudia Molinaro
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy
| | - Mariangela Scalise
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
| | - Isabella Leo
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
| | - Luca Salerno
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
| | - Jolanda Sabatino
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
| | - Nadia Salerno
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
| | - Salvatore De Rosa
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy
| | - Daniele Torella
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
| | - Eleonora Cianflone
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy
| | - Fabiola Marino
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
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Farahzadi R, Valipour B, Montazersaheb S, Fathi E. Targeting the stem cell niche micro-environment as therapeutic strategies in aging. Front Cell Dev Biol 2023; 11:1162136. [PMID: 37274742 PMCID: PMC10235764 DOI: 10.3389/fcell.2023.1162136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 05/02/2023] [Indexed: 06/06/2023] Open
Abstract
Adult stem cells (ASCs) reside throughout the body and support various tissue. Owing to their self-renewal capacity and differentiation potential, ASCs have the potential to be used in regenerative medicine. Their survival, quiescence, and activation are influenced by specific signals within their microenvironment or niche. In better words, the stem cell function is significantly influenced by various extrinsic signals derived from the niche. The stem cell niche is a complex and dynamic network surrounding stem cells that plays a crucial role in maintaining stemness. Studies on stem cell niche have suggested that aged niche contributes to the decline in stem cell function. Notably, functional loss of stem cells is highly associated with aging and age-related disorders. The stem cell niche is comprised of complex interactions between multiple cell types. Over the years, essential aspects of the stem cell niche have been revealed, including cell-cell contact, extracellular matrix interaction, soluble signaling factors, and biochemical and biophysical signals. Any alteration in the stem cell niche causes cell damage and affects the regenerative properties of the stem cells. A pristine stem cell niche might be essential for the proper functioning of stem cells and the maintenance of tissue homeostasis. In this regard, niche-targeted interventions may alleviate problems associated with aging in stem cell behavior. The purpose of this perspective is to discuss recent findings in the field of stem cell aging, heterogeneity of stem cell niches, and impact of age-related changes on stem cell behavior. We further focused on how the niche affects stem cells in homeostasis, aging, and the progression of malignant diseases. Finally, we detail the therapeutic strategies for tissue repair, with a particular emphasis on aging.
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Affiliation(s)
- Raheleh Farahzadi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behnaz Valipour
- Department of Anatomical Sciences, Sarab Faculty of Medical Sciences, Sarab, Iran
| | - Soheila Montazersaheb
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ezzatollah Fathi
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
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Xiong W, Li R, Li B, Wang X, Wang H, Sun Y, Wang X, Li Y, Ren F. Nobiletin Mitigates D-Galactose-Induced Memory Impairment via Improving Hippocampal Neurogenesis in Mice. Nutrients 2023; 15:2228. [PMID: 37432372 DOI: 10.3390/nu15092228] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/05/2023] [Accepted: 05/06/2023] [Indexed: 07/12/2023] Open
Abstract
Memory impairment is a characteristic of brain aging, and it is associated with a decrease in neurogenesis. Therefore, enhancing neurogenesis is a potential method for mitigating brain aging. Nobiletin (NOB) is a natural polymethoxylated flavonoid derived from citrus peels. It acts as an antioxidant, enhances anti-inflammation, and displays neuroprotective properties. However, the mechanism of NOB on brain aging has not been elucidated. In this study, D-galactose-induced aging mice were treated with NOB (100 mg/kg/day) for 10 weeks. NOB administration attenuated D-galactose-induced memory impairment and restored hippocampal neurogenesis, including the number of newborn neurons and neural stem cells in mice. Furthermore, it downregulated the pro-inflammatory mediators IL-1 β, IL-6, and pP65 (by 42.2%, 22.9%, and 46.4% of those in the D-galactose treated group, respectively) in the hippocampus and blocked microglia and astrocyte activation. In vitro, NOB inhibited D-galactose-induced inflammatory responses in BV2 cells, and the conditioned medium prepared from NOB- and D-galactose-co-treated BV2 cells elevated the viability (90.3% of control) and differential ability (94.9% of control) of C17.2 cells, compared to the D-galactose-treated group alone. It was concluded that NOB could restore memory impairment via the improvement of neurogenesis by ameliorating neuroinflammation in the hippocampus. Overall, NOB is a potential candidate neurogenesis enhancer for improving brain function.
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Affiliation(s)
- Wei Xiong
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China
- Food Laboratory of Zhongyuan, Luohe 462000, China
| | - Rongzi Li
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China
| | - Boying Li
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China
- Food Laboratory of Zhongyuan, Luohe 462000, China
| | - Xifan Wang
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China
| | - Huihui Wang
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China
| | - Yanan Sun
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China
| | - Xiaoyu Wang
- Key Laboratory of Functional Dairy, Co-Constructed by Ministry of Education and Beijing Municipality, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Yixuan Li
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China
| | - Fazheng Ren
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100083, China
- Food Laboratory of Zhongyuan, Luohe 462000, China
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35
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Li X, Yang S, Wang S, Shi Y, Dai Y, Zhang X, Liu Y, Guo Y, He J, Xiu M. Regulation and mechanism of Astragalus polysaccharide on ameliorating aging in Drosophila melanogaster. Int J Biol Macromol 2023; 234:123632. [PMID: 36801290 DOI: 10.1016/j.ijbiomac.2023.123632] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 01/27/2023] [Accepted: 02/06/2023] [Indexed: 02/18/2023]
Abstract
Astragalus polysaccharide (APS) is a notable bioactive component of Astragalus membranaceus and has been extensively investigated for its pharmacological activities, including antioxidant, neuroprotection, and anticancer effects. However, the beneficial effects and mechanisms of APS on anti-aging diseases remain largely unknown. Here, we utilized the classic model organism Drosophila melanogaster to investigate the beneficial effects and mechanism of APS on aging-related intestinal homeostasis imbalance, sleeping disorders, and neurodegenerative diseases. The results showed that administration of APS significantly attenuated age-associated disruption of the intestinal barrier, loss of gastrointestinal acid-base balance, reduction in intestinal length, overproliferation of the intestinal stem cells (ISCs), and sleeping disorders upon aging. Furthermore, APS supplementation delayed the onset of Alzheimer's phenotypes in Aβ42-induced Alzheimer's disease (AD) flies, including the extension of lifespan and the increase in motility, but without rescuing neurobehavioral deficits in the AD model of taupathy and Parkinson's disease (PD) model of Pink1 mutation. In addition, transcriptomics was used to dissect updated mechanisms of APS on anti-aging, such as JAK-STAT signaling, Toll signaling, and IMD signaling pathways. Taken together, these studies indicate that APS plays a beneficial role in modulating aging-related diseases, thereby as a potential natural drug to delay aging.
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Affiliation(s)
- Xu Li
- College of Public Health, Gansu University of Chinese Medicine, Lanzhou 730000, China; Institute of Infection, the First Hospital of Lanzhou University, Lanzhou 730000, China
| | - Shipei Yang
- Provincial-level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and University, Gansu University of Chinese Medicine, Lanzhou 730000, China; College of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, China
| | - Shuwei Wang
- College of Public Health, Gansu University of Chinese Medicine, Lanzhou 730000, China
| | - Yan Shi
- Provincial-level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and University, Gansu University of Chinese Medicine, Lanzhou 730000, China; College of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, China
| | - Yuting Dai
- College of Public Health, Gansu University of Chinese Medicine, Lanzhou 730000, China
| | - Xueyan Zhang
- College of Public Health, Gansu University of Chinese Medicine, Lanzhou 730000, China
| | - Yongqi Liu
- Provincial-level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and University, Gansu University of Chinese Medicine, Lanzhou 730000, China; Key Laboratory for Transfer of Dunhuang Medicine at the Provincial and Ministerial Level, Gansu University of Chinese Medicine, Lanzhou 730000, China
| | - Yaqiong Guo
- Second Provincial People's Hospital of Gansu, Lanzhou 730000, China
| | - Jianzheng He
- Provincial-level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and University, Gansu University of Chinese Medicine, Lanzhou 730000, China; College of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, China; Key Laboratory for Transfer of Dunhuang Medicine at the Provincial and Ministerial Level, Gansu University of Chinese Medicine, Lanzhou 730000, China.
| | - Minghui Xiu
- College of Public Health, Gansu University of Chinese Medicine, Lanzhou 730000, China; Key Laboratory for Transfer of Dunhuang Medicine at the Provincial and Ministerial Level, Gansu University of Chinese Medicine, Lanzhou 730000, China.
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36
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Zheng K, Hong W, Ye H, Zhou Z, Ling S, Li Y, Dai Y, Zhong Z, Yang Z, Zheng Y. Chito-oligosaccharides and macrophages have synergistic effects on improving ovarian stem cells function by regulating inflammatory factors. J Ovarian Res 2023; 16:76. [PMID: 37060101 PMCID: PMC10103396 DOI: 10.1186/s13048-023-01143-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 03/19/2023] [Indexed: 04/16/2023] Open
Abstract
BACKGROUND Chronic low-grade inflammation and ovarian germline stem cells (OGSCs) aging are important reasons for the decline of ovarian reserve function, resulting in ovarian aging and infertility. Regulation of chronic inflammation is expected to promote the proliferation and differentiation of OGSCs, which will become a key means for maintaining and remodeling ovarian function. Our previous study demonstrated that Chitosan Oligosaccharides (Cos) promoted the OGSCs proliferation and remodelled the ovarian function through improving the secretion of immune related factors,but the mechanism remains unclear, and the role of macrophages, the important source of various inflammatory mediators in the ovary needs to be further studied. In this study, we used the method of macrophages and OGSCs co-culture to observe the effect and mechanism of Cos on OGSCs, and explore what contribution macrophages give during this process. Our finding provides new drug treatment options and methods for the prevention and treatment of premature ovarian failure and infertility. METHODS We used the method of macrophages and OGSCs co-culture to observe the effect and mechanism of Cos on OGSCs, and explore the important contribution of macrophages in it. The immunohistochemical staining was used to locate the OGSCs in the mouse ovary. Immunofluorescent staining, RT-qPCR and ALP staining were used to identify the OGSCs. CCK-8 and western blot were used to evaluate the OGSCs proliferation. β-galactosidase(SA-β-Gal) staining and western blot were used to detect the changing of cyclin-dependent kinase inhibitor 1A(P21), P53, Recombinant Sirtuin 1(SIRT1) and Recombinant Sirtuin 3(SIRT3). The levels of immune factors IL-2, IL-10, TNF-α and TGF-β were explored by using Western blot and ELISA. RESULTS We found that Cos promoted OGSCs proliferation in a dose-and time-dependent manner, accompanied by IL-2, TNF-α increase and IL-10, TGF-β decrease. Mouse monocyte-macrophages Leukemia cells(RAW) can also produce the same effect as Cos. When combined with Cos, it can enhance the proliferative effect of Cos in OGSCs, and further increase IL-2, TNF-α and further decrease IL-10, TGF-β. The macrophages can enhance the proliferative effect of Cos in OGSCs is also associated with the further increase in IL-2, TNF-α and the further decrease in IL-10, TGF-β. In this study, we determined that the anti-aging genes SIRT-1 and SIRT-3 protein levels were increased by Cos and RAW respectively, whereas the senescence-associated SA-β-Gal and aging genes P21 and P53 were decreased. Cos and RAW had a protective effect on OGSCs delaying aging. Furthermore, RAW can further decrease the SA-β-Gal and aging genes P21 and P53 by Cos, and further increase SIRT1 and SIRT3 protein levels in OGSCs by Cos. CONCLUSION In conclusion, Cos and macrophages have synergistic effects on improving OGSCs function and delaying ovarian aging by regulating inflammatory factors.
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Affiliation(s)
- K Zheng
- Reproductive Health Department, Shenzhen Traditional Chinese Medicine Hospital, the Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Wenli Hong
- Reproductive Health Department, Shenzhen Traditional Chinese Medicine Hospital, the Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
- Shenzhen University Health Science Center, Shenzhen, China
| | - Haifeng Ye
- Institute of Regenerative Biology and Medicine, Helmholtz Zentrum München, München, Germany
| | - Ziqiong Zhou
- Reproductive Health Department, Shenzhen Traditional Chinese Medicine Hospital, the Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Shuyi Ling
- Reproductive Health Department, Shenzhen Traditional Chinese Medicine Hospital, the Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Yuan Li
- Reproductive Health Department, Shenzhen Traditional Chinese Medicine Hospital, the Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Yuqing Dai
- Reproductive Health Department, Shenzhen Traditional Chinese Medicine Hospital, the Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Zhisheng Zhong
- Reproductive Health Department, Shenzhen Traditional Chinese Medicine Hospital, the Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Ziwei Yang
- Reproductive Health Department, Shenzhen Traditional Chinese Medicine Hospital, the Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China.
| | - Yuehui Zheng
- Reproductive Health Department, Shenzhen Traditional Chinese Medicine Hospital, the Fourth Clinical Medical College of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China.
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He Y, Ji Q, Wu Z, Cai Y, Yin J, Zhang Y, Zhang S, Liu X, Zhang W, Liu GH, Wang S, Song M, Qu J. 4E-BP1 counteracts human mesenchymal stem cell senescence via maintaining mitochondrial homeostasis. Protein Cell 2023; 14:202-216. [PMID: 36929036 PMCID: PMC10098039 DOI: 10.1093/procel/pwac037] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 05/22/2022] [Indexed: 11/13/2022] Open
Abstract
Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders, the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown. Here, we report that the expression of 4E-BP1 decreases along with the senescence of human mesenchymal stem cells (hMSCs). Genetic inactivation of 4E-BP1 in hMSCs compromises mitochondrial respiration, increases mitochondrial reactive oxygen species (ROS) production, and accelerates cellular senescence. Mechanistically, the absence of 4E-BP1 destabilizes proteins in mitochondrial respiration complexes, especially several key subunits of complex III including UQCRC2. Ectopic expression of 4E-BP1 attenuates mitochondrial abnormalities and alleviates cellular senescence in 4E-BP1-deficient hMSCs as well as in physiologically aged hMSCs. These f indings together demonstrate that 4E-BP1 functions as a geroprotector to mitigate human stem cell senescence and maintain mitochondrial homeostasis, particularly for the mitochondrial respiration complex III, thus providing a new potential target to counteract human stem cell senescence.
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Affiliation(s)
- Yifang He
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Qianzhao Ji
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zeming Wu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
| | - Yusheng Cai
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
| | - Jian Yin
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yiyuan Zhang
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Sheng Zhang
- University of Chinese Academy of Sciences, Beijing 100049, China
- State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Brain-Intelligence Technology (Shanghai), Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Xiaoqian Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
| | - Weiqi Zhang
- University of Chinese Academy of Sciences, Beijing 100049, China
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- China National Center for Bioinformation, Beijing 100101, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- The Fifth People’s Hospital of Chongqing, Chongqing 400062, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
| | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
| | - Si Wang
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- The Fifth People’s Hospital of Chongqing, Chongqing 400062, China
| | - Moshi Song
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- The Fifth People’s Hospital of Chongqing, Chongqing 400062, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
| | - Jing Qu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
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Zheng Y, Deng J, Wang G, Zhang X, Wang L, Ma X, Dai Y, E L, Liu X, Zhang R, Zhang Y, Liu H. P53 negatively regulates the osteogenic differentiation in jaw bone marrow MSCs derived from diabetic osteoporosis. Heliyon 2023; 9:e15188. [PMID: 37096002 PMCID: PMC10121411 DOI: 10.1016/j.heliyon.2023.e15188] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 03/27/2023] [Accepted: 03/29/2023] [Indexed: 04/05/2023] Open
Abstract
Patients with diabetic osteoporosis (DOP) often suffer from poor osseointegration of artificial implants, which is a challenge that affects implant outcomes. The osteogenic differentiation ability of human jaw bone marrow mesenchymal stem cells (JBMMSCs) is the key to implant osseointegration. Studies have shown that the microenvironment of hyperglycemia affects the osteogenic differentiation of mesenchymal stem cells (MSC), but the mechanism is still unclear. Therefore, the aim of this study was to isolate and culture JBMMSCs from surgically derived bone fragments from DOP patients and control patients to investigate the differences in their osteogenic differentiation ability and to elucidate its mechanisms. The results showed that the osteogenic ability of hJBMMSCs was significantly decreased in the DOP environment. Mechanism study showed that the expression of senescence marker gene P53 was significantly increased in DOP hJBMMSCs compared to control hJBMMSCs according to RNA-sequencing result. Further, DOP hJBMMSCs were found to display significant senescence using β-galactosidase staining, mitochondrial membrane potential and ROS assay, qRT-PCR and WB analysis. Overexpression of P53 in hJBMMSCs, knockdown of P53 in DOP hJBMMSCs, and knockdown followed by overexpression of P53 significantly affected the osteogenic differentiation ability of hJBMMSCs. These results suggest that MSC senescence is an important reason for decreasing osteogenic capacity in DOP patients. P53 is a key target in regulating hJBMMSCs aging, and knocking down P53 can effectively restore the osteogenic differentiation ability of DOP hJBMMSCs and promote osteosynthesis in DOP dental implants. It provided a new idea to elucidate the pathogenesis and treatment of diabetic bone metabolic diseases.
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Affiliation(s)
- Ying Zheng
- Medical School of Chinese PLA, Beijing 100853, China
- Institute of Stomatology & Oral Maxilla Facial Key Laboratory, Department of Stomatology, First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Junhao Deng
- Senior Department of Orthopedics, The Fourth Medical Center of Chinese PLA General Hospital, Beijing, 100048, China
| | - Gang Wang
- Medical School of Chinese PLA, Beijing 100853, China
- Institute of Stomatology & Oral Maxilla Facial Key Laboratory, Department of Stomatology, First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Xiaru Zhang
- Department of Experimental Hematology and Biochemistry, Beijing Institute of Radiation Medicine, Beijing 100085, China
| | - Lin Wang
- Medical School of Chinese PLA, Beijing 100853, China
- Institute of Stomatology & Oral Maxilla Facial Key Laboratory, Department of Stomatology, First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Xiaocao Ma
- Institute of Stomatology & Oral Maxilla Facial Key Laboratory, Department of Stomatology, First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Yawen Dai
- Medical School of Chinese PLA, Beijing 100853, China
- Institute of Stomatology & Oral Maxilla Facial Key Laboratory, Department of Stomatology, First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Lingling E
- Institute of Stomatology & Oral Maxilla Facial Key Laboratory, Department of Stomatology, First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Xiangwei Liu
- Medical School of Chinese PLA, Beijing 100853, China
- Institute of Stomatology & Oral Maxilla Facial Key Laboratory, Department of Stomatology, First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Rong Zhang
- Institute of Stomatology & Oral Maxilla Facial Key Laboratory, Department of Stomatology, First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Yi Zhang
- Department of Experimental Hematology and Biochemistry, Beijing Institute of Radiation Medicine, Beijing 100085, China
- Corresponding author.
| | - Hongchen Liu
- Medical School of Chinese PLA, Beijing 100853, China
- Institute of Stomatology & Oral Maxilla Facial Key Laboratory, Department of Stomatology, First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
- Corresponding author. Medical School of Chinese PLA, Beijing 100853, China.
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39
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Sousa NS, Brás MF, Antunes IB, Lindholm P, Neves J, Sousa-Victor P. Aging disrupts MANF-mediated immune modulation during skeletal muscle regeneration. NATURE AGING 2023; 3:585-599. [PMID: 37118549 DOI: 10.1038/s43587-023-00382-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 02/16/2023] [Indexed: 04/30/2023]
Abstract
Age-related decline in skeletal muscle regenerative capacity is multifactorial, yet the contribution of immune dysfunction to regenerative failure is unknown. Macrophages are essential for effective debris clearance and muscle stem cell activity during muscle regeneration, but the regulatory mechanisms governing macrophage function during muscle repair are largely unexplored. Here, we uncover a new mechanism of immune modulation operating during skeletal muscle regeneration that is disrupted in aged animals and relies on the regulation of macrophage function. The immune modulator mesencephalic astrocyte-derived neurotrophic factor (MANF) is induced following muscle injury in young mice but not in aged animals, and its expression is essential for regenerative success. Regenerative impairments in aged muscle are associated with defects in the repair-associated myeloid response similar to those found in MANF-deficient models and could be improved through MANF delivery. We propose that restoring MANF levels is a viable strategy to improve myeloid response and regenerative capacity in aged muscle.
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Affiliation(s)
- Neuza S Sousa
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Margarida F Brás
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Inês B Antunes
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Päivi Lindholm
- Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Joana Neves
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
| | - Pedro Sousa-Victor
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
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40
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Haubitz M, von Petersdorff VS, Helsen I, Brunold C, Oppliger Leibundgut E, Baerlocher GM. Higher Age (≥60 Years) Increases the Risk for Adverse Events during Autologous Hematopoietic Stem Cell Transplantation. Cancers (Basel) 2023; 15:cancers15051584. [PMID: 36900376 PMCID: PMC10000699 DOI: 10.3390/cancers15051584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 02/22/2023] [Accepted: 02/28/2023] [Indexed: 03/08/2023] Open
Abstract
Autologous hematopoietic stem cell transplantation (autoHSCT) is a standard of care for patients with hemato-oncologic diseases. This procedure is highly regulated, and a quality assurance system needs to be in place. Deviations from defined processes and outcomes are reported as adverse events (AEs: any untoward medical occurrence temporally associated with an intervention that may or may not have a causal relationship), including adverse reactions (ARs: a response to a medicinal product which is noxious and unintended). Only a few reports on AEs cover the procedure of autoHSCT from collection until infusion. Our aim was to investigate the occurrence and severity of AEs in a large data set of patients who were treated by autoHSCT. In this retrospective, observational, single-center study on 449 adult patients during the years 2016-2019, AEs occurred in 19.6% of the patients. However, only 6.0% of patients had ARs, which is a low rate compared to the percentages (13.5-56.9%) found in other studies; 25.8% of the AEs were serious and 57.5% were potentially serious. Larger leukapheresis volumes, lower numbers of collected CD34+ cells and larger transplant volumes significantly correlated with the occurrence and number of AEs. Importantly, we found more AEs in patients >60 years (see graphical abstract). By preventing potentially serious AEs of quality and procedural issues, AEs could be reduced by 36.7%. Our results provide a broad view on AEs and point out steps and parameters for the potential optimization of the autoHSCT procedure, especially in elderly patients.
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Affiliation(s)
- Monika Haubitz
- Laboratory for Hematopoiesis and Molecular Genetics, Experimental Hematology, Department for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland
| | - Vittoria S. von Petersdorff
- Laboratory for Hematopoiesis and Molecular Genetics, Experimental Hematology, Department for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland
| | - Ingrid Helsen
- Laboratory for Hematopoiesis and Molecular Genetics, Experimental Hematology, Department for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland
| | - Claudio Brunold
- Department of Hematology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
| | - Elisabeth Oppliger Leibundgut
- Laboratory for Hematopoiesis and Molecular Genetics, Experimental Hematology, Department for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland
- Department of Hematology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
| | - Gabriela M. Baerlocher
- Laboratory for Hematopoiesis and Molecular Genetics, Experimental Hematology, Department for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland
- Department of Hematology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
- Correspondence:
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41
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Reece AS, Hulse GK. Clinical Epigenomic Explanation of the Epidemiology of Cannabinoid Genotoxicity Manifesting as Transgenerational Teratogenesis, Cancerogenesis and Aging Acceleration. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:3360. [PMID: 36834053 PMCID: PMC9967951 DOI: 10.3390/ijerph20043360] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 02/07/2023] [Accepted: 02/13/2023] [Indexed: 05/16/2023]
Abstract
As global interest in the therapeutic potential of cannabis and its' derivatives for the management of selected diseases increases, it is increasingly imperative that the toxic profile of cannabinoids be thoroughly understood in order to correctly assess the balance between the therapeutic risks and benefits. Modern studies across a number of jurisdictions, including Canada, Australia, the US and Europe have confirmed that some of the most worrying and severe historical reports of both congenital anomalies and cancer induction following cannabis exposure actually underestimate the multisystem thousand megabase-scale transgenerational genetic damage. These findings from teratogenic and carcinogenic literature are supported by recent data showing the accelerated patterns of chronic disease and the advanced DNA methylation epigenomic clock age in cannabis exposed patients. Together, the increased multisystem carcinogenesis, teratogenesis and accelerated aging point strongly to cannabinoid-related genotoxicity being much more clinically significant than it is widely supposed and, thus, of very considerable public health and multigenerational impact. Recently reported longitudinal epigenome-wide association studies elegantly explain many of these observed effects with considerable methodological sophistication, including multiple pathways for the inhibition of the normal chromosomal segregation and DNA repair, the inhibition of the basic epigenetic machinery for DNA methylation and the demethylation and telomerase acceleration of the epigenomic promoter hypermethylation characterizing aging. For cancer, 810 hits were also noted. The types of malignancy which were observed have all been documented epidemiologically. Detailed epigenomic explications of the brain, heart, face, uronephrological, gastrointestinal and limb development were provided, which amply explained the observed teratological patterns, including the inhibition of the key morphogenic gradients. Hence, these major epigenomic insights constituted a powerful new series of arguments which advanced both our understanding of the downstream sequalae of multisystem multigenerational cannabinoid genotoxicity and also, since mechanisms are key to the causal argument, inveighed strongly in favor of the causal nature of the relationship. In this introductory conceptual overview, we present the various aspects of this novel synthetic paradigmatic framework. Such concepts suggest and, indeed, indicate numerous fields for further investigation and basic science research to advance the exploration of many important issues in biology, clinical medicine and population health. Given this, it is imperative we correctly appraise the risk-benefit ratio for each potential cannabis application, considering the potency, severity of disease, stage of human development and duration of use.
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Affiliation(s)
- Albert Stuart Reece
- Division of Psychiatry, University of Western Australia, Crawley, WA 6009, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia
| | - Gary Kenneth Hulse
- Division of Psychiatry, University of Western Australia, Crawley, WA 6009, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia
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42
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Lin JB, Shen X, Pfeifer CW, Shiau F, Santeford A, Ruzycki PA, Clark BS, Liu Q, Huang AJW, Apte RS. Dry eye disease in mice activates adaptive corneal epithelial regeneration distinct from constitutive renewal in homeostasis. Proc Natl Acad Sci U S A 2023; 120:e2204134120. [PMID: 36595669 PMCID: PMC9926235 DOI: 10.1073/pnas.2204134120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 11/28/2022] [Indexed: 01/05/2023] Open
Abstract
Many epithelial compartments undergo constitutive renewal in homeostasis but activate unique regenerative responses following injury. The clear corneal epithelium is crucial for vision and is renewed from limbal stem cells (LSCs). Using single-cell RNA sequencing, we profiled the mouse corneal epithelium in homeostasis, aging, diabetes, and dry eye disease (DED), where tear deficiency predisposes the cornea to recurrent injury. In homeostasis, we capture the transcriptional states that accomplish continuous tissue turnover. We leverage our dataset to identify candidate genes and gene networks that characterize key stages across homeostatic renewal, including markers for LSCs. In aging and diabetes, there were only mild changes with <15 dysregulated genes. The constitutive cell types that accomplish homeostatic renewal were conserved in DED but were associated with activation of cell states that comprise "adaptive regeneration." We provide global markers that distinguish cell types in homeostatic renewal vs. adaptive regeneration and markers that specifically define DED-elicited proliferating and differentiating cell types. We validate that expression of SPARC, a marker of adaptive regeneration, is also induced in corneal epithelial wound healing and accelerates wound closure in a corneal epithelial cell scratch assay. Finally, we propose a classification system for LSC markers based on their expression fidelity in homeostasis and disease. This transcriptional dissection uncovers the dramatically altered transcriptional landscape of the corneal epithelium in DED, providing a framework and atlas for future study of these ocular surface stem cells in health and disease.
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Affiliation(s)
- Joseph B. Lin
- John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO63110
- Division of Biology and Biomedical Sciences Neurosciences Graduate Program, Washington University School of Medicine, St. Louis, MO63110
| | - Xiaolei Shen
- Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO63110
- Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO63110
| | - Charles W. Pfeifer
- John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO63110
- Division of Biology and Biomedical Sciences Neurosciences Graduate Program, Washington University School of Medicine, St. Louis, MO63110
| | - Fion Shiau
- John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO63110
| | - Andrea Santeford
- John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO63110
| | - Philip A. Ruzycki
- John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO63110
| | - Brian S. Clark
- John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO63110
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO63110
- Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO63110
| | - Qin Liu
- John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO63110
- Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO63110
- Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO63110
| | - Andrew J. W. Huang
- John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO63110
| | - Rajendra S. Apte
- John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO63110
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO63110
- Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO63110
- Department of Medicine, Washington University School of Medicine, St. Louis, MO63110
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43
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Tripathi AK, Ray AK, Mishra SK, Bishen SM, Mishra H, Khurana A. Molecular and Therapeutic Insights of Alpha-Lipoic Acid as a Potential Molecule for Disease Prevention. REVISTA BRASILEIRA DE FARMACOGNOSIA : ORGAO OFICIAL DA SOCIEDADE BRASILEIRA DE FARMACOGNOSIA 2023; 33:272-287. [PMID: 36778891 PMCID: PMC9904877 DOI: 10.1007/s43450-023-00370-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 01/25/2023] [Indexed: 02/10/2023]
Abstract
Alpha-lipoic acid is an organic, sulfate-based compound produced by plants, humans, and animals. As a potent antioxidant and a natural dithiol compound, it performs a crucial role in mitochondrial bioenergetic reactions. A healthy human body, on the other hand, can synthesize enough α-lipoic acid to scavenge reactive oxygen species and increase endogenous antioxidants; however, the amount of α-lipoic acid inside the body decreases significantly with age, resulting in endothelial dysfunction. Molecular orbital energy and spin density analysis indicate that the sulfhydryl (-SH) group of molecules has the greatest electron donating activity, which would be responsible for the antioxidant potential and free radical scavenging activity. α-Lipoic acid acts as a chelating agent for metal ions, a quenching agent for reactive oxygen species, and a reducing agent for the oxidized form of glutathione and vitamins C and E. α-Lipoic acid enantiomers and its reduced form have antioxidant, cognitive, cardiovascular, detoxifying, anti-aging, dietary supplement, anti-cancer, neuroprotective, antimicrobial, and anti-inflammatory properties. α-Lipoic acid has cytotoxic and antiproliferative effects on several cancers, including polycystic ovarian syndrome. It also has usefulness in the context of female and male infertility. Although α-lipoic acid has numerous clinical applications, the majority of them stem from its antioxidant properties; however, its bioavailability in its pure form is low (approximately 30%). However, nanoformulations have shown promise in this regard. The proton affinity and electron donating activity, as a redox-active agent, would be responsible for the antioxidant potential and free radical scavenging activity of the molecule. This review discusses the most recent clinical data on α-lipoic acid in the prevention, management, and treatment of a variety of diseases, including coronavirus disease 2019. Based on current evidence, the preclinical and clinical potential of this molecule is discussed. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s43450-023-00370-1.
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Affiliation(s)
- Amit Kumar Tripathi
- School of Basic and Applied Science, Galgotias University, Gautam Buddha Nagar, UP Noida, India
- Molecular Biology Unit, Institute of Medical Science, Banaras Hindu University, Varanasi, 221005 India
| | - Anup Kumar Ray
- Department of Natural Products, National Institute of Pharmaceutical Education and Research, Sahibzada Ajit Singh Nagar, Punjab, India
| | - Sunil Kumar Mishra
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, 221005 India
| | - Siddharth Mall Bishen
- Department of Physics, Banaras Hindu University, Mahila Maha Vidyalaya, Varanasi, India
| | - Hirdyesh Mishra
- Department of Physics, Banaras Hindu University, Mahila Maha Vidyalaya, Varanasi, India
| | - Aman Khurana
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, 221005 India
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44
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Jang H, Jo Y, Lee JH, Choi S. Aging of hair follicle stem cells and their niches. BMB Rep 2023; 56:2-9. [PMID: 36379515 PMCID: PMC9887102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/14/2022] [Accepted: 11/14/2022] [Indexed: 01/28/2023] Open
Abstract
Hair follicles in the skin undergo cyclic rounds of regeneration, degeneration, and rest throughout life. Stem cells residing in hair follicles play a pivotal role in maintaining tissue homeostasis and hair growth cycles. Research on hair follicle aging and age-related hair loss has demonstrated that a decline in hair follicle stem cell (HFSC) activity with aging can decrease the regeneration capacity of hair follicles. This review summarizes our understanding of how age-associated HFSC intrinsic and extrinsic mechanisms can induce HFSC aging and hair loss. In addition, we discuss approaches developed to attenuate ageassociated changes in HFSCs and their niches, thereby promoting hair regrowth. [BMB Reports 2023; 56(1): 2-9].
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Affiliation(s)
- Hansaem Jang
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea, Incheon 21983, Korea
| | - Yemin Jo
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea, Incheon 21983, Korea
| | - Jung Hyun Lee
- Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA 98109, Korea
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA, Incheon 21983, Korea
| | - Sekyu Choi
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea, Incheon 21983, Korea
- School of Medical Science and Engineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea
- School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea
- Institute for Convergence Research and Education in Advanced Technology (I_CREATE), Yonsei University, Incheon 21983, Korea
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45
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Jang H, Jo Y, Lee JH, Choi S. Aging of hair follicle stem cells and their niches. BMB Rep 2023; 56:2-9. [PMID: 36379515 PMCID: PMC9887102 DOI: 10.5483/bmbrep.2022-0183] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/14/2022] [Accepted: 11/14/2022] [Indexed: 09/06/2023] Open
Abstract
Hair follicles in the skin undergo cyclic rounds of regeneration, degeneration, and rest throughout life. Stem cells residing in hair follicles play a pivotal role in maintaining tissue homeostasis and hair growth cycles. Research on hair follicle aging and age-related hair loss has demonstrated that a decline in hair follicle stem cell (HFSC) activity with aging can decrease the regeneration capacity of hair follicles. This review summarizes our understanding of how age-associated HFSC intrinsic and extrinsic mechanisms can induce HFSC aging and hair loss. In addition, we discuss approaches developed to attenuate ageassociated changes in HFSCs and their niches, thereby promoting hair regrowth. [BMB Reports 2023; 56(1): 2-9].
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Affiliation(s)
- Hansaem Jang
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea, Incheon 21983, Korea
| | - Yemin Jo
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea, Incheon 21983, Korea
| | - Jung Hyun Lee
- Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA 98109, Korea
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA, Incheon 21983, Korea
| | - Sekyu Choi
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea, Incheon 21983, Korea
- School of Medical Science and Engineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea
- School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea
- Institute for Convergence Research and Education in Advanced Technology (I_CREATE), Yonsei University, Incheon 21983, Korea
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46
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Lee EH, Zinshteyn D, Miglo F, Wang MQ, Reinach J, Chau CM, Grosstephan JM, Correa I, Costa K, Vargas A, Johnson A, Longo SM, Alexander JI, O'Reilly AM. Sequential events during the quiescence to proliferation transition establish patterns of follicle cell differentiation in the Drosophila ovary. Biol Open 2023; 12:bio059625. [PMID: 36524613 PMCID: PMC9867896 DOI: 10.1242/bio.059625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 12/07/2022] [Indexed: 12/23/2022] Open
Abstract
Stem cells cycle between periods of quiescence and proliferation to promote tissue health. In Drosophila ovaries, quiescence to proliferation transitions of follicle stem cells (FSCs) are exquisitely feeding-dependent. Here, we demonstrate feeding-dependent induction of follicle cell differentiation markers, eyes absent (Eya) and castor (Cas) in FSCs, a patterning process that does not depend on proliferation induction. Instead, FSCs extend micron-scale cytoplasmic projections that dictate Eya-Cas patterning. We identify still life and sickie as necessary and sufficient for FSC projection growth and Eya-Cas induction. Our results suggest that sequential, interdependent events establish long-term differentiation patterns in follicle cell precursors, independently of FSC proliferation induction.
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Affiliation(s)
- Eric H. Lee
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
- Immersion Science Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Daniel Zinshteyn
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Fred Miglo
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
- Immersion Science Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Melissa Q. Wang
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
- Immersion Science Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Jessica Reinach
- Immersion Science Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Cindy M. Chau
- Immersion Science Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | | | - Iliana Correa
- Immersion Science Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Kelly Costa
- Immersion Science Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Alberto Vargas
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Aminah Johnson
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Sheila M. Longo
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
- Drexel University College of Medicine, Molecular and Cellular Biology and Genetics Graduate Program, Philadelphia, PA 19129, USA
| | - Jennifer I. Alexander
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
- Immersion Science Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Alana M. O'Reilly
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
- Immersion Science Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
- Drexel University College of Medicine, Molecular and Cellular Biology and Genetics Graduate Program, Philadelphia, PA 19129, USA
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47
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Montserrat-Vazquez S, Ali NJ, Matteini F, Lozano J, Zhaowei T, Mejia-Ramirez E, Marka G, Vollmer A, Soller K, Sacma M, Sakk V, Mularoni L, Mallm JP, Plass M, Zheng Y, Geiger H, Florian MC. Transplanting rejuvenated blood stem cells extends lifespan of aged immunocompromised mice. NPJ Regen Med 2022; 7:78. [PMID: 36581635 PMCID: PMC9800381 DOI: 10.1038/s41536-022-00275-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 12/16/2022] [Indexed: 12/30/2022] Open
Abstract
One goal of regenerative medicine is to rejuvenate tissues and extend lifespan by restoring the function of endogenous aged stem cells. However, evidence that somatic stem cells can be targeted in vivo to extend lifespan is still lacking. Here, we demonstrate that after a short systemic treatment with a specific inhibitor of the small RhoGTPase Cdc42 (CASIN), transplanting aged hematopoietic stem cells (HSCs) from treated mice is sufficient to extend the healthspan and lifespan of aged immunocompromised mice without additional treatment. In detail, we show that systemic CASIN treatment improves strength and endurance of aged mice by increasing the myogenic regenerative potential of aged skeletal muscle stem cells. Further, we show that CASIN modifies niche localization and H4K16ac polarity of HSCs in vivo. Single-cell profiling reveals changes in HSC transcriptome, which underlie enhanced lymphoid and regenerative capacity in serial transplantation assays. Overall, we provide proof-of-concept evidence that a short systemic treatment to decrease Cdc42 activity improves the regenerative capacity of different endogenous aged stem cells in vivo, and that rejuvenated HSCs exert a broad systemic effect sufficient to extend murine health- and lifespan.
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Affiliation(s)
- Sara Montserrat-Vazquez
- grid.417656.7Stem Cell Aging Group, Regenerative Medicine Program, The Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain ,grid.417656.7Program for advancing the Clinical Translation of Regenerative Medicine of Catalonia, P-CMR[C], L’Hospitalet de Llobregat, Barcelona, Spain
| | - Noelle J. Ali
- grid.6582.90000 0004 1936 9748Institute of Molecular Medicine, University of Ulm, Ulm, Germany
| | - Francesca Matteini
- grid.417656.7Stem Cell Aging Group, Regenerative Medicine Program, The Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain ,grid.417656.7Program for advancing the Clinical Translation of Regenerative Medicine of Catalonia, P-CMR[C], L’Hospitalet de Llobregat, Barcelona, Spain
| | - Javier Lozano
- grid.417656.7Stem Cell Aging Group, Regenerative Medicine Program, The Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain ,grid.417656.7Program for advancing the Clinical Translation of Regenerative Medicine of Catalonia, P-CMR[C], L’Hospitalet de Llobregat, Barcelona, Spain
| | - Tu Zhaowei
- grid.239573.90000 0000 9025 8099Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
| | - Eva Mejia-Ramirez
- grid.417656.7Stem Cell Aging Group, Regenerative Medicine Program, The Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain ,grid.417656.7Program for advancing the Clinical Translation of Regenerative Medicine of Catalonia, P-CMR[C], L’Hospitalet de Llobregat, Barcelona, Spain ,grid.512890.7Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain
| | - Gina Marka
- grid.6582.90000 0004 1936 9748Institute of Molecular Medicine, University of Ulm, Ulm, Germany
| | - Angelika Vollmer
- grid.6582.90000 0004 1936 9748Institute of Molecular Medicine, University of Ulm, Ulm, Germany
| | - Karin Soller
- grid.6582.90000 0004 1936 9748Institute of Molecular Medicine, University of Ulm, Ulm, Germany
| | - Mehmet Sacma
- grid.6582.90000 0004 1936 9748Institute of Molecular Medicine, University of Ulm, Ulm, Germany
| | - Vadim Sakk
- grid.6582.90000 0004 1936 9748Institute of Molecular Medicine, University of Ulm, Ulm, Germany
| | - Loris Mularoni
- grid.417656.7Program for advancing the Clinical Translation of Regenerative Medicine of Catalonia, P-CMR[C], L’Hospitalet de Llobregat, Barcelona, Spain
| | | | - Mireya Plass
- grid.417656.7Program for advancing the Clinical Translation of Regenerative Medicine of Catalonia, P-CMR[C], L’Hospitalet de Llobregat, Barcelona, Spain ,grid.512890.7Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain ,grid.417656.7Gene Regulation of Cell Identity Group, Regenerative Medicine Program, The Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
| | - Yi Zheng
- grid.239573.90000 0000 9025 8099Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
| | - Hartmut Geiger
- grid.6582.90000 0004 1936 9748Institute of Molecular Medicine, University of Ulm, Ulm, Germany
| | - M. Carolina Florian
- grid.417656.7Stem Cell Aging Group, Regenerative Medicine Program, The Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain ,grid.417656.7Program for advancing the Clinical Translation of Regenerative Medicine of Catalonia, P-CMR[C], L’Hospitalet de Llobregat, Barcelona, Spain ,grid.512890.7Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain
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48
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Salomao N, Maslah N, Giulianelli A, Drevon L, Aguinaga L, Gu X, Cassinat B, Giraudier S, Fenaux P, Fahraeus R. Reduced murine double minute 2 and
4
protein, but not
messenger RNA
, expression is associated with more severe disease in myelodysplastic syndromes and acute myeloblastic leukaemia. Br J Haematol 2022; 201:234-248. [PMID: 36546586 DOI: 10.1111/bjh.18608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 12/04/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022]
Abstract
The human homologues of murine double minute 2 (MDM2) and 4 (MDM4) negatively regulate p53 tumour suppressor activity and are reported to be frequently overexpressed in human malignancies, prompting clinical trials with drugs that prevent interactions between MDM2/MDM4 and p53. Bone marrow samples from 111 patients with acute myeloblastic leukaemia, myelodysplastic syndrome or chronic myelomonocytic leukaemia were examined for protein (fluorescence-activated cell sorting) and messenger RNA (mRNA) expression (quantitative polymerase chain reaction) of MDM2, MDM4 and tumour protein p53 (TP53). Low protein expression of MDM2 and MDM4 was observed in immature cells from patients with excess of marrow blasts (>5%) compared with CD34+ /CD45low cells from healthy donors and patients without excess of marrow blasts (<5%). The mRNA levels were indistinguishable in all samples examined regardless of disease status or blast levels. Low MDM2 and MDM4 protein expression were correlated with poor survival. These data show a poor correlation between mRNA and protein expression levels, suggesting that quantitative flow cytometry analysis of protein expression levels should be used to predict and validate the efficacy of MDM2 and MDM4 inhibitors. These findings show that advanced disease is associated with reduced MDM2 and MDM4 protein expression and indicate that the utility of MDM2 and MDM4 inhibitors may have to be reconsidered in the treatment of advanced myeloid malignancies.
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Affiliation(s)
- Norman Salomao
- Inserm UMRS1131, Institut de Recherche Saint‐Louis, Institut de Génétique Moléculaire, Université de Paris‐Cité, Hôpital St. Louis Paris France
| | - Nabih Maslah
- Inserm UMRS1131, Institut de Recherche Saint‐Louis, Institut de Génétique Moléculaire, Université de Paris‐Cité, Hôpital St. Louis Paris France
| | - Anouk Giulianelli
- Service d'Hématologie Senior—Hôpital Saint‐Louis—Assistance Publique Hôpitaux de Paris, and Paris Cité university Paris France
| | - Louis Drevon
- Inserm UMRS1131, Institut de Recherche Saint‐Louis, Institut de Génétique Moléculaire, Université de Paris‐Cité, Hôpital St. Louis Paris France
- Service d'Hématologie Senior—Hôpital Saint‐Louis—Assistance Publique Hôpitaux de Paris, and Paris Cité university Paris France
| | - Lorea Aguinaga
- Inserm UMRS1131, Institut de Recherche Saint‐Louis, Institut de Génétique Moléculaire, Université de Paris‐Cité, Hôpital St. Louis Paris France
- Service d'Hématologie Senior—Hôpital Saint‐Louis—Assistance Publique Hôpitaux de Paris, and Paris Cité university Paris France
| | - Xiaolian Gu
- Department of Medical Biosciences Building 6M, Umeå University Umeå Sweden
| | - Bruno Cassinat
- Inserm UMRS1131, Institut de Recherche Saint‐Louis, Institut de Génétique Moléculaire, Université de Paris‐Cité, Hôpital St. Louis Paris France
- Service d'Hématologie Senior—Hôpital Saint‐Louis—Assistance Publique Hôpitaux de Paris, and Paris Cité university Paris France
| | - Stephane Giraudier
- Inserm UMRS1131, Institut de Recherche Saint‐Louis, Institut de Génétique Moléculaire, Université de Paris‐Cité, Hôpital St. Louis Paris France
- Service d'Hématologie Senior—Hôpital Saint‐Louis—Assistance Publique Hôpitaux de Paris, and Paris Cité university Paris France
| | - Pierre Fenaux
- Service d'Hématologie Senior—Hôpital Saint‐Louis—Assistance Publique Hôpitaux de Paris, and Paris Cité university Paris France
| | - Robin Fahraeus
- Inserm UMRS1131, Institut de Recherche Saint‐Louis, Institut de Génétique Moléculaire, Université de Paris‐Cité, Hôpital St. Louis Paris France
- Department of Medical Biosciences Building 6M, Umeå University Umeå Sweden
- RECAMO, Masaryk Memorial Cancer Institute Brno Czech Republic
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49
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Reece AS, Hulse GK. Epigenomic and Other Evidence for Cannabis-Induced Aging Contextualized in a Synthetic Epidemiologic Overview of Cannabinoid-Related Teratogenesis and Cannabinoid-Related Carcinogenesis. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:16721. [PMID: 36554603 PMCID: PMC9778714 DOI: 10.3390/ijerph192416721] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/30/2022] [Accepted: 12/07/2022] [Indexed: 05/16/2023]
Abstract
BACKGROUND Twelve separate streams of empirical data make a strong case for cannabis-induced accelerated aging including hormonal, mitochondriopathic, cardiovascular, hepatotoxic, immunological, genotoxic, epigenotoxic, disruption of chromosomal physiology, congenital anomalies, cancers including inheritable tumorigenesis, telomerase inhibition and elevated mortality. METHODS Results from a recently published longitudinal epigenomic screen were analyzed with regard to the results of recent large epidemiological studies of the causal impacts of cannabis. We also integrate theoretical syntheses with prior studies into these combined epigenomic and epidemiological results. RESULTS Cannabis dependence not only recapitulates many of the key features of aging, but is characterized by both age-defining and age-generating illnesses including immunomodulation, hepatic inflammation, many psychiatric syndromes with a neuroinflammatory basis, genotoxicity and epigenotoxicity. DNA breaks, chromosomal breakage-fusion-bridge morphologies and likely cycles, and altered intergenerational DNA methylation and disruption of both the histone and tubulin codes in the context of increased clinical congenital anomalies, cancers and heritable tumors imply widespread disruption of the genome and epigenome. Modern epigenomic clocks indicate that, in cannabis-dependent patients, cannabis advances cellular DNA methylation age by 25-30% at age 30 years. Data have implications not only for somatic but also stem cell and germ line tissues including post-fertilization zygotes. This effect is likely increases with the square of chronological age. CONCLUSION Recent epigenomic studies of cannabis exposure provide many explanations for the broad spectrum of cannabis-related teratogenicity and carcinogenicity and appear to account for many epidemiologically observed findings. Further research is indicated on the role of cannabinoids in the aging process both developmentally and longitudinally, from stem cell to germ cell to blastocystoids to embryoid bodies and beyond.
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Affiliation(s)
- Albert Stuart Reece
- Division of Psychiatry, University of Western Australia, Crawley, WA 6009, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia
| | - Gary Kenneth Hulse
- Division of Psychiatry, University of Western Australia, Crawley, WA 6009, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia
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50
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Cai Y, Ji Z, Wang S, Zhang W, Qu J, Belmonte JCI, Liu GH. Genetic enhancement: an avenue to combat aging-related diseases. LIFE MEDICINE 2022; 1:307-318. [PMID: 39872744 PMCID: PMC11749557 DOI: 10.1093/lifemedi/lnac054] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 11/14/2022] [Indexed: 01/30/2025]
Abstract
Aging is a major risk factor for multiple diseases, including cardiovascular diseases, neurodegenerative disorders, osteoarthritis, and cancer. It is accompanied by the dysregulation of stem cells and other differentiated cells, and the impairment of their microenvironment. Cell therapies to replenish the abovementioned cells provide a promising approach to restore tissue homeostasis and alleviate aging and aging-related chronic diseases. Importantly, by leveraging gene editing technologies, genetic enhancement, an enhanced strategy for cell therapy, can be developed to improve the safety and efficacy of transplanted therapeutic cells. In this review, we provide an overview and discussion of the current progress in the genetic enhancement field, including genetic modifications of mesenchymal stem cells, neural stem cells, hematopoietic stem cells, vascular cells, and T cells to target aging and aging-associated diseases. We also outline questions regarding safety and current limitations that need to be addressed for the continued development of genetic enhancement strategies for cell therapy to enable its further applications in clinical trials to combat aging-related diseases.
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Affiliation(s)
- Yusheng Cai
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Zhejun Ji
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Si Wang
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Weiqi Zhang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- China National Center for Bioinformation, Beijing 100101, China
| | - Jing Qu
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | | | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
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