1,276 results on '"Buck Institute for Research on Aging"'
Search Results
2. Variations in Ketone Metabolism (STAK-VKM)
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Buck Institute for Research on Aging
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- 2023
3. Integrated genomic and molecular characterization of cervical cancer.
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Cancer Genome Atlas Research Network, Albert Einstein College of Medicine, Analytical Biological Services, Barretos Cancer Hospital, Baylor College of Medicine, Beckman Research Institute of City of Hope, Buck Institute for Research on Aging, Canada's Michael Smith Genome Sciences Centre, Harvard Medical School, Helen F. Graham Cancer Center &Research Institute at Christiana Care Health Services, HudsonAlpha Institute for Biotechnology, ILSbio, LLC, Indiana University School of Medicine, Institute of Human Virology, Institute for Systems Biology, International Genomics Consortium, Leidos Biomedical, Massachusetts General Hospital, McDonnell Genome Institute at Washington University, Medical College of Wisconsin, Medical University of South Carolina, Memorial Sloan Kettering Cancer Center, Montefiore Medical Center, NantOmics, National Cancer Institute, National Hospital, Abuja, Nigeria, National Human Genome Research Institute, National Institute of Environmental Health Sciences, National Institute on Deafness &Other Communication Disorders, Ontario Tumour Bank, London Health Sciences Centre, Ontario Tumour Bank, Ontario Institute for Cancer Research, Ontario Tumour Bank, The Ottawa Hospital, Oregon Health &Science University, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, SRA International, St Joseph's Candler Health System, Eli &Edythe L. Broad Institute of Massachusetts Institute of Technology &Harvard University, Research Institute at Nationwide Children's Hospital, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, University of Bergen, University of Texas MD Anderson Cancer Center, University of Abuja Teaching Hospital, University of Alabama at Birmingham, University of California, Irvine, University of California Santa Cruz, University of Kansas Medical Center, University of Lausanne, University of New Mexico Health Sciences Center, University of North Carolina at Chapel Hill, University of Oklahoma Health Sciences Center, University of Pittsburgh, University of São Paulo, Ribeir ão Preto Medical School, University of Southern California, University of Washington, University of Wisconsin School of Medicine &Public Health, Van Andel Research Institute, and Washington University in St Louis
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Cancer Genome Atlas Research Network ,Albert Einstein College of Medicine ,Analytical Biological Services ,Barretos Cancer Hospital ,Baylor College of Medicine ,Beckman Research Institute of City of Hope ,Buck Institute for Research on Aging ,Canada's Michael Smith Genome Sciences Centre ,Harvard Medical School ,Helen F. Graham Cancer Center &Research Institute at Christiana Care Health Services ,HudsonAlpha Institute for Biotechnology ,ILSbio ,LLC ,Indiana University School of Medicine ,Institute of Human Virology ,Institute for Systems Biology ,International Genomics Consortium ,Leidos Biomedical ,Massachusetts General Hospital ,McDonnell Genome Institute at Washington University ,Medical College of Wisconsin ,Medical University of South Carolina ,Memorial Sloan Kettering Cancer Center ,Montefiore Medical Center ,NantOmics ,National Cancer Institute ,National Hospital ,Abuja ,Nigeria ,National Human Genome Research Institute ,National Institute of Environmental Health Sciences ,National Institute on Deafness &Other Communication Disorders ,Ontario Tumour Bank ,London Health Sciences Centre ,Ontario Tumour Bank ,Ontario Institute for Cancer Research ,Ontario Tumour Bank ,The Ottawa Hospital ,Oregon Health &Science University ,Samuel Oschin Comprehensive Cancer Institute ,Cedars-Sinai Medical Center ,SRA International ,St Joseph's Candler Health System ,Eli &Edythe L. Broad Institute of Massachusetts Institute of Technology &Harvard University ,Research Institute at Nationwide Children's Hospital ,Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University ,University of Bergen ,University of Texas MD Anderson Cancer Center ,University of Abuja Teaching Hospital ,University of Alabama at Birmingham ,University of California ,Irvine ,University of California Santa Cruz ,University of Kansas Medical Center ,University of Lausanne ,University of New Mexico Health Sciences Center ,University of North Carolina at Chapel Hill ,University of Oklahoma Health Sciences Center ,University of Pittsburgh ,University of São Paulo ,Ribeir ão Preto Medical School ,University of Southern California ,University of Washington ,University of Wisconsin School of Medicine &Public Health ,Van Andel Research Institute ,Washington University in St Louis ,Humans ,Adenocarcinoma ,Carcinoma ,Squamous Cell ,Protein-Serine-Threonine Kinases ,Mitogen-Activated Protein Kinase Kinases ,Receptor ,erbB-3 ,DNA-Binding Proteins ,Receptors ,Transforming Growth Factor beta ,Nuclear Proteins ,Transcription Factors ,HLA-A Antigens ,Proteomics ,Genomics ,Virus Integration ,Signal Transduction ,Mutation ,Uterine Cervical Neoplasms ,Female ,Proto-Oncogene Proteins p21(ras) ,PTEN Phosphohydrolase ,Human papillomavirus 16 ,Keratins ,Caspase 8 ,Phosphatidylinositol 3-Kinases ,Molecular Targeted Therapy ,Programmed Cell Death 1 Ligand 2 Protein ,RNA ,Long Noncoding ,APOBEC-1 Deaminase ,B7-H1 Antigen ,Receptor ,Transforming Growth Factor-beta Type II ,Receptor ,ErbB-3 ,Biotechnology ,Clinical Research ,Human Genome ,Cancer ,Sexually Transmitted Infections ,Cervical Cancer ,Genetics ,2.1 Biological and endogenous factors ,General Science & Technology - Abstract
Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, one of the largest comprehensive genomic studies of cervical cancer to date. We observed notable APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered amplifications in immune targets CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2), and the BCAR4 long non-coding RNA, which has been associated with response to lapatinib. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76% of HPV16-related samples, and was associated with structural aberrations and increased target-gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumours with relatively high frequencies of KRAS, ARID1A and PTEN mutations. Integrative clustering of 178 samples identified keratin-low squamous, keratin-high squamous and adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers.
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- 2017
4. Paradoxical implication of BAX/BAK in the persistence of tetraploid cells
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Deng, Jiayin, Gutiérrez, Lucía, Stoll, Gautier, Motiño, Omar, Martins, Isabelle, Núñez, Lucía, Bravo-San Pedro, José, Humeau, Juliette, Bordenave, Chloé, Pan, Juncheng, Fohrer-Ting, Hélène, Souquere, Sylvie, Pierron, Gerard, Hetz, Claudio, Villalobos, Carlos, Kroemer, Guido, Senovilla, Laura, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institut Gustave Roussy (IGR), Universidad de Valladolid [Valladolid] (UVa), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Université de Montréal (UdeM), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Universidad de Chile = University of Chile [Santiago] (UCHILE), Buck Institute for Research on Aging, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), and Gestionnaire, Hal Sorbonne Université
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Mice, Knockout ,Cell death ,QH573-671 ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Fibroblasts ,Endoplasmic Reticulum ,Senescence ,Microtubules ,Article ,Cell Line ,Clone Cells ,Sarcoplasmic Reticulum Calcium-Transporting ATPases ,Mice, Inbred C57BL ,Tetraploidy ,Cell growth ,bcl-2 Homologous Antagonist-Killer Protein ,Animals ,Humans ,Calcium ,Calcium Signaling ,biological phenomena, cell phenomena, and immunity ,Cytology ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,Cellular Senescence ,bcl-2-Associated X Protein - Abstract
International audience; Pro-apoptotic multi-domain proteins of the BCL2 family such as BAX and BAK are well known for their important role in the induction of mitochondrial outer membrane permeabilization (MOMP), which is the rate-limiting step of the intrinsic pathway of apoptosis. Human or mouse cells lacking both BAX and BAK (due to a double knockout, DKO) are notoriously resistant to MOMP and cell death induction. Here we report the surprising finding that BAX/BAK DKO cells proliferate less than control cells expressing both BAX and BAK (or either BAX or BAK) when they are driven into tetraploidy by transient exposure to the microtubule inhibitor nocodazole. Mechanistically, in contrast to their BAX/BAK-sufficient controls, tetraploid DKO cells activate a senescent program, as indicated by the overexpression of several cyclin-dependent kinase inhibitors and the activation of β-galactosidase. Moreover, DKO cells manifest alterations in ionomycin-mobilizable endoplasmic reticulum (ER) Ca 2+ stores and store-operated Ca 2+ entry that are affected by tetraploidization. DKO cells manifested reduced expression of endogenous sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase 2a (Serca2a) and transfection-enforced reintroduction of Serca2a, or reintroduction of an ER-targeted variant of BAK into DKO cells reestablished the same pattern of Ca 2+ fluxes as observed in BAX/BAK-sufficient control cells. Serca2a reexpression and ER-targeted BAK also abolished the tetraploidy-induced senescence of DKO cells, placing ER Ca 2+ fluxes downstream of the regulation of senescence by BAX/BAK. In conclusion, it appears that BAX/BAK prevent the induction of a tetraploidization-associated senescence program. Speculatively, this may contribute to the low incidence of cancers in BAX/BAK DKO mice and explain why human cancers rarely lose the expression of both BAX and BAK.
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- 2021
5. Characterising proteolysis during SARS-CoV-2 infection identifies viral cleavage sites and cellular targets with therapeutic potential
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Jeanne Chiaravalli, Marius Walter, Edward Emmott, Emma Sierecki, Stacy Gellenoncourt, Philip Brownridge, Arturas Grauslys, Andrew R. Jones, Fabrice Agou, Charles S. Craik, Marco Vignuzzi, Yann Gambin, Patrick A. Eyers, Lisa A. Chakrabarti, Eric Verdin, Leonard A. Daly, Bjoern Meyer, Dominic P. Bryne, Claire E. Eyers, Populations virales et Pathogenèse - Viral Populations and Pathogenesis, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Criblage chémogénomique et biologique (Plateforme) - Chemogenomic and Biological Screening Platform (PF-CCB), Institut Pasteur [Paris] (IP), Virus et Immunité - Virus and immunity (CNRS-UMR3569), University of Liverpool, Buck Institute for Research on Aging, University of California [San Francisco] (UC San Francisco), University of California (UC), University of New South Wales [Sydney] (UNSW), This work was supported by the Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (grant ANR-10-LABX-62-IBEID) to M.V. S.G. is the recipient of a MESR/Ecole Doctorale BioSPC ED562, Université de Paris fellowship. L.A.C. is supported by Institut Pasteur TASK FORCE SARS COV-2 (Tropicoro project), DIM ELICIT Region Ile-de-France, and ANRS. E.E. is supported by startup funding from the University of Liverpool, as well as a Wellcome Trust ISSF Interdisciplinary & Industry Award. E.E. is grateful for the support of GoFundMe donors for sponsoring SARS-CoV-2 research in his laboratory., and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)
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Proteomics ,MESH: Virus Internalization ,viruses ,medicine.medical_treatment ,General Physics and Astronomy ,Virus Replication ,MESH: Dipeptides ,MESH: RNA, Small Interfering ,2.2 Factors relating to the physical environment ,MESH: COVID-19 ,MESH: Animals ,MESH: Myosin-Light-Chain Kinase ,RNA, Small Interfering ,Aetiology ,skin and connective tissue diseases ,Lung ,MESH: Protease Inhibitors ,MESH: Viral Proteases ,Multidisciplinary ,medicine.diagnostic_test ,Viral Proteases ,MESH: Proteomics ,Proteases ,Dipeptides ,src-Family Kinases ,Infectious Diseases ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,Infection ,Biotechnology ,Proto-oncogene tyrosine-protein kinase Src ,MESH: Antiviral Agents ,MESH: Mutation ,Science ,Proteolysis ,MESH: Proteolysis ,Context (language use) ,Biology ,Small Interfering ,Antiviral Agents ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Vaccine Related ,Viral Proteins ,Biodefense ,medicine ,Animals ,Humans ,Protease Inhibitors ,MESH: SARS-CoV-2 ,Myosin-Light-Chain Kinase ,MESH: Humans ,Protease ,SARS-CoV-2 ,Prevention ,fungi ,MESH: Virus Replication ,COVID-19 ,MYLK ,Pneumonia ,General Chemistry ,Virus Internalization ,MESH: Viral Proteins ,Virology ,COVID-19 Drug Treatment ,MESH: Cell Line ,body regions ,Emerging Infectious Diseases ,Good Health and Well Being ,MESH: src-Family Kinases ,Viral replication ,Mutation ,RNA ,Immunization - Abstract
SARS-CoV-2 is the causative agent behind the COVID-19 pandemic, responsible for over 170 million infections, and over 3.7 million deaths worldwide. Efforts to test, treat and vaccinate against this pathogen all benefit from an improved understanding of the basic biology of SARS-CoV-2. Both viral and cellular proteases play a crucial role in SARS-CoV-2 replication. Here, we study proteolytic cleavage of viral and cellular proteins in two cell line models of SARS-CoV-2 replication using mass spectrometry to identify protein neo-N-termini generated through protease activity. We identify previously unknown cleavage sites in multiple viral proteins, including major antigens S and N: the main targets for vaccine and antibody testing efforts. We discover significant increases in cellular cleavage events consistent with cleavage by SARS-CoV-2 main protease, and identify 14 potential high-confidence substrates of the main and papain-like proteases. We show that siRNA depletion of these cellular proteins inhibits SARS-CoV-2 replication, and that drugs targeting two of these proteins: the tyrosine kinase SRC and Ser/Thr kinase MYLK, show a dose-dependent reduction in SARS-CoV-2 titres. Overall, our study provides a powerful resource to understand proteolysis in the context of viral infection, and to inform the development of targeted strategies to inhibit SARS-CoV-2 and treat COVID-19., During SARS-CoV-2 replication, viral and cellular proteases play crucial roles and have been shown to be promising anti-viral targets. Here, Meyer et al. apply mass spectrometry to characterize the proteolytic cleavage profile of viral and cellular proteins in vitro.
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- 2021
6. Therapy-induced senescence: opportunities to improve anti-cancer therapy
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Jeffrey Hildesheim, Mansoor M. Ahmed, François Paris, Ana O'Loghlen, Gabriela Riscuta, Dan Xi, Jörg J. Goronzy, Pataje G. S. Prasanna, Daohong Zhou, Judith Campisi, Scott W. Lowe, Sundar Venkatachalam, Guangrong Zheng, David Gius, Clemens A. Schmitt, Paul B. Romesser, C. Norman Coleman, Ann Richmond, Mohamed E Abazeed, Stephen L. Brown, Sandeep Burma, Laura J. Niedernhofer, Jesús Gil, Alexandros G. Georgakilas, David A. Gewirtz, Stephen J. Kron, Marc S. Mendonca, James L. Kirkland, Norman E. Sharpless, Jan M. van Deursen, Deborah Citrin, Mitchell Steven Anscher, Bernardo, Elizabeth, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), University of Florida [Gainesville] (UF), Mayo Clinic [Rochester], Stanford University, University of Chicago, U.S. Food and Drug Administration (FDA), Buck Institute for Research on Aging, Henry Ford Hospital, University of Minnesota [Twin Cities] (UMN), University of Minnesota System, Queen Mary University of London (QMUL), National Technical University of Athens [Athens] (NTUA), Endothelium Radiobiology and Targeting (CRCINA-ÉQUIPE 14), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), University of Texas Southwestern Medical Center [Dallas], Virginia Commonwealth University (VCU), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Vanderbilt University [Nashville], Memorial Sloane Kettering Cancer Center [New York], Indiana University School of Medicine, Indiana University System, University of Texas Health Science Center, and The University of Texas Health Science Center at Houston (UTHealth)
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Senescence ,Cancer Research ,Aging ,medicine.medical_treatment ,Oncology and Carcinogenesis ,Radiation Therapy ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,"One-Two Punch" Cancer Therapy ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Senotherapeutics ,Commentaries ,Neoplasms ,Medicine ,Humans ,1112 Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,Cellular Senescence ,030304 developmental biology ,Cancer ,0303 health sciences ,Chemotherapy ,Radiation ,business.industry ,Mechanism (biology) ,Senolytics ,Prevention ,medicine.disease ,Chemotherapy regimen ,Radiation therapy ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Cancer Therapy ,Senescence-Associated Secretory Phenotype ,Senomorphics ,Therapy-Induced Senescence ,AcademicSubjects/MED00010 ,business ,Cell aging ,Biomarkers - Abstract
Cellular senescence is an essential tumor suppressive mechanism that prevents the propagation of oncogenically activated, genetically unstable, and/or damaged cells. Induction of tumor cell senescence is also one of the underlying mechanisms by which cancer therapies exert antitumor activity. However, an increasing body of evidence from preclinical studies demonstrates that radiation and chemotherapy cause accumulation of senescent cells (SnCs) both in tumor and normal tissue. SnCs in tumors can, paradoxically, promote tumor relapse, metastasis, and resistance to therapy, in part, through expression of the senescence-associated secretory phenotype. In addition, SnCs in normal tissue can contribute to certain radiation- and chemotherapy-induced side effects. Because of its multiple roles, cellular senescence could serve as an important target in the fight against cancer. This commentary provides a summary of the discussion at the National Cancer Institute Workshop on Radiation, Senescence, and Cancer (August 10-11, 2020, National Cancer Institute, Bethesda, MD) regarding the current status of senescence research, heterogeneity of therapy-induced senescence, current status of senotherapeutics and molecular biomarkers, a concept of “one-two punch” cancer therapy (consisting of therapeutics to induce tumor cell senescence followed by selective clearance of SnCs), and its integration with personalized adaptive tumor therapy. It also identifies key knowledge gaps and outlines future directions in this emerging field to improve treatment outcomes for cancer patients.
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- 2021
7. FOXO3 targets are reprogrammed as Huntington's disease neural cells and striatal neurons face senescence with p16 INK4a increase
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Voisin, Jessica, Farina, Francesca, Naphade, Swati, Fontaine, Morgane, Tshilenge, Kizito‐Tshitoko, Galicia Aguirre, Carlos, Lopez‐Ramirez, Alejandro, Dancourt, Julia, Ginisty, Aurélie, Sasidharan Nair, Satish, Lakshika Madushani, Kuruwitage, Zhang, Ningzhe, Lejeune, François‐Xavier, Verny, Marc, Campisi, Judith, Ellerby, Lisa M., Neri, Christian, Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Buck Institute for Research on Aging, Lawrence Berkeley National Laboratory [Berkeley] (LBNL), Gestionnaire, Hal Sorbonne Université, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
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Huntington's Disease ,Aging ,1.1 Normal biological development and functioning ,[SDV]Life Sciences [q-bio] ,Neurodegenerative ,Medical and Health Sciences ,Rare Diseases ,neurodegenerative disease ,Neural Stem Cells ,Humans ,2.1 Biological and endogenous factors ,response mechanisms ,neoplasms ,neuronal differentiation ,Cyclin-Dependent Kinase Inhibitor p16 ,Neurons ,temporal dynamics ,Forkhead Box Protein O3 ,Neurosciences ,Original Articles ,Biological Sciences ,Stem Cell Research ,Brain Disorders ,[SDV] Life Sciences [q-bio] ,neuronal senescence ,Huntington Disease ,nervous system ,Neurological ,Original Article ,Stem Cell Research - Nonembryonic - Non-Human ,Developmental Biology - Abstract
Neurodegenerative diseases (ND) have been linked to the critical process in aging—cellular senescence. However, the temporal dynamics of cellular senescence in ND conditions is unresolved. Here, we show senescence features develop in human Huntington's disease (HD) neural stem cells (NSCs) and medium spiny neurons (MSNs), including the increase of p16INK4a, a key inducer of cellular senescence. We found that HD NSCs reprogram the transcriptional targets of FOXO3, a major cell survival factor able to repress cell senescence, antagonizing p16INK4a expression via the FOXO3 repression of the transcriptional modulator ETS2. Additionally, p16INK4a promotes cellular senescence features in human HD NSCs and MSNs. These findings suggest that cellular senescence may develop during neuronal differentiation in HD and that the FOXO3‐ETS2‐p16INK4a axis may be part of molecular responses aimed at mitigating this phenomenon. Our studies identify neuronal differentiation with accelerated aging of neural progenitors and neurons as an alteration that could be linked to NDs., Increasingly pronounced senescence features develop in human Huntington's disease (HD) neural stem cells and striatal neurons, including the increase of p16INK4a. The FOXO3/ß‐catenin complex can oppose these cellular senescence features via transcriptional reprogramming in a Ryk‐dependent manner, antagonizing p16INK4a expression via the repression of the transcriptional modulator ETS2. The HD brain neural lineage may thus face a continuous senescence process.
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- 2020
8. Mitochondrial and cytosolic sources of hydrogen peroxide in resting C2C12 myoblasts
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Bérengère Benoit, Hoi Shan Wong, Martin D. Brand, Buck Institute for Research on Aging, Université de Lyon, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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0301 basic medicine ,Antioxidant ,Pyridones ,medicine.medical_treatment ,Myoblasts, Skeletal ,[SDV]Life Sciences [q-bio] ,Mitochondrion ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Cytosol ,Physiology (medical) ,Catalytic Domain ,medicine ,Animals ,Rats, Wistar ,Hydrogen peroxide ,Cells, Cultured ,Cellular Senescence ,ComputingMilieux_MISCELLANEOUS ,Mice, Inbred C3H ,Superoxide ,NADPH Oxidases ,Glutathione ,Hydrogen Peroxide ,Mitochondria ,Rats ,030104 developmental biology ,chemistry ,Mitochondrial matrix ,Pyrazoles ,Female ,C2C12 ,030217 neurology & neurosurgery - Abstract
The relative contributions of different mitochondrial and cytosolic sources of superoxide and hydrogen peroxide in cells are not well established because of a lack of suitable quantitative assays. To address this problem using resting C2C12 myoblasts we measured the effects of specific inhibitors that do not affect other pathways on the rate of appearance of hydrogen peroxide in the extracellular medium. We used inhibitors of NADPH oxidases (NOXs), suppressors of site IQ electron leak (S1QELs) at mitochondrial Complex I, and suppressors of site IIIQo electron leak (S3QELs) at mitochondrial Complex III. Around 40% of net cellular hydrogen peroxide release was from NOXs and approximately 45% was from the two mitochondrial sites; 30% from site IIIQo and 15% from site IQ. As expected, decreasing cytosolic antioxidant capacity by lowering glutathione levels increased the absolute rates from all sites without changing their proportions, whereas decreasing antioxidant defenses in the mitochondrial matrix increased only the absolute and relative contributions of the two mitochondrial sites. These results show directly that mitochondria are a major contributor to cytosolic hydrogen peroxide in resting C2C12 myoblasts, and provide the first direct evidence of superoxide/hydrogen peroxide production from site IQ in unstressed cells.
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- 2019
9. Cellular Senescence: Defining a Path Forward
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John M. Sedivy, Paul D. Robbins, Cleo L. Bishop, Vassilis G. Gorgoulis, Konstantinos Vougas, Konstantinos Evangelou, Valery Krizhanovsky, Dorothy C. Bennett, Eiji Hara, Diana Jurk, Gerardo Ferbeyre, Judith Campisi, Masashi Narita, Laura J. Niedernhofer, Manuel Serrano, Clemens A. Schmitt, Peter D. Adams, Oliver Bischof, Andrea Alimonti, Marco Demaria, Jesús Gil, Daohong Zhou, Manuel Collado, Thomas von Zglinicki, Andrea B. Maier, João F. Passos, Institut Pasteur [Paris], National and Kapodistrian University of Athens (NKUA), University of Manchester [Manchester], Biomedical Research Foundation of the Academy of Athens (BRFAA), Institute of Cancer Sciences [Glasgow, UK] (CR-UK Beatson Institute), University of Glasgow, Sanford Burnham Prebys Medical Discovery Institute, Oncology Institute of Southern Switzerland (IOSI), Università della Svizzera italiana = University of Italian Switzerland (USI), Universita degli Studi di Padova, Veneto Institute of Molecular Medicine [Padova, Italy] (VIMM), University of London [London], Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Bart's and The London School of Medicine and Dentistry, Queen Mary University of London (QMUL), Buck Institute for Research on Aging, Universidade de Santiago de Compostela [Spain] (USC ), Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Université de Montréal (UdeM), MRC London Institute of Medical Sciences (LMC), Imperial College London, Research Institute for Microbial Diseases [Osaka, Japan] (RIMD), Osaka University [Osaka], Department of Molecular Cell Biology [Rehovot], Weizmann Institute of Science [Rehovot, Israël], Robert and Arlene Kogod Center on Aging [Rochester, MN, USA], Mayo Clinic, Vrije Universiteit Amsterdam [Amsterdam] (VU), University of Melbourne, University of Cambridge [UK] (CAM), University of Minnesota [Twin Cities] (UMN), University of Minnesota System, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Kepler University Hospital, Brown University, Newcastle University [Newcastle], University of Florida [Gainesville] (UF), Institute for Research in Biomedicine [Barcelona, Spain] (IRB), University of Barcelona-Barcelona Institute of Science and Technology (BIST), Institució Catalana de Recerca i Estudis Avançats (ICREA), University of Groningen [Groningen], European Research Institute for the Biology of Ageing [Groningen] (ERIBA), University Medical Center Groningen [Groningen] (UMCG), M.D. is funded by the Dutch Cancer Foundation, Netherlands (grant ID 10989). V.G., K.E., and K.V. were financially supported by the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grants agreement no. 722729 (SYNTRAIN), the Welfare Foundation for Social & Cultural Sciences (KIKPE), Greece, the KIKPE Foundation, Athens, Greece, Pentagon Biotechnology, UK, DeepMed IO, UK, grant no. 775 from the Hellenic Foundation for Research and Innovation (HFRI), and NKUA-SARG grants 70/3/9816, 70/3/12128, and 70/3/15603. M.S.: is funded by the IRB and by grants from the Spanish Ministry of Economy co-funded by the European Regional Development Fund (ERDF) (SAF2013-48256-R), the European Research Council (ERC-2014-AdG/669622), and 'laCaixa' Foundation., We would like to thank Nikolaos Kastrinakis, Panagiotis V.S. Vasileiou, Gkikas Magiorkinis, Eleni Fitsiou, and Michela Borghesan for their valuable support to this work. We apologize in advance that, for reason of space, we have omitted the citations of relevant papers and reviews., National and Kapodistrian University of Athens = University of Athens (NKUA | UoA), Organisation Nucléaire et Oncogenèse - Nuclear Organization and Oncogenesis, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], University of Santiago de Compostela [Spain] (USC), Centre de recherche du Chum [Montréal] (CRCHUM), Université de Montréal [Montréal], Research Institute for Microbial Diseases, Weizmann Institute of Science, University of Minnesota [Twin Cities], Max Delbrück Center for Molecular Medicine [Berlin], Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, University of Florida [Gainesville], University of Barcelona, Università degli Studi di Padova = University of Padua (Unipd), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Narita, Masashi [0000-0001-7764-577X], and Apollo - University of Cambridge Repository
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Senescence ,EXPRESSION ,Aging ,Cell cycle checkpoint ,[SDV]Life Sciences [q-bio] ,Cell ,DNA-DAMAGE RESPONSE ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Computational biology ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Mitochondrion ,Biology ,General Biochemistry, Genetics and Molecular Biology ,CHROMATIN LANDSCAPE ,03 medical and health sciences ,0302 clinical medicine ,MITOCHONDRIA ,ONCOGENE-INDUCED SENESCENCE ,medicine ,Humans ,OXIDATIVE STRESS ,Senolytic ,Cellular Senescence ,11 Medical and Health Sciences ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,P53 ,[SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology ,Genetic Diseases, Inborn ,DARK SIDE ,Cell Cycle Checkpoints ,06 Biological Sciences ,CANCER ,Chromatin ,medicine.anatomical_structure ,Gene Expression Regulation ,CELLS ,Developmental biology ,030217 neurology & neurosurgery ,Biomarkers ,Developmental Biology - Abstract
International audience; Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especially in vivo, is essential. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers. We also present a resource tool to facilitate the identification of genes linked with senescence, SeneQuest (available at http://Senequest.net). Lastly, we propose an algorithm to accurately assess and quantify senescence, both in cultured cells and in vivo.
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- 2019
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10. Characterization of Stimulus-Secretion Coupling in the Human Pancreatic EndoC-βH1 Beta Cell Line
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Vladimir V. Sharoyko, Raphael Scharfmann, David G. Nicholls, Annika Bagge, Peter Spégel, Philippe Ravassard, Lotta Andersson, Bérengère Valtat, Hindrik Mulder, Unit of Molecular Metabolism, Lund University [Lund]-Clinical Research Centre (CRC), Bioenergetics laboratory, Buck Institute for Research on Aging, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This study was funded by research grantsfrom the Crafoordska (www.crafoord.se), Knut andAlice Wallenberg (www.wallenberg.com/kaw), LarsHiertas Minne (www.larshiertasminne.se), Söderberg(www.torstensoderbergsstiftelse.se), O.E. och EdlaJohansson (www.stiftelsen.rago.se), and AlbertPåhlsson foundations, and the Swedish ResearchCouncil (VR 14196-12-5,www.vr.se)., Bos, Mireille, Clinical Research Centre (CRC)- Lund University Diabetes Centre (LUDC), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), and Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )
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medicine.medical_treatment ,lcsh:Medicine ,030209 endocrinology & metabolism ,Carbohydrate metabolism ,Biology ,Endocrinology and Diabetes ,Calcium in biology ,Cell Line ,Membrane Potentials ,03 medical and health sciences ,0302 clinical medicine ,Adenosine Triphosphate ,Oxygen Consumption ,Insulin-Secreting Cells ,Extracellular ,medicine ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Humans ,Insulin ,Glycolysis ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,lcsh:Science ,[ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,Multidisciplinary ,Cell growth ,lcsh:R ,Glucose ,Biochemistry ,Cell culture ,Metabolome ,lcsh:Q ,Calcium ,Beta cell ,Research Article - Abstract
International audience; AIMS/HYPOTHESIS:Studies on beta cell metabolism are often conducted in rodent beta cell lines due to the lack of stable human beta cell lines. Recently, a human cell line, EndoC-βH1, was generated. Here we investigate stimulus-secretion coupling in this cell line, and compare it with that in the rat beta cell line, INS-1 832/13, and human islets.METHODS:Cells were exposed to glucose and pyruvate. Insulin secretion and content (radioimmunoassay), gene expression (Gene Chip array), metabolite levels (GC/MS), respiration (Seahorse XF24 Extracellular Flux Analyzer), glucose utilization (radiometric), lactate release (enzymatic colorimetric), ATP levels (enzymatic bioluminescence) and plasma membrane potential and cytoplasmic Ca2+ responses (microfluorometry) were measured. Metabolite levels, respiration and insulin secretion were examined in human islets.RESULTS:Glucose increased insulin release, glucose utilization, raised ATP production and respiratory rates in both lines, and pyruvate increased insulin secretion and respiration. EndoC-βH1 cells exhibited higher insulin secretion, while plasma membrane depolarization was attenuated, and neither glucose nor pyruvate induced oscillations in intracellular calcium concentration or plasma membrane potential. Metabolite profiling revealed that glycolytic and TCA-cycle intermediate levels increased in response to glucose in both cell lines, but responses were weaker in EndoC-βH1 cells, similar to those observed in human islets. Respiration in EndoC-βH1 cells was more similar to that in human islets than in INS-1 832/13 cells.CONCLUSIONS/INTERPRETATION:Functions associated with early stimulus-secretion coupling, with the exception of plasma membrane potential and Ca2+ oscillations, were similar in the two cell lines; insulin secretion, respiration and metabolite responses were similar in EndoC-βH1 cells and human islets. While both cell lines are suitable in vitro models, with the caveat of replicating key findings in isolated islets, EndoC-βH1 cells have the advantage of carrying the human genome, allowing studies of human genetic variants, epigenetics and regulatory RNA molecules.
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- 2015
11. The 'mitoflash' probe cpYFP does not respond to superoxide
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Paul T. Schumacker, Christine C. Winterbourn, Stephan Wagner, Joseph S. Beckman, Andreas J. Meyer, Yulia G. Ermakova, Tobias P. Dick, Andrew P. Halestrap, Mark D. Fricker, Markus Schwarzländer, Garry R. Buettner, Rafael Radi, Ursula Jakob, Michael R. Duchen, Florian L. Muller, Nicolas Demaurex, David G. Nicholls, S. James Remington, Henry Jay Forman, Bruce A. Morgan, Nick S. Jones, David C. Logan, Barry Halliwell, Lee J. Sweetlove, Michael P. Murphy, Vsevolod V. Belousov, David Gems, Iain G. Johnston, Institute of Crop Science and Resource Conservation, Rheinische Friedrich-Wilhelms-Universität Bonn, Shemyakin Oychinnikov Institute Bioorgan Chemistry, Russian Academy of Sciences [Moscow] (RAS), Departamento de Bioquı´mica, and Center for Free Radical and BiomedicalResearch, Facultad deMedicina, Universidad de la República [Montevideo] (UCUR), Univ Republica, Fac Med, Ctr Free Rad & Biomed Res, Montevideo 11800, Uruguay, Université Paris Diderot - Paris 7 (UPD7), Linus Pauling Institute, Environmental Health Sciences Center, Department of Biochemistry and Biophysics, Oregon State University (OSU), Department of Radiation Oncology and Interdisciplinary Grad Program Human Toxicology, University of Iowa [Iowa City], Univ Iowa, ESR Facil, Coll Med, Med Labs B180K, Iowa City, IA 52242 USA, Univ Iowa, Dept Radiat Oncol, Iowa City, IA 52242 USA, Department of Cell Physiology and Metabolism, University of Geneva Medical School, Department of Cell and Developmental Biology and Consortium for Mitochondrial Research, University College of London [London] (UCL), UCL, Consortium Mitochondrial Res, London WC1E 6BT, England, Davis School Gerontology, Andrus Gerontoogyl Center, University of Southern California (USC), Life and Environmental Science Unit, University of California [Merced], University of California-University of California, Department of Plant Sciences, University of Oxford [Oxford], Dept of Genetics, Evolution and Environment [London] (UCL-GEE), UCL, Inst Hlth Ageing, London WC1E 6BT, England, School of Biochemistry and Bristol CardioVascular, University of Bristol [Bristol], Department of Biochemistry, National University of Singapore (NUS), Molecular, Cellular and Development Biology Department, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of Mathematics [Imperial College London], Imperial College London, Institut de Recherche en Horticulture et Semences (IRHS), AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA)-Université d'Angers (UA), Division of Redox Regulation, DKFZ ZMBH Alliance, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department Cancer Biology, The University of Texas M.D. Anderson Cancer Center [Houston], Buck Institute for Research on Aging, Institut of Molecular Biology, Department of Physic, University of Oregon [Eugene], Division of Neonatology, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Department Pathology, Centre Free Radical Research, University of Otago [Dunedin, Nouvelle-Zélande], Department of Plant Science, Institut of Crop Science and Resource Conservation INRES, Mitochondrial Biology Unit, Medical Research Council, Université d'Angers (UA)-Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Institute of Crop Science and Resource Conservation [Bonn], AGROCAMPUS OUEST, and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de la Recherche Agronomique (INRA)-Université d'Angers (UA)
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Yellow fluorescent protein ,Male ,Aging ,Bioenergetics ,General Science & Technology ,PH ,1.1 Normal biological development and functioning ,[SDV]Life Sciences [q-bio] ,Longevity ,Biology ,Mitochondrion ,chemistry.chemical_compound ,Underpinning research ,Superoxides ,SIGNALS ,Mitochondria/metabolism ,Animals ,ddc:612 ,Caenorhabditis elegans ,MITOCHONDRIAL SUPEROXIDE ,Caenorhabditis elegans/metabolism ,Multidisciplinary ,Superoxide ,FLASHES ,Metabolism ,biology.organism_classification ,Cell biology ,Mitochondria ,chemistry ,Biochemistry ,Ageing ,biology.protein ,Generic health relevance ,Superoxides/metabolism ,Function (biology) - Abstract
Arising from E.-Z. Shen et al. , 128–132 (2014); doi:10.1038/nature1301210.1038/nature13012 Ageing and lifespan of organisms are determined by complicated interactions between their genetics and the environment, but the cellular mechanisms remain controversial; several studies suggest that cellular energy metabolism and free radical dynamics affect lifespan, implicating mitochondrial function. Recently, Shen et al.1 provided apparent mechanistic insight by reporting that mitochondrial oscillations of ‘free radical production’, called ‘mitoflashes’, in the pharynx of three-day old Caenorhabditis elegans correlated inversely with lifespan. The interpretation of mitoflashes as ‘bursts of superoxide radicals’ assumes that circularly permuted yellow fluorescent protein (cpYFP) is a reliable indicator of mitochondrial superoxide2, but this interpretation has been criticized because experiments and theoretical considerations both show that changes in cpYFP fluorescence are due to alterations in pH, not superoxide3,4,5,6,7. Here we show that purified cpYFP is completely unresponsive to superoxide, and that mitoflashes do not reflect superoxide generation or provide a link between mitochondrial free radical dynamics and lifespan. There is a Reply to this Brief Communication Arising by Cheng, H. Nature 514, http://dx.doi.org/10.1038/nature13859 (2014).
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- 2014
12. The Ribosomal Protein Rpl22 Controls Ribosome Composition by Directly Repressing Expression of Its Own Paralog, Rpl22l1
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Carly A. Holstein, David L. Wiest, Matt Kaeberlein, John Morton, Yong Zhang, Emmeline C. Academia, Warren C. Ladiges, Pamela J. Fink, Monique N. O’Leary, Vivian L. MacKay, Anne Cécile E Duc, Katherine H. Schreiber, Shuyun Rao, J. Scott Hale, Brian K. Kennedy, Shreya R. Shah, Daniel Martin, Department of Biochemistry [Washington ], University of Washington [Seattle], Buck Institute for Research on Aging, Fox Chase Cancer Center, Department of Immunology, Department of Comparative Medicine, Institute for Systems Biology [Seattle] (ISB), and Department of Pathology
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Ribosomal Proteins ,Cancer Research ,lcsh:QH426-470 ,Mouse ,Molecular Sequence Data ,Protein Synthesis ,Biology ,Biochemistry ,Ribosome ,Mice ,03 medical and health sciences ,5S ribosomal RNA ,Model Organisms ,Ribosomal protein ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Genetics ,Animals ,Eukaryotic Small Ribosomal Subunit ,Amino Acid Sequence ,Molecular Biology ,Genetics (clinical) ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,0303 health sciences ,Sequence Homology, Amino Acid ,Eukaryotic Large Ribosomal Subunit ,030302 biochemistry & molecular biology ,Proteins ,RNA-Binding Proteins ,Translation (biology) ,Animal Models ,RNA stability ,Ribosomal RNA ,Regulatory Proteins ,lcsh:Genetics ,Gene Expression Regulation ,Protein Biosynthesis ,RNA ,Gene expression ,Eukaryotic Ribosome ,Ribosomes ,Research Article - Abstract
Most yeast ribosomal protein genes are duplicated and their characterization has led to hypotheses regarding the existence of specialized ribosomes with different subunit composition or specifically-tailored functions. In yeast, ribosomal protein genes are generally duplicated and evidence has emerged that paralogs might have specific roles. Unlike yeast, most mammalian ribosomal proteins are thought to be encoded by a single gene copy, raising the possibility that heterogenous populations of ribosomes are unique to yeast. Here, we examine the roles of the mammalian Rpl22, finding that Rpl22−/− mice have only subtle phenotypes with no significant translation defects. We find that in the Rpl22−/− mouse there is a compensatory increase in Rpl22-like1 (Rpl22l1) expression and incorporation into ribosomes. Consistent with the hypothesis that either ribosomal protein can support translation, knockdown of Rpl22l1 impairs growth of cells lacking Rpl22. Mechanistically, Rpl22 regulates Rpl22l1 directly by binding to an internal hairpin structure and repressing its expression. We propose that ribosome specificity may exist in mammals, providing evidence that one ribosomal protein can influence composition of the ribosome by regulating its own paralog., Author Summary Translation is the process by which proteins are made within a cell. Ribosomes are the main macromolecular complexes involved in this process. Ribosomes are composed of ribosomal RNA and ribosomal proteins. Ribosomal proteins are generally thought to be structural components of the ribosome but recent findings have suggested that they might have a regulatory function as well. A growing number of human diseases have been linked to mutations in genes encoding factors involved in ribosome biogenesis and translation. These include developmental malformations, inherited bone marrow failure syndromes and cancer in a variety of organisms. Here, we describe the role of one ribosomal protein regulating another. We provide evidence that ribosomal proteins can influence the composition of the ribosome, which we hypothesize, may impact the function of the ribosome.
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- 2013
13. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes
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Klionsky, Daniel J., Abeliovich, Hagai, Agostinis, Patrizia, Agrawal, Devendra K., Aliev, Giumrakch, Askew, David S., Baba, Misuzu, Baehrecke, Eric H., Bahr, Ben A., Ballabio, Andrea, Bamber, Bruce A., Bassham, Diane C., Bergamini, Ettore, Bi, Xiaoning, Biard-Piechaczyk, Martine, Blum, Janice S., Breclesen, Dale E., Brodsky, Jeffrey, Brumell, John H., Brunk, Ulf T., Bursch, Wilfried, Camougrand, Nadine, Cebollero, Eduardo, Cecconi, Francesco, Chen, Yingyu, Chin, Lih-Shen, Choi, Augustine, Chu, Charleen T., Chung, Jongkyeong, Clarke, Peter G. H., Clark, Robert S. B., Clarke, Steven G., Clavé, Corinne, Cleveland, John L., Codogno, Patrice, Colombo, Maria I., Coto-Montes, Ana, Cregg, James M., Cuervo, Ana Maria, Debnath, Jayanta, Demarchi, Francesca, Dennis, Patrick B., Dennis, Phillip A., Deretic, Vojo, Devenish, Rodney J., Di Sano, Federica, Dice, J. Fred, Difiglia, Marian, Dinesh-Kumar, Savithramma, Distelhorst, Clark W., Djavaheri-Mergny, Mojgan, Dorsey, Frank C., Dröge, Wulf, Dron, Michel, Dunn Jr., William A., Duszenko, Michael, Eissa, N. Tony, Elazar, Zvulun, Esclatine, Audrey, Eskelinen, Eeva-Liisa, Fesus, Laszlo, Finley, Kim D., Fuentes, José M., Fueyo, Juan, Fujisaki, Kozo, Galliot, Brigitte, Gao, Fen-Biao, Gewirtz, David A., Gibson, Spencer B., Gohla, Antje, Goldberg, Alfred L., Gonzalez, Ramon, González-Estévez, Cristina, Gorski, Sharon, Gottlieb, Roberta A., Häussinger, Dieter, He, You-Wen, Heidenreich, Kim, Hill, Joseph A., Hoyer-Hansen, Maria, Hu, Xun, Huang, Wei-Pang, Iwasaki, Akiko, Jäättelä, Marja, Jackson, William T., Jiang, Xuejun, Jin, Shengkan, Johansen, Terje, Jung, Jae U., Kadowaki, Motoni, Kang, Chanhee, Kelekar, Ameeta, Kessel, David H., Kiel, Jan A.K.W., Kim, Hong Pyo, Kimchi, Adi, Kinsella, Timothy J., Kiselyov, Kirill, Kitamoto, Katsuhiko, Knecht, Erwin, Komatsu, Masaaki, Kominami, Eiki, Konclo, Seiji, University of Michigan [Ann Arbor], University of Michigan System, Hebrew University of Jerusalem, Université Catholique de Louvain = Catholic University of Louvain (UCL), Creighton University, The University of Texas Health Science Center at Houston (UTHealth), University of Cincinnati (UC), Department of Chemical and Biological Sciences, University of Huddersfield, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), University of Connecticut (UCONN), Telethon Institute of Genetics and Medicine, University of Toledo, Department of Genetics, Development, and Cell Biology, Iowa State University (ISU), Universita degli studi di Pisa, Basic Medical Sciences, Western University of Health Sciences, Centre National de la Recherche Scientifique (CNRS), Indiana University, Indiana University System, Buck Institute for Research on Aging, Department of Biological Sciences, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Massachusetts General Hospital [Boston], Cell Biology Program, Utrecht University [Utrecht], Linköping University (LIU), Medizinische Universität Wien = Medical University of Vienna, Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Università degli Studi di Roma Tor Vergata [Roma], Peking University, School of Medicine / Department of Pharmacology, University of California, Harvard University [Cambridge], Pennsylvania Commonwealth System of Higher Education (PCSHE), Korea Advanced Institute of Science and Technology (KAIST), Université de Lausanne (UNIL), Department of Chemistry and Biochemistry, University of California [Los Angeles] (UCLA), University of California-University of California, Molecular Biology Institute, Université de Bordeaux Ségalen [Bordeaux 2], Scripps Research Institute, Université Paris-Sud - Paris 11 (UP11), Signalisation et physiopathologie des cellules épithéliales, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Oviedo [Oviedo], Keck Graduate Institute [Claremont, Californie] (KGI), Albert Einstein College of Medicine [New York], University of California [San Francisco] (UCSF), Consorzio Interuniversitario, National Cancer Institute, The University of New Mexico [Albuquerque], Monash University, Dipartimento Biol, University of Naples Federico II, Tufts University, Dept Neurol, Syngenta, Yale University, Partenaires INRAE, Case Western Reserve University [Cleveland], University Hospitals of Cleveland, Immunotec Research Ltd., Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), University of Florida [Gainesville] (UF), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Baylor College of Medicine (BCM), Department of Biological Chemistry, Weizmann Institute of Science [Rehovot, Israël], University of Helsinki, University of Debrecen, Hungarian Academy of Sciences (MTA), Salk Institute for Biological Studies, Plant Molecular and Cellular Biology Laboratory, Universidad de Extremadura (UEX), University of Texas, Kagoshima University, Department of Zoology and Animal Biology, University of Geneva [Switzerland], Virginia Commonwealth University (VCU), University of Manitoba, University of Manitoba [Winnipeg], Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Department of Cell Biology, Charles University [Prague] (CU), University of Nottingham, UK (UON), British Columbia Cancer Agency, San Diego State University (SDSU), Duke University [Durham], University of Colorado [Boulder], University of Texas Southwestern Medical Center, Danish Cancer Society, Zhejiang University, National Taiwan Normal University (NTNU), Yale University [New Haven], Medical College of Wisconsin, Memorial Sloan Kettering Cancer Center, The University of Texas M.D. Anderson Cancer Center [Houston], University of Medecine and Dentistry of New Jersey, and ProdInra, Migration
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[SDV] Life Sciences [q-bio] ,phagophore ,stress ,[SDV]Life Sciences [q-bio] ,autophagosome ,autolysosome - Abstract
La liste complète des auteurs est disponible sur la notice WOS : http://gateway.isiknowledge.com/gateway/Gateway.cgi?&GWVersion=2&SrcAuth=INRA&SrcApp=INRA&DestLinkType=FullRecord&DestApp=WOS&KeyUT=ISI:000253008800003; International audience
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- 2008
14. Efficient identification of critical residues based only on protein structure by network analysis
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Dale E. Bredesen, Gabriel del Rio, Michael P. Cusack, Boris Thibert, Buck Institute for Research on Aging, Modélisation Géométrique & Multirésolution pour l'Image (MGMI), Laboratoire Jean Kuntzmann (LJK), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS), Department of Neurology [UCLA], University of California [Los Angeles] (UCLA), University of California-University of California-David Geffen School of Medicine [Los Angeles], University of California-University of California, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), and Centre National de la Recherche Scientifique (CNRS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Centre National de la Recherche Scientifique (CNRS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF)
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Protein structure database ,Protein Conformation ,Science ,030303 biophysics ,Protein design ,Computational Biology/Macromolecular Structure Analysis ,Computational biology ,Bioinformatics ,[INFO.INFO-CG]Computer Science [cs]/Computational Geometry [cs.CG] ,03 medical and health sciences ,Protein sequencing ,Protein structure ,030304 developmental biology ,Physics ,0303 health sciences ,Automatic sequence ,Internet ,Multidisciplinary ,Proteins ,Reproducibility of Results ,Protein structure prediction ,Biochemistry/Bioinformatics ,Medicine ,Function (biology) ,Algorithms ,Network analysis ,Research Article - Abstract
International audience; Despite the increasing number of published protein structures, and the fact that each protein's function relies on its three-dimensional structure, there is limited access to automatic programs used for the identification of critical residues from the protein structure, compared with those based on protein sequence. Here we present a new algorithm based on network analysis applied exclusively on protein structures to identify critical residues. Our results show that this method identifies critical residues for protein function with high reliability and improves automatic sequence-based approaches and previous network-based approaches. The reliability of the method depends on the conformational diversity screened for the protein of interest. We have designed a web site to give access to this software at http://bis.ifc.unam.mx/jamming/. In summary, a new method is presented that relates critical residues for protein function with the most traversed residues in networks derived from protein structures. A unique feature of the method is the inclusion of the conformational diversity of proteins in the prediction, thus reproducing a basic feature of the structure/function relationship of proteins.
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- 2007
15. Multimodal Transformers and Their Applications in Drug Target Discovery for Aging and Age-Related Diseases.
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Steurer B, Vanhaelen Q, and Zhavoronkov A
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- Humans, Artificial Intelligence, Longevity drug effects, Machine Learning, Neural Networks, Computer, Aging physiology, Drug Discovery methods
- Abstract
Given the unprecedented rate of global aging, advancing aging research and drug discovery to support healthy and productive longevity is a pressing socioeconomic need. Holistic models of human and population aging that account for biomedical background, environmental context, and lifestyle choices are fundamental to address these needs, but integration of diverse data sources and large data sets into comprehensive models is challenging using traditional approaches. Recent advances in artificial intelligence and machine learning, and specifically multimodal transformer-based neural networks, have enabled the development of highly capable systems that can generalize across multiple data types. As such, multimodal transformers can generate systemic models of aging that can predict health status and disease risks, identify drivers, or breaks of physiological aging, and aid in target discovery against age-related disease. The unprecedented capacity of transformers to extract and integrate information from large and diverse data modalities, combined with the ever-increasing availability of biological and medical data, has the potential to revolutionize healthcare, promoting healthy longevity and mitigating the societal and economic impacts of global aging., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)
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- 2024
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16. Bringing Geroscience into the Mainstream: From Education to Clinical Practice, What Will It Take?
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Al-Naggar IM, Campellone KG, Espinoza SE, Justice JN, Orr ME, Kozikowski C, van der Willik O, Thatcher C, Schmader K, Pignolo RJ, Newman JC, and Kuchel GA
- Subjects
- Humans, Geriatrics education
- Published
- 2024
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17. Ketone monoester attenuates oxygen desaturation during weighted ruck exercise under acute hypoxic exposure but does not impact cognitive performance.
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McClure TS, Phillips J, Kernagis D, Coleman K, Chappe E, Cutter GR, Egan B, Norell T, Stubbs BJ, Bamman MM, and Koutnik AP
- Abstract
Acute ingestion of exogenous ketone supplements in the form of a (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (R-BD R-βHB) ketone monoester (KME) can attenuate declines in oxygen availability during hypoxic exposure and might impact cognitive performance at rest and in response to moderate-intensity exercise. In a single-blind randomized crossover design, 16 males performed assessments of cognitive performance before and during hypoxic exposure with moderate exercise [2 × 20 min weighted ruck (∼22 kg) at 3.2 km/h at 10% incline] in a normobaric altitude chamber (4572 m, 11.8% O
2 ). The R-BD R-βHB KME (573 mg/kg) or a calorie- and taste-matched placebo (∼50 g maltodextrin) were co-ingested with 40 g of dextrose before exposure to hypoxia. The R-βHB concentrations were rapidly elevated and sustained (>3 mM; P < 0.001) by KME. The decline in oxygen saturation during hypoxic exposure was attenuated in KME conditions by 2.4%-4.2% (P < 0.05) compared with placebo. Outcomes of cognitive performance tasks, in the form of the Defense Automated Neurobehavioral Assessment (DANA) code substitution task, the Stroop color and word task, and a shooting simulation, did not differ between trials before and during hypoxic exposure. These data suggest that the acute exogenous ketosis induced by KME ingestion can attenuate declining blood oxygen saturation during acute hypoxic exposure both at rest and during moderate-intensity exercise, but this did not translate into differences in cognitive performance before or after exercise in the conditions investigated. HIGHLIGHTS: What is the central question of this study? Can exogenous ketosis act as a countermeasure to declines in blood oxygen saturation and cognitive performance during acute hypoxic exposure while performing a weighted ruck exercise? What is the main finding and its importance? Acute exogenous ketosis via ingestion of a drink containing the (R)-3-hydroxybutyl (R)-3-hydroxybutyrate ketone monoester prior to acute hypoxic exposure attenuated hypoxia-induced declines in blood oxygen saturation but had no effect on cognitive performance during exercise., (© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)- Published
- 2024
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18. Obesity intensifies sex-specific interferon signaling to selectively worsen central nervous system autoimmunity in females.
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Cordeiro B, Ahn JJ, Gawde S, Ucciferri C, Alvarez-Sanchez N, Revelo XS, Stickle N, Massey K, Brooks DG, Guthridge JM, Pardo G, Winer DA, Axtell RC, and Dunn SE
- Abstract
Obesity has been implicated in the rise of autoimmunity in women. We report that obesity induces a serum protein signature that is associated with T helper 1 (Th1), interleukin (IL)-17, and multiple sclerosis (MS) signaling pathways selectively in human females. Females, but not male mice, subjected to diet-induced overweightness/obesity (DIO) exhibited upregulated Th1/IL-17 inflammation in the central nervous system during experimental autoimmune encephalomyelitis, a model of MS. This was associated with worsened disability and a heightened expansion of myelin-specific Th1 cells in the peripheral lymphoid organs. Moreover, at steady state, DIO increased serum levels of interferon (IFN)-α and potentiated STAT1 expression and IFN-γ production by naive CD4
+ T cells uniquely in female mice. This T cell phenotype was driven by increased adiposity and was prevented by the removal of ovaries or knockdown of the type I IFN receptor in T cells. Our findings offer a mechanistic explanation of how obesity enhances autoimmunity., Competing Interests: Declaration of interests J.J.A. is currently an employee of Bristol Myers Squibb. R.C.A. is on the advisory board for Progentec Diagnostics Inc., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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19. Stem cell transcriptional profiles from mouse subspecies reveal cis-regulatory evolution at translation genes.
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Simon NM, Kim Y, Bautista DM, Dutton JR, and Brem RB
- Abstract
A key goal of evolutionary genomics is to harness molecular data to draw inferences about selective forces that have acted on genomes. The field progresses in large part through the development of advanced molecular-evolution analysis methods. Here we explored the intersection between classical sequence-based tests for selection and an empirical expression-based approach, using stem cells from Mus musculus subspecies as a model. Using a test of directional, cis-regulatory evolution across genes in pathways, we discovered a unique program of induction of translation genes in stem cells of the Southeast Asian mouse M. m. castaneus relative to its sister taxa. We then mined population-genomic sequences to pursue underlying regulatory mechanisms for this expression divergence, finding robust evidence for alleles unique to M. m. castaneus at the upstream regions of the translation genes. We interpret our data under a model of changes in lineage-specific pressures across Mus musculus in stem cells with high translational capacity. Our findings underscore the rigor of integrating expression and sequence-based methods to generate hypotheses about evolutionary events from long ago., (© 2024. The Author(s).)
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- 2024
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20. Molecular Mechanisms of Autophagy Decline during Aging.
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Lim SHY, Hansen M, and Kumsta C
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- Humans, Animals, Autophagy genetics, Aging genetics, Aging metabolism
- Abstract
Macroautophagy (hereafter autophagy) is a cellular recycling process that degrades cytoplasmic components, such as protein aggregates and mitochondria, and is associated with longevity and health in multiple organisms. While mounting evidence supports that autophagy declines with age, the underlying molecular mechanisms remain unclear. Since autophagy is a complex, multistep process, orchestrated by more than 40 autophagy-related proteins with tissue-specific expression patterns and context-dependent regulation, it is challenging to determine how autophagy fails with age. In this review, we describe the individual steps of the autophagy process and summarize the age-dependent molecular changes reported to occur in specific steps of the pathway that could impact autophagy. Moreover, we describe how genetic manipulations of autophagy-related genes can affect lifespan and healthspan through studies in model organisms and age-related disease models. Understanding the age-related changes in each step of the autophagy process may prove useful in developing approaches to prevent autophagy decline and help combat a number of age-related diseases with dysregulated autophagy.
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- 2024
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21. Hypoxia decreases mitochondrial ROS production in cells.
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Sen B, Benoit B, and Brand MD
- Abstract
We re-examined the reported increase in mitochondrial ROS production during acute hypoxia in cells. Using the Amplex Ultrared/horseradish peroxidase assay we found a decrease, not increase, in hydrogen peroxide release from HEK293 cells under acute hypoxia, at times ranging from 1 min to 3 h. The rates of superoxide/hydrogen peroxide production from each of the three major sites (site I
Q in complex I and site IIIQo in complex III in mitochondria, and NADH oxidases (NOX) in the cytosol) were decreased to the same extent by acute hypoxia, with no change in the cells' ability to degrade added hydrogen peroxide. A similar decrease in ROS production under acute hypoxia was found using the diacetyldichlorofluorescein assay. Using a HIF1α reporter cell line we confirmed earlier observations that suppression of superoxide production by site IIIQo decreases HIF1α expression, and found similar effects of suppressing site IQ or NOX. We conclude that increased mitochondrial ROS do not drive the response of HIF1α to acute hypoxia, but suggest that cytosolic H2 O2 derived from site IQ , site IIIQo and NOX in cells is necessary to permit HIF1α stabilization by other signals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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22. Daily consumption of ketone ester, bis-octanoyl (R)-1,3-butanediol, is safe and tolerable in healthy older adults in a randomized, parallel arm, double-blind, placebo-controlled, pilot study.
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Stubbs BJ, Stephens EB, Senadheera C, Peralta S, Roa-Diaz S, Alexander L, Silverman-Martin W, Garcia TY, Yukawa M, Morris J, Blonquist TM, Johnson JB, and Newman JC
- Abstract
Objectives: Ketone bodies are endogenous metabolites produced during fasting or a ketogenic diet that have pleiotropic effects on aging pathways. Ketone esters (KEs) are compounds that induce ketosis without dietary changes, but KEs have not been studied in an older adult population. The primary objective of this trial was to assess the tolerability and safety of KE ingestion in a cohort of older adults., Design: Randomized, placebo-controlled, double-blinded, parallel-arm trial (NCT05585762)., Setting: General community, Northern California, USA., Participants: Community-dwelling older adults, independent in activities of daily living, with no unstable acute medical conditions (n = 30; M = 15, F = 15; age = 76 y, range 65-90 y) were randomized and n = 23 (M = 14, F = 9) completed the protocol., Intervention: Participants were randomly allocated to consume either KE (25 g bis-octanoyl (R)-1,3-butanediol) or a taste, appearance, and calorie-matched placebo (PLA) containing canola oil daily for 12 weeks., Measurements: Tolerability was assessed using a composite score from a daily log for 2-weeks, and then via a bi-weekly phone interview. Safety was assessed by vital signs and lab tests at screening and weeks 0, 4 and 12, along with tabulation of adverse events., Results: There was no difference in the prespecified primary outcome of proportion of participants reporting moderate or severe nausea, headache, or dizziness on more than one day in a two-week reporting period (KE n = 2 (14.3% [90% CI = 2.6-38.5]); PLA n = 1 (7.1% [90% CI = 0.4-29.7]). Dropouts numbered four in the PLA group and two in the KE group. A greater number of symptoms were reported in both groups during the first two weeks; symptoms were reported less frequently between 2 and 12 weeks. There were no clinically relevant changes in safety labs or vital signs in either group., Conclusions: This KE was safe and well-tolerated in this study of healthy older adults. These results provide an initial foundation for use of KEs in clinical research with older adults., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
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- 2024
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23. Precious2GPT: the combination of multiomics pretrained transformer and conditional diffusion for artificial multi-omics multi-species multi-tissue sample generation.
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Sidorenko D, Pushkov S, Sakip A, Leung GHD, Lok SWY, Urban A, Zagirova D, Veviorskiy A, Tihonova N, Kalashnikov A, Kozlova E, Naumov V, Pun FW, Aliper A, Ren F, and Zhavoronkov A
- Abstract
Synthetic data generation in omics mimics real-world biological data, providing alternatives for training and evaluation of genomic analysis tools, controlling differential expression, and exploring data architecture. We previously developed Precious1GPT, a multimodal transformer trained on transcriptomic and methylation data, along with metadata, for predicting biological age and identifying dual-purpose therapeutic targets potentially implicated in aging and age-associated diseases. In this study, we introduce Precious2GPT, a multimodal architecture that integrates Conditional Diffusion (CDiffusion) and decoder-only Multi-omics Pretrained Transformer (MoPT) models trained on gene expression and DNA methylation data. Precious2GPT excels in synthetic data generation, outperforming Conditional Generative Adversarial Networks (CGANs), CDiffusion, and MoPT. We demonstrate that Precious2GPT is capable of generating representative synthetic data that captures tissue- and age-specific information from real transcriptomics and methylomics data. Notably, Precious2GPT surpasses other models in age prediction accuracy using the generated data, and it can generate data beyond 120 years of age. Furthermore, we showcase the potential of using this model in identifying gene signatures and potential therapeutic targets in a colorectal cancer case study., (© 2024. The Author(s).)
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- 2024
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24. Characteristics, Complications, and Outcomes of Critical Illness in Patients with Parkinson Disease.
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Lieberman OJ, Douglas VC, and LaHue SC
- Abstract
Background: Adults with Parkinson disease (PD) are hospitalized at higher rates than age-matched controls, and these hospitalizations are associated with significant morbidity. However, little is known about the consequences of critical illness requiring intensive care unit (ICU)-level care in patients with PD. The aim of this study was to define the characteristics and outcomes of adults with PD admitted to the ICU., Methods: We performed a retrospective nested case-control study using the Medical Information Mart for Intensive Care IV data set. Adults with PD were identified, and the index ICU admission for these subjects was matched 1:4 with index ICU admissions without a PD diagnosis based on age, sex, comorbidities, illness severity, ICU type, and need for mechanical ventilation. Primary outcomes were in-hospital mortality and discharge location. Secondary outcomes were length of stay and prespecified complications., Results: A total of 630 adults with PD were identified. Patients with PD were older and were more likely to be male, have more comorbidities, and have higher illness severity at presentation. A matched analysis revealed adults with PD did not have a significant difference in in-hospital mortality but were more likely to be discharged to a higher level of care. Adults with PD had longer hospital lengths of stay and increased odds of delirium, pressure ulcers, and ileus., Conclusions: During critical illness, patients with PD are at increased risk for longer hospital lengths of stay and complications and require a higher level of care at discharge than matched controls. These findings reveal targets for interventions to improve outcomes for patients with PD and may inform discussions about goals of care in this population., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)
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- 2024
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25. Sirt5 regulates chondrocyte metabolism and osteoarthritis development through protein lysine malonylation.
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Liu H, Binoy A, Ren S, Martino TC, Miller AE, Willis CRG, Veerabhadraiah SR, Sukul A, Bons J, Rose JP, Schilling B, Jurynec MJ, and Zhu S
- Abstract
Objectives: Chondrocyte metabolic dysfunction plays an important role in osteoarthritis (OA) development during aging and obesity. Protein post-translational modifications (PTMs) have recently emerged as an important regulator of cellular metabolism. We aim to study one type of PTM, lysine malonylation (MaK) and its regulator Sirt5 in OA development., Methods: Human and mouse cartilage tissues were used to measure SIRT5 and MaK levels. Both systemic and cartilage-specific conditional knockout mouse models were subject to high-fat diet (HFD) treatment to induce obesity and OA. Proteomics analysis was performed in Sirt5
-/- and WT chondrocytes. SIRT5 mutation was identified in the Utah Population Database (UPDB)., Results: We found that SIRT5 decreases while MAK increases in the cartilage during aging. A combination of Sirt5 deficiency and obesity exacerbates joint degeneration in a sex dependent manner in mice. We further delineate the malonylome in chondrocytes, pinpointing MaK's predominant impact on various metabolic pathways such as carbon metabolism and glycolysis. Lastly, we identified a rare coding mutation in SIRT5 that dominantly segregates in a family with OA. The mutation results in substitution of an evolutionally invariant phenylalanine (Phe-F) to leucine (Leu-L) (F101L) in the catalytic domain. The mutant protein results in higher MaK level and decreased expression of cartilage ECM genes and upregulation of inflammation associated genes., Conclusions: We found that Sirt5 mediated MaK is an important regulator of chondrocyte cellular metabolism and dysregulation of Sirt5-MaK could be an important mechanism underlying aging and obesity associated OA development.- Published
- 2024
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26. Role of the National Institute on Aging in Transforming Aging Research Through Geroscience and Gerotherapeutics-50 Years of Innovation.
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Newman JC, Al-Naggar IM, and Kuchel GA
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- 2024
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27. Development of an epigenetic clock resistant to changes in immune cell composition.
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Tomusiak A, Floro A, Tiwari R, Riley R, Matsui H, Andrews N, Kasler HG, and Verdin E
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- Humans, Adult, Female, Male, Young Adult, Middle Aged, Aged, Cellular Senescence genetics, Cellular Senescence immunology, Adolescent, Epigenesis, Genetic, DNA Methylation, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Aging genetics, Aging immunology
- Abstract
Epigenetic clocks are age predictors that use machine-learning models trained on DNA CpG methylation values to predict chronological or biological age. Increases in predicted epigenetic age relative to chronological age (epigenetic age acceleration) are connected to aging-associated pathologies, and changes in epigenetic age are linked to canonical aging hallmarks. However, epigenetic clocks rely on training data from bulk tissues whose cellular composition changes with age. Here, we found that human naive CD8
+ T cells, which decrease in frequency during aging, exhibit an epigenetic age 15-20 years younger than effector memory CD8+ T cells from the same individual. Importantly, homogenous naive T cells isolated from individuals of different ages show a progressive increase in epigenetic age, indicating that current epigenetic clocks measure two independent variables, aging and immune cell composition. To isolate the age-associated cell intrinsic changes, we created an epigenetic clock, the IntrinClock, that did not change among 10 immune cell types tested. IntrinClock shows a robust predicted epigenetic age increase in a model of replicative senescence in vitro and age reversal during OSKM-mediated reprogramming., (© 2024. The Author(s).)- Published
- 2024
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28. The Space Omics and Medical Atlas (SOMA) and international astronaut biobank.
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Overbey EG, Kim J, Tierney BT, Park J, Houerbi N, Lucaci AG, Garcia Medina S, Damle N, Najjar D, Grigorev K, Afshin EE, Ryon KA, Sienkiewicz K, Patras L, Klotz R, Ortiz V, MacKay M, Schweickart A, Chin CR, Sierra MA, Valenzuela MF, Dantas E, Nelson TM, Cekanaviciute E, Deards G, Foox J, Narayanan SA, Schmidt CM, Schmidt MA, Schmidt JC, Mullane S, Tigchelaar SS, Levitte S, Westover C, Bhattacharya C, Lucotti S, Wain Hirschberg J, Proszynski J, Burke M, Kleinman AS, Butler DJ, Loy C, Mzava O, Lenz J, Paul D, Mozsary C, Sanders LM, Taylor LE, Patel CO, Khan SA, Suhail Mohamad M, Byhaqui SGA, Aslam B, Gajadhar AS, Williamson L, Tandel P, Yang Q, Chu J, Benz RW, Siddiqui A, Hornburg D, Blease K, Moreno J, Boddicker A, Zhao J, Lajoie B, Scott RT, Gilbert RR, Lai Polo SH, Altomare A, Kruglyak S, Levy S, Ariyapala I, Beer J, Zhang B, Hudson BM, Rininger A, Church SE, Beheshti A, Church GM, Smith SM, Crucian BE, Zwart SR, Matei I, Lyden DC, Garrett-Bakelman F, Krumsiek J, Chen Q, Miller D, Shuga J, Williams S, Nemec C, Trudel G, Pelchat M, Laneuville O, De Vlaminck I, Gross S, Bolton KL, Bailey SM, Granstein R, Furman D, Melnick AM, Costes SV, Shirah B, Yu M, Menon AS, Mateus J, Meydan C, and Mason CE
- Subjects
- Humans, Aerospace Medicine, Metabolomics, Proteomics, Epigenomics, Precision Medicine, Male, Internationality, Microbiota genetics, Atlases as Topic, Animals, Astronauts, Space Flight, Biological Specimen Banks, Genomics
- Abstract
Spaceflight induces molecular, cellular and physiological shifts in astronauts and poses myriad biomedical challenges to the human body, which are becoming increasingly relevant as more humans venture into space
1-6 . Yet current frameworks for aerospace medicine are nascent and lag far behind advancements in precision medicine on Earth, underscoring the need for rapid development of space medicine databases, tools and protocols. Here we present the Space Omics and Medical Atlas (SOMA), an integrated data and sample repository for clinical, cellular and multi-omic research profiles from a diverse range of missions, including the NASA Twins Study7 , JAXA CFE study8,9 , SpaceX Inspiration4 crew10-12 , Axiom and Polaris. The SOMA resource represents a more than tenfold increase in publicly available human space omics data, with matched samples available from the Cornell Aerospace Medicine Biobank. The Atlas includes extensive molecular and physiological profiles encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics and microbiome datasets, which reveal some consistent features across missions, including cytokine shifts, telomere elongation and gene expression changes, as well as mission-specific molecular responses and links to orthologous, tissue-specific mouse datasets. Leveraging the datasets, tools and resources in SOMA can help to accelerate precision aerospace medicine, bringing needed health monitoring, risk mitigation and countermeasure data for upcoming lunar, Mars and exploration-class missions., (© 2024. The Author(s).)- Published
- 2024
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29. A second space age spanning omics, platforms and medicine across orbits.
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Mason CE, Green J, Adamopoulos KI, Afshin EE, Baechle JJ, Basner M, Bailey SM, Bielski L, Borg J, Borg J, Broddrick JT, Burke M, Caicedo A, Castañeda V, Chatterjee S, Chin CR, Church G, Costes SV, De Vlaminck I, Desai RI, Dhir R, Diaz JE, Etlin SM, Feinstein Z, Furman D, Garcia-Medina JS, Garrett-Bakelman F, Giacomello S, Gupta A, Hassanin A, Houerbi N, Irby I, Javorsky E, Jirak P, Jones CW, Kamal KY, Kangas BD, Karouia F, Kim J, Kim JH, Kleinman AS, Lam T, Lawler JM, Lee JA, Limoli CL, Lucaci A, MacKay M, McDonald JT, Melnick AM, Meydan C, Mieczkowski J, Muratani M, Najjar D, Othman MA, Overbey EG, Paar V, Park J, Paul AM, Perdyan A, Proszynski J, Reynolds RJ, Ronca AE, Rubins K, Ryon KA, Sanders LM, Glowe PS, Shevde Y, Schmidt MA, Scott RT, Shirah B, Sienkiewicz K, Sierra MA, Siew K, Theriot CA, Tierney BT, Venkateswaran K, Hirschberg JW, Walsh SB, Walter C, Winer DA, Yu M, Zea L, Mateus J, and Beheshti A
- Subjects
- Humans, United States National Aeronautics and Space Administration, Astronauts, United States, Genomics, Biomarkers metabolism, Biomarkers analysis, Pharmacogenetics, Space Flight, Precision Medicine methods, Precision Medicine trends, Aerospace Medicine trends
- Abstract
The recent acceleration of commercial, private and multi-national spaceflight has created an unprecedented level of activity in low Earth orbit, concomitant with the largest-ever number of crewed missions entering space and preparations for exploration-class (lasting longer than one year) missions. Such rapid advancement into space from many new companies, countries and space-related entities has enabled a 'second space age'. This era is also poised to leverage, for the first time, modern tools and methods of molecular biology and precision medicine, thus enabling precision aerospace medicine for the crews. The applications of these biomedical technologies and algorithms are diverse, and encompass multi-omic, single-cell and spatial biology tools to investigate human and microbial responses to spaceflight. Additionally, they extend to the development of new imaging techniques, real-time cognitive assessments, physiological monitoring and personalized risk profiles tailored for astronauts. Furthermore, these technologies enable advancements in pharmacogenomics, as well as the identification of novel spaceflight biomarkers and the development of corresponding countermeasures. In this Perspective, we highlight some of the recent biomedical research from the National Aeronautics and Space Administration, Japan Aerospace Exploration Agency, European Space Agency and other space agencies, and detail the entrance of the commercial spaceflight sector (including SpaceX, Blue Origin, Axiom and Sierra Space) into aerospace medicine and space biology, the first aerospace medicine biobank, and various upcoming missions that will utilize these tools to ensure a permanent human presence beyond low Earth orbit, venturing out to other planets and moons., (© 2024. Springer Nature Limited.)
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- 2024
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30. A Multiomics, Molecular Atlas of Breast Cancer Survivors.
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Bauer BA, Schmidt CM, Ruddy KJ, Olson JE, Meydan C, Schmidt JC, Smith SY, Couch FJ, Earls JC, Price ND, Dudley JT, Mason CE, Zhang B, Phipps SM, and Schmidt MA
- Abstract
Breast cancer imposes a significant burden globally. While the survival rate is steadily improving, much remains to be elucidated. This observational, single time point, multiomic study utilizing genomics, proteomics, targeted and untargeted metabolomics, and metagenomics in a breast cancer survivor (BCS) and age-matched healthy control cohort (N = 100) provides deep molecular phenotyping of breast cancer survivors. In this study, the BCS cohort had significantly higher polygenic risk scores for breast cancer than the control group. Carnitine and hexanoyl carnitine were significantly different. Several bile acid and fatty acid metabolites were significantly dissimilar, most notably the Omega-3 Index (O3I) (significantly lower in BCS). Proteomic and metagenomic analyses identified group and pathway differences, which warrant further investigation. The database built from this study contributes a wealth of data on breast cancer survivorship where there has been a paucity, affording the ability to identify patterns and novel insights that can drive new hypotheses and inform future research. Expansion of this database in the treatment-naïve, newly diagnosed, controlling for treatment confounders, and through the disease progression, can be leveraged to profile and contextualize breast cancer and breast cancer survivorship, potentially leading to the development of new strategies to combat this disease and improve the quality of life for its victims.
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- 2024
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31. Aberrant bowel movement frequencies coincide with increased microbe-derived blood metabolites associated with reduced organ function.
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Johnson-Martínez JP, Diener C, Levine AE, Wilmanski T, Suskind DL, Ralevski A, Hadlock J, Magis AT, Hood L, Rappaport N, and Gibbons SM
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- Humans, Male, Female, Adult, Middle Aged, Indican blood, Gastrointestinal Motility physiology, Constipation blood, Constipation microbiology, Aged, Gastrointestinal Microbiome physiology
- Abstract
Bowel movement frequency (BMF) directly impacts the gut microbiota and is linked to diseases like chronic kidney disease or dementia. In particular, prior work has shown that constipation is associated with an ecosystem-wide switch from fiber fermentation and short-chain fatty acid production to more detrimental protein fermentation and toxin production. Here, we analyze multi-omic data from generally healthy adults to see how BMF affects their molecular phenotypes, in a pre-disease context. Results show differential abundances of gut microbial genera, blood metabolites, and variation in lifestyle factors across BMF categories. These differences relate to inflammation, heart health, liver function, and kidney function. Causal mediation analysis indicates that the association between lower BMF and reduced kidney function is partially mediated by the microbially derived toxin 3-indoxyl sulfate (3-IS). This result, in a generally healthy context, suggests that the accumulation of microbiota-derived toxins associated with abnormal BMF precede organ damage and may be drivers of chronic, aging-related diseases., Competing Interests: Declaration of interests L.H. is a former shareholder of Arivale. A.T.M. was a former employee of Arivale. Arivale is no longer a commercially operating company as of April 2019., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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32. The infrapatellar fat pad in inflammaging, knee joint health, and osteoarthritis.
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Wang MG, Seale P, and Furman D
- Abstract
Osteoarthritis (OA) is the most common form of arthritis and accounts for nearly $140 billion in annual healthcare expenditures only in the United States. Obesity, aging, and joint injury are major risk factors for OA development and progression, but the mechanisms contributing to pathology remain unclear. Emerging evidence suggests that cellular dysregulation and inflammation in joint tissues, including intra-articular adipose tissue depots, may contribute to disease severity. In particular, the infrapatellar fat pad (IFP), located in the knee joint, which provides a protective cushion for joint loading, also secretes multiple endocrine factors and inflammatory cytokines (inflammaging) that can regulate joint physiology and disease. Correlates of cartilage degeneration and OA-associated disease severity include inflammation and fibrosis of IFP in model organisms and human studies. In this article, we discuss recent progress in understanding the roles and regulation of intra-articular fat tissue in regulating joint biology and OA., (© 2024. The Author(s).)
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- 2024
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33. 17-β-estradiol and phytoestrogens elicit NO production and vasodilatation through PI3K, PKA and EGF receptors pathways, evidencing functional selectivity.
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Catalán-Salas V, Sagredo P, Melgarejo W, Donoso MV, Cárdenas JC, Zakarian A, Valdés D, Acuña-Castillo C, and Huidobro-Toro JP
- Subjects
- Animals, Rats, Male, Isoflavones pharmacology, Endothelial Cells drug effects, Endothelial Cells metabolism, Genistein pharmacology, Receptors, Estrogen metabolism, Rats, Wistar, Phytoestrogens pharmacology, Estradiol pharmacology, Nitric Oxide metabolism, Signal Transduction drug effects, Vasodilation drug effects, Cyclic AMP-Dependent Protein Kinases metabolism, Phosphatidylinositol 3-Kinases metabolism, ErbB Receptors metabolism
- Abstract
Endothelial cells express multiple receptors mediating estrogen responses; including the G protein-coupled estrogen receptor (GPER). Past studies on nitric oxide (NO) production elicited by estrogens raised the question whether 17-β-estradiol (E2) and natural phytoestrogens activate equivalent mechanisms. We hypothesized that E2 and phytoestrogens elicit NO production via coupling to distinct intracellular pathways signalling. To this aim, perfusion of E2 and phytoestrogens to the precontracted rat mesentery bed examined vasorelaxation, while fluorescence microscopy on primary endothelial cells cultures quantified single cell NO production determined following 4-amino-5-methylamino-2',7'-difluoroescein diacetate (DAF) incubation. Daidzein (DAI) and genistein (GEN) induced rapid vasodilatation associated to NO production. Multiple estrogen receptor activity was inferred based on the reduction of DAF-NO signals; G-36 (GPER antagonist) reduced 75 % of all estrogen responses, while fulvestrant (selective nuclear receptor antagonist) reduced significantly more the phytoestrogens responses than E2. The joint application of both antagonists abolished the E2 response but not the phytoestrogen-induced DAF-NO signals. Wortmannin or LY-294002 (PI3K inhibitors), reduced by 90% the E2-evoked signal while altering significantly less the DAI-induced response. In contrast, H-89 (PKA inhibitor), elicited a 23% reduction of the E2-induced signal while blocking 80% of the DAI-induced response. Desmethylxestospongin-B (IP3 receptor antagonist), decreased to equal extent the E2 or the DAI-induced signal. Epidermal growth factor (EGF) induced NO production, cell treatment with AG-1478, an EGF receptor kinase inhibitor reduced 90% DAI-induced response while only 53% the E2-induced signals; highlighting GPER induced EGF receptor trans-modulation. Receptor functional selectivity may explain distinct signalling pathways mediated by E2 and phytoestrogens., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)
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- 2024
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34. Microbial community-scale metabolic modelling predicts personalized short-chain fatty acid production profiles in the human gut.
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Quinn-Bohmann N, Wilmanski T, Sarmiento KR, Levy L, Lampe JW, Gurry T, Rappaport N, Ostrem EM, Venturelli OS, Diener C, and Gibbons SM
- Subjects
- Humans, Prebiotics, Probiotics metabolism, Probiotics administration & dosage, Models, Biological, Diet, Bacteria metabolism, Bacteria genetics, Cohort Studies, Gastrointestinal Tract microbiology, Gastrointestinal Tract metabolism, Adult, Fatty Acids, Volatile metabolism, Gastrointestinal Microbiome
- Abstract
Microbially derived short-chain fatty acids (SCFAs) in the human gut are tightly coupled to host metabolism, immune regulation and integrity of the intestinal epithelium. However, the production of SCFAs can vary widely between individuals consuming the same diet, with lower levels often associated with disease. A systems-scale mechanistic understanding of this heterogeneity is lacking. Here we use a microbial community-scale metabolic modelling (MCMM) approach to predict individual-specific SCFA production profiles to assess the impact of different dietary, prebiotic and probiotic inputs. We evaluate the quantitative accuracy of our MCMMs using in vitro and ex vivo data, plus published human cohort data. We find that MCMM SCFA predictions are significantly associated with blood-derived clinical chemistries, including cardiometabolic and immunological health markers, across a large human cohort. Finally, we demonstrate how MCMMs can be leveraged to design personalized dietary, prebiotic and probiotic interventions aimed at optimizing SCFA production in the gut. Our model represents an approach to direct gut microbiome engineering for precision health and nutrition., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2024
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35. Succinylation of Park7 activates a protective metabolic response to acute kidney injury.
- Author
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Pfister K, Young V, Frankel B, Silva Barbosa A, Burton J, Bons J, Zhang B, Chiba T, Uhlean R, Goetzman E, Schilling B, and Sims-Lucas S
- Subjects
- Animals, Protein Processing, Post-Translational, Mice, Inbred C57BL, Disease Models, Animal, Male, Sirtuins metabolism, NF-E2-Related Factor 2 metabolism, Signal Transduction, Mice, Oxidative Stress, Lysine metabolism, Acute Kidney Injury metabolism, Acute Kidney Injury prevention & control, Acute Kidney Injury pathology, Kidney Tubules, Proximal metabolism, Kidney Tubules, Proximal pathology, Protein Deglycase DJ-1 metabolism, Protein Deglycase DJ-1 genetics
- Abstract
Acute kidney injury (AKI) is extremely prevalent among hospitalizations and presents a significant risk for the development of chronic kidney disease and increased mortality. Ischemia caused by shock, trauma, and transplant are common causes of AKI. To attenuate ischemic AKI therapeutically, we need a better understanding of the physiological and cellular mechanisms underlying damage. Instances of ischemia are most damaging in proximal tubule epithelial cells (PTECs) where hypoxic signaling cascades, and perhaps more rapidly, posttranslational modifications (PTMs), act in concert to change cellular metabolism. Here, we focus on the effects of the understudied PTM, lysine succinylation. We have previously shown a protective effect of protein hypersuccinylation on PTECs after depletion of the desuccinylase sirtuin5. General trends in the results suggested that hypersuccinylation led to upregulation of peroxisomal activity and was protective against kidney injury. Included in the list of changes was the Parkinson's-related deglycase Park7. There is little known about any links between peroxisome activity and Park7. In this study, we show in vitro and in vivo that Park7 has a crucial role in protection from AKI and upregulated peroxisome activity. These data in combination with published results of Park7's protective role in cardiovascular damage and chronic kidney disease lead us to hypothesize that succinylation of Park7 may ameliorate oxidative damage resulting from AKI and prevent disease progression. This novel mechanism provides a potential therapeutic mechanism that can be targeted. NEW & NOTEWORTHY Succinylation is an understudied posttranslational modification that has been shown to increase peroxisomal activity. Furthermore, increased peroxisomal activity has been shown to reduce oxidative stress and protect proximal tubules after acute kidney injury. Analysis of mass spectrometry succinylomic and proteomic data reveals a novel role for Parkinson's related Park7 in mediating Nrf2 antioxidant response after kidney injury. This novel protection pathway provides new insights for kidney injury prevention and development of novel therapeutics.
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- 2024
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36. A Brief History of Slow Spinal Potentials, Gate Theory of Pain, and Spinal Cord Stimulation.
- Author
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Bikson M and Sharma M
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- Humans, History, 20th Century, Pain physiopathology, Pain Management methods, Pain Management history, History, 21st Century, Spinal Cord Stimulation methods, Spinal Cord Stimulation history, Spinal Cord physiology
- Abstract
Competing Interests: Conflict of Interest The City University of New York holds patents on brain stimulation with Marom Bikson as inventor. Marom Bikson has equity in Soterix Medical Inc; consults, received grants, assigned inventions, and/or served on the scientific advisory board of SafeToddles, Boston Scientific, GlaxoSmithKline, Biovisics, Mecta, Lumenis, Halo Neuroscience, Google-X, i-Lumen, Humm, Allergan (Abbvie), Apple, Ybrain, Ceragem, and Remz; and is supported by grants from Harold Shames and the National Institutes of Health (NIH): NIH-National Institute on Drug Abuse (NIDA) UG3DA048502, NIH-National Institute of General Medical Sciences (NIGMS) T34 GM137858, NIH-National Institute of Neurological Disorders and Stroke (NINDS) R01 NS112996, NIH-NINDS R01 NS101362, and NIH-Graduate Research Training Initiative for Student Enhancement T32GM136499. Mahima Sharma reported no conflict of interest.
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- 2024
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37. Navigating the Landscape of Translational Geroscience in Canada: A Comprehensive Evaluation of Current Progress and Future Directions.
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Hajj-Boutros G, Faust A, Muscedere J, Kim P, Abumrad N, Chevalier S, Aubertin-Leheudre M, Bergman H, Bowdish D, Burford J, Carrington-Lawrence S, Côté H, Dawe DE, Barreto PS, Farrelly C, Fowler R, Gouspillou G, Harrington L, Lautrup S, Howlett S, Imani M, Kirkland J, Kuchel G, Mallette FA, Morais JA, Newman JC, Pullman D, Sierra F, Van Raamsdonk J, Watt J, Rylett RJ, and Duque G
- Subjects
- Humans, Canada, Aging genetics, Aging physiology, Quality of Life, Aged, Forecasting, Geriatrics trends, Translational Research, Biomedical
- Abstract
The inaugural Canadian Conferences on Translational Geroscience were held as 2 complementary sessions in October and November 2023. The conferences explored the profound interplay between the biology of aging, social determinants of health, the potential societal impact of geroscience, and the maintenance of health in aging individuals. Although topics such as cellular senescence, molecular and genetic determinants of aging, and prevention of chronic disease were addressed, the conferences went on to emphasize practical applications for enhancing older people's quality of life. This article summarizes the proceeding and underscores the synergy between clinical and fundamental studies. Future directions highlight national and global collaborations and the crucial integration of early-career investigators. This work charts a course for a national framework for continued innovation and advancement in translational geroscience in Canada., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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38. Author Correction: PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy.
- Author
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Dou X, Fu Q, Long Q, Liu S, Zou Y, Fu D, Xu Q, Jiang Z, Ren X, Zhang G, Wei X, Li Q, Campisi J, Zhao Y, and Sun Y
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- 2024
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39. Applying the area fraction fractionator (AFF) probe for total volume estimations of somatic, dendritic and axonal domains of the nigrostriatal dopaminergic system in a murine model.
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Oñate-Ponce A, Muñoz-Muñoz C, Catenaccio A, Court FA, and Henny P
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- Animals, Corpus Striatum, Male, Dopaminergic Neurons metabolism, Mice, Microscopy, Confocal methods, Substantia Nigra metabolism, Axons metabolism, Dendrites, Mice, Inbred C57BL
- Abstract
Background: The Cavalieri estimator is used for volume measurement of brain and brain regions. Derived from this estimator is the Area Fraction Fractionator (AFF), used for efficient area and number estimations of small 2D elements, such as axons in cross-sectioned nerves. However, to our knowledge, the AFF has not been combined with serial sectioning analysis to measure the volume of small-size nervous structures., New Method: Using the nigrostriatal dopaminergic system as an illustrative case, we describe a protocol based on Cavalieri's principle and AFF to estimate the volume of its somatic, nuclear, dendritic, axonal and axon terminal cellular compartments in the adult mouse. The protocol consists of (1) systematic random sampling of sites within and across sections in regions of interest (substantia nigra, the nigrostriatal tract, caudate-putamen), (2) confocal image acquisition of sites, (3) marking of cellular domains using Cavalieri's 2D point-counting grids, and 4) determination of compartments' total volume using the estimated area of each compartment, and between-sections distance., Results: The volume of the nigrostriatal system per hemisphere is ∼0.38 mm
3 , with ∼5 % corresponding to perikarya and cell nuclei, ∼10 % to neuropil/dendrites, and ∼85 % to axons and varicosities., Comparison With Existing Methods: In contrast to other methods to measure volume of discrete objects, such as the optical nucleator or 3D reconstructions, it stands out for its versatility and ease of use., Conclusions: The use of a simple quantitative, unbiased approach to assess the global state of a system may allow quantification of compartment-specific changes that may accompany neurodegenerative processes., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)- Published
- 2024
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40. Characterizing phenotypic data of Peromyscus leucopus compared to C57BL/6J Mus musculus and diversity outbred (DO) Mus musculus.
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Wimer LA, Davis-Castillo A, Galkina S, Ciotlos S, Patterson C, Prado L, Munoz MC, Martin N, Epstein S, Schaum N, and Melov S
- Subjects
- Animals, Mice, Muscle, Skeletal physiology, Male, Models, Animal, Female, Species Specificity, Peromyscus physiology, Mice, Inbred C57BL, Phenotype, Aging physiology, Body Composition physiology
- Abstract
Translational research is commonly performed in the C57B6/J mouse strain, chosen for its genetic homogeneity and phenotypic uniformity. Here, we evaluate the suitability of the white-footed deer mouse (Peromyscus leucopus) as a model organism for aging research, offering a comparative analysis against C57B6/J and diversity outbred (DO) Mus musculus strains. Our study includes comparisons of body composition, skeletal muscle function, and cardiovascular parameters, shedding light on potential applications and limitations of P. leucopus in aging studies. Notably, P. leucopus exhibits distinct body composition characteristics, emphasizing reduced muscle force exertion and a unique metabolism, particularly in fat mass. Cardiovascular assessments showed changes in arterial stiffness, challenging conventional assumptions and highlighting the need for a nuanced interpretation of aging-related phenotypes. Our study also highlights inherent challenges associated with maintaining and phenotyping P. leucopus cohorts. Behavioral considerations, including anxiety-induced responses during handling and phenotyping assessment, pose obstacles in acquiring meaningful data. Moreover, the unique anatomy of P. leucopus necessitates careful adaptation of protocols designed for Mus musculus. While showcasing potential benefits, further extensive analyses across broader age ranges and larger cohorts are necessary to establish the reliability of P. leucopus as a robust and translatable model for aging studies., (© 2024. The Author(s).)
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- 2024
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41. A Fully-Automated Senescence Test (FAST) for the high-throughput quantification of senescence-associated markers.
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Neri F, Takajjart SN, Lerner CA, Desprez PY, Schilling B, Campisi J, and Gerencser AA
- Subjects
- Humans, Cells, Cultured, Image Processing, Computer-Assisted, Fibroblasts, Single-Cell Analysis methods, Cellular Senescence physiology, Biomarkers metabolism, High-Throughput Screening Assays methods, beta-Galactosidase metabolism
- Abstract
Cellular senescence is a major driver of aging and age-related diseases. Quantification of senescent cells remains challenging due to the lack of senescence-specific markers and generalist, unbiased methodology. Here, we describe the Fully-Automated Senescence Test (FAST), an image-based method for the high-throughput, single-cell assessment of senescence in cultured cells. FAST quantifies three of the most widely adopted senescence-associated markers for each cell imaged: senescence-associated β-galactosidase activity (SA-β-Gal) using X-Gal, proliferation arrest via lack of 5-ethynyl-2'-deoxyuridine (EdU) incorporation, and enlarged morphology via increased nuclear area. The presented workflow entails microplate image acquisition, image processing, data analysis, and graphing. Standardization was achieved by (i) quantifying colorimetric SA-β-Gal via optical density; (ii) implementing staining background controls; and (iii) automating image acquisition, image processing, and data analysis. In addition to the automated threshold-based scoring, a multivariate machine learning approach is provided. We show that FAST accurately quantifies senescence burden and is agnostic to cell type and microscope setup. Moreover, it effectively mitigates false-positive senescence marker staining, a common issue arising from culturing conditions. Using FAST, we compared X-Gal with fluorescent C
12 FDG live-cell SA-β-Gal staining on the single-cell level. We observed only a modest correlation between the two, indicating that those stains are not trivially interchangeable. Finally, we provide proof of concept that our method is suitable for screening compounds that modify senescence burden. This method will be broadly useful to the aging field by enabling rapid, unbiased, and user-friendly quantification of senescence burden in culture, as well as facilitating large-scale experiments that were previously impractical., (© 2024. The Author(s).)- Published
- 2024
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42. Amyloid β accelerates age-related proteome-wide protein insolubility.
- Author
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Anderton E, Chamoli M, Bhaumik D, King CD, Xie X, Foulger A, Andersen JK, Schilling B, and Lithgow GJ
- Subjects
- Animals, Humans, Proteomics, Proteostasis, Solubility, Disease Models, Animal, Amyloid beta-Peptides metabolism, Proteome metabolism, Aging metabolism, Aging genetics, Caenorhabditis elegans metabolism, Alzheimer Disease metabolism, Alzheimer Disease genetics
- Abstract
Loss of proteostasis is a highly conserved feature of aging across model organisms and results in the accumulation of insoluble protein aggregates. Protein insolubility is also a unifying feature of major age-related neurodegenerative diseases, including Alzheimer's Disease (AD), in which hundreds of insoluble proteins associate with aggregated amyloid beta (Aβ) in senile plaques. Despite the connection between aging and AD risk, therapeutic approaches to date have overlooked aging-driven generalized protein insolubility as a contributing factor. However, proteins that become insoluble during aging in model organisms are capable of accelerating Aβ aggregation in vitro and lifespan in vivo. Here, using an unbiased proteomics approach, we questioned the relationship between Aβ and age-related protein insolubility. Specifically, we uncovered that Aβ expression drives proteome-wide protein insolubility in C. elegans, even in young animals, and this insoluble proteome is highly similar to the insoluble proteome driven by normal aging, this vulnerable sub-proteome we term the core insoluble proteome (CIP). We show that the CIP is enriched with proteins that modify Aβ toxicity in vivo, suggesting the possibility of a vicious feedforward cycle in the context of AD. Importantly, using human genome-wide association studies (GWAS), we show that the CIP is replete with biological processes implicated not only in neurodegenerative diseases but also across a broad array of chronic, age-related diseases (CARDs). This provides suggestive evidence that age-related loss of proteostasis could play a role in general CARD risk. Finally, we show that the geroprotective, gut-derived metabolite, Urolithin A, relieves Aβ toxicity, supporting its use in clinical trials for dementia and age-related diseases., (© 2024. The Author(s).)
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- 2024
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43. Protocol for mass spectrometric profiling of lysine malonylation by lysine acetyltransferase in CRISPRi K562 cell lines.
- Author
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Zhang R, Bons J, Rose JP, Schilling B, and Verdin E
- Subjects
- Humans, K562 Cells, CRISPR-Cas Systems, Protein Processing, Post-Translational, Malonates metabolism, RNA, Guide, CRISPR-Cas Systems metabolism, Lysine metabolism, Mass Spectrometry methods, Lysine Acetyltransferases metabolism, Lysine Acetyltransferases genetics
- Abstract
Lysine malonylation is a protein posttranslational modification. We present a protocol to generate stable gene-knockdown K562 cell lines through lentiviral infection of a CRISPR interference (CRISPRi) system followed by lysine malonylation measurement using mass spectrometry (MS). We detail guide RNA (gRNA) vector cloning, lentiviral infection, cell line purification, protein digestion, malonyl-lysine enrichment, desalting, and MS acquisition and analysis. For complete details on the use and execution of this protocol, please refer to Zhang et al.
1 and Bons et al.2 ., Competing Interests: Declaration of interests E.V. is a scientific co-founder of Napa Therapeutics and serves on the scientific advisory board of Seneque., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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44. Mitochondrial division inhibitor (mdivi-1) induces extracellular matrix (ECM)-detachment of viable breast cancer cells by a DRP1-independent mechanism.
- Author
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Silva-Pavez E, Mendoza E, Morgado-Cáceres P, Ahumada-Castro U, Bustos G, Kangme-Encalada M, de Arbina AL, Puebla-Huerta A, Muñoz F, Cereceda L, Varas-Godoy M, Hidalgo Y, and Cardenas JC
- Subjects
- Humans, Female, Cell Line, Tumor, Cell Adhesion drug effects, Cell Movement drug effects, Cell Survival drug effects, Cell Proliferation drug effects, Mitochondria metabolism, Mitochondria drug effects, Dynamins metabolism, Breast Neoplasms metabolism, Breast Neoplasms pathology, Breast Neoplasms drug therapy, Extracellular Matrix metabolism, Extracellular Matrix drug effects, Quinazolinones pharmacology, Mitochondrial Dynamics drug effects
- Abstract
Increasing evidence supports the hypothesis that cancer progression is under mitochondrial control. Mitochondrial fission plays a pivotal role in the maintenance of cancer cell homeostasis. The inhibition of DRP1, the main regulator of mitochondrial fission, with the mitochondrial division inhibitor (mdivi-1) had been associated with cancer cell sensitivity to chemotherapeutics and decrease proliferation. Here, using breast cancer cells we find that mdivi-1 induces the detachment of the cells, leading to a bulk of floating cells that conserved their viability. Despite a decrease in their proliferative and clonogenic capabilities, these floating cells maintain the capacity to re-adhere upon re-seeding and retain their migratory and invasive potential. Interestingly, the cell detachment induced by mdivi-1 is independent of DRP1 but relies on inhibition of mitochondrial complex I. Furthermore, mdivi-1 induces cell detachment rely on glucose and the pentose phosphate pathway. Our data evidence a novel DRP1-independent effect of mdivi-1 in the attachment of cancer cells. The generation of floating viable cells restricts the use of mdivi-1 as a therapeutic agent and demonstrates that mdivi-1 effect on cancer cells are more complex than anticipated., (© 2024. The Author(s).)
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- 2024
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45. Ketogenic diet administration later in life improves memory by modifying the synaptic cortical proteome via the PKA signaling pathway in aging mice.
- Author
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Acuña-Catalán D, Shah S, Wehrfritz C, Nomura M, Acevedo A, Olmos C, Quiroz G, Huerta H, Bons J, Ampuero E, Wyneken U, Sanhueza M, Arancibia F, Contreras D, Cárdenas JC, Morales B, Schilling B, Newman JC, and González-Billault C
- Subjects
- Animals, Mice, Male, Mice, Inbred C57BL, Hippocampus metabolism, Synapses metabolism, Brain-Derived Neurotrophic Factor metabolism, Neuronal Plasticity physiology, Phosphorylation, Cyclic AMP-Dependent Protein Kinases metabolism, Aging physiology, Aging metabolism, Signal Transduction, Diet, Ketogenic methods, Proteome metabolism, Memory physiology, Long-Term Potentiation physiology
- Abstract
Aging compromises brain function leading to cognitive decline. A cyclic ketogenic diet (KD) improves memory in aged mice after long-term administration; however, short-term effects later in life and the molecular mechanisms that govern such changes remain unclear. Here, we explore the impact of a short-term KD treatment starting at elderly stage on brain function of aged mice. Behavioral testing and long-term potentiation (LTP) recordings reveal that KD improves working memory and hippocampal LTP. Furthermore, the synaptosome proteome of aged mice fed a KD long-term evidence changes predominantly at the presynaptic compartment associated to the protein kinase A (PKA) signaling pathway. These findings were corroborated in vivo by western blot analysis, with high BDNF abundance and PKA substrate phosphorylation. Overall, we show that a KD modifies brain function even when it is administered later in life and recapitulates molecular features of long-term administration, including the PKA signaling pathway, thus promoting synaptic plasticity at advanced age., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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46. Primary oocytes with cellular senescence features are involved in ovarian aging in mice.
- Author
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Yan H, Miranda EAD, Jin S, Wilson F, An K, Godbee B, Zheng X, Brau-Rodríguez AR, and Lei L
- Subjects
- Animals, Female, Mice, Sulfonamides pharmacology, Ovarian Follicle metabolism, Ovarian Follicle drug effects, Ovarian Follicle cytology, Aniline Compounds pharmacology, Senescence-Associated Secretory Phenotype, Senotherapeutics pharmacology, Oocytes metabolism, Oocytes drug effects, Oocytes cytology, Cellular Senescence, Aging physiology, Ovary metabolism, Ovary cytology, Ovary physiology
- Abstract
In mammalian females, quiescent primordial follicles serve as the ovarian reserve and sustain normal ovarian function and egg production via folliculogenesis. The loss of primordial follicles causes ovarian aging. Cellular senescence, characterized by cell cycle arrest and production of the senescence-associated secretory phenotype (SASP), is associated with tissue aging. In the present study, we report that some quiescent primary oocytes in primordial follicles become senescent in adult mouse ovaries. The senescent primary oocytes share senescence markers characterized in senescent somatic cells. The senescent primary oocytes were observed in young adult mouse ovaries, remained at approximately 15% of the total primary oocytes during ovarian aging from 6 to 12 months, and accumulated in aged ovaries. Administration of a senolytic drug ABT263 to 3-month-old mice reduced the percentage of senescent primary oocytes and the transcription of the SASP factors in the ovary, in addition, led to increased numbers of primordial and total follicles and a higher rate of oocyte maturation. Our study provides experimental evidence that primary oocytes, a germline cell type that is arrested in meiosis, become senescent in adult mouse ovaries and that senescent cell clearance reduced primordial follicle loss and mitigated ovarian aging phenotypes., (© 2024. The Author(s).)
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- 2024
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47. Shear wave elastography to assess stiffness of the human ovary and other reproductive tissues across the reproductive lifespan in health and disease†.
- Author
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Zaniker EJ, Zhang M, Hughes L, La Follette L, Atazhanova T, Trofimchuk A, Babayev E, and Duncan FE
- Subjects
- Humans, Female, Aging physiology, Reproduction physiology, Reproductive Health, Elasticity Imaging Techniques methods, Ovary diagnostic imaging, Ovary physiology
- Abstract
The ovary is one of the first organs to show overt signs of aging in the human body, and ovarian aging is associated with a loss of gamete quality and quantity. The age-dependent decline in ovarian function contributes to infertility and an altered endocrine milieu, which has ramifications for overall health. The aging ovarian microenvironment becomes fibro-inflammatory and stiff with age, and this has implications for ovarian physiology and pathology, including follicle growth, gamete quality, ovulation dynamics, and ovarian cancer. Thus, developing a non-invasive tool to measure and monitor the stiffness of the human ovary would represent a major advance for female reproductive health and longevity. Shear wave elastography is a quantitative ultrasound imaging method for evaluation of soft tissue stiffness. Shear wave elastography has been used clinically in assessment of liver fibrosis and characterization of tendinopathies and various neoplasms in thyroid, breast, prostate, and lymph nodes as a non-invasive diagnostic and prognostic tool. In this study, we review the underlying principles of shear wave elastography and its current clinical uses outside the reproductive tract as well as its successful application of shear wave elastography to reproductive tissues, including the uterus and cervix. We also describe an emerging use of this technology in evaluation of human ovarian stiffness via transvaginal ultrasound. Establishing ovarian stiffness as a clinical biomarker of ovarian aging may have implications for predicting the ovarian reserve and outcomes of Assisted Reproductive Technologies as well as for the assessment of the efficacy of emerging therapeutics to extend reproductive longevity. This parameter may also have broad relevance in other conditions where ovarian stiffness and fibrosis may be implicated, such as polycystic ovarian syndrome, late off target effects of chemotherapy and radiation, premature ovarian insufficiency, conditions of differences of sexual development, and ovarian cancer. Summary sentence: Shear Wave Elastography is a non-invasive technique to study human tissue stiffness, and here we review its clinical applications and implications for reproductive health and disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for the Study of Reproduction.)
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- 2024
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48. Single-cell multi-ome and immune profiles of the Inspiration4 crew reveal conserved, cell-type, and sex-specific responses to spaceflight.
- Author
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Kim J, Tierney BT, Overbey EG, Dantas E, Fuentealba M, Park J, Narayanan SA, Wu F, Najjar D, Chin CR, Meydan C, Loy C, Mathyk B, Klotz R, Ortiz V, Nguyen K, Ryon KA, Damle N, Houerbi N, Patras LI, Schanzer N, Hutchinson GA, Foox J, Bhattacharya C, Mackay M, Afshin EE, Hirschberg JW, Kleinman AS, Schmidt JC, Schmidt CM, Schmidt MA, Beheshti A, Matei I, Lyden D, Mullane S, Asadi A, Lenz JS, Mzava O, Yu M, Ganesan S, De Vlaminck I, Melnick AM, Barisic D, Winer DA, Zwart SR, Crucian BE, Smith SM, Mateus J, Furman D, and Mason CE
- Subjects
- Animals, Female, Male, Humans, Mice, Astronauts, Cytokines metabolism, T-Lymphocytes immunology, Sex Factors, Gene Expression Profiling, Oxidative Phosphorylation, Space Flight, Single-Cell Analysis, Transcriptome
- Abstract
Spaceflight induces an immune response in astronauts. To better characterize this effect, we generated single-cell, multi-ome, cell-free RNA (cfRNA), biochemical, and hematology data for the SpaceX Inspiration4 (I4) mission crew. We found that 18 cytokines/chemokines related to inflammation, aging, and muscle homeostasis changed after spaceflight. In I4 single-cell multi-omics data, we identified a "spaceflight signature" of gene expression characterized by enrichment in oxidative phosphorylation, UV response, immune function, and TCF21 pathways. We confirmed the presence of this signature in independent datasets, including the NASA Twins Study, the I4 skin spatial transcriptomics, and 817 NASA GeneLab mouse transcriptomes. Finally, we observed that (1) T cells showed an up-regulation of FOXP3, (2) MHC class I genes exhibited long-term suppression, and (3) infection-related immune pathways were associated with microbiome shifts. In summary, this study reveals conserved and distinct immune disruptions occurring and details a roadmap for potential countermeasures to preserve astronaut health., (© 2024. The Author(s).)
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- 2024
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49. Single-cell analysis identifies conserved features of immune dysfunction in simulated microgravity and spaceflight.
- Author
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Wu F, Du H, Overbey E, Kim J, Makhijani P, Martin N, Lerner CA, Nguyen K, Baechle J, Valentino TR, Fuentealba M, Bartleson JM, Halaweh H, Winer S, Meydan C, Garrett-Bakelman F, Sayed N, Melov S, Muratani M, Gerencser AA, Kasler HG, Beheshti A, Mason CE, Furman D, and Winer DA
- Subjects
- Animals, Female, Humans, Male, Mice, Immunity, Innate, Inflammation immunology, Killer Cells, Natural immunology, Machine Learning, Mice, Inbred C57BL, Quercetin pharmacology, Signal Transduction, T-Lymphocytes immunology, Weightlessness, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear metabolism, Single-Cell Analysis, Space Flight, Weightlessness Simulation
- Abstract
Microgravity is associated with immunological dysfunction, though the mechanisms are poorly understood. Here, using single-cell analysis of human peripheral blood mononuclear cells (PBMCs) exposed to short term (25 hours) simulated microgravity, we characterize altered genes and pathways at basal and stimulated states with a Toll-like Receptor-7/8 agonist. We validate single-cell analysis by RNA sequencing and super-resolution microscopy, and against data from the Inspiration-4 (I4) mission, JAXA (Cell-Free Epigenome) mission, Twins study, and spleens from mice on the International Space Station. Overall, microgravity alters specific pathways for optimal immunity, including the cytoskeleton, interferon signaling, pyroptosis, temperature-shock, innate inflammation (e.g., Coronavirus pathogenesis pathway and IL-6 signaling), nuclear receptors, and sirtuin signaling. Microgravity directs monocyte inflammatory parameters, and impairs T cell and NK cell functionality. Using machine learning, we identify numerous compounds linking microgravity to immune cell transcription, and demonstrate that the flavonol, quercetin, can reverse most abnormal pathways. These results define immune cell alterations in microgravity, and provide opportunities for countermeasures to maintain normal immunity in space., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
50. Telomeric RNA (TERRA) increases in response to spaceflight and high-altitude climbing.
- Author
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Al-Turki TM, Maranon DG, Nelson CB, Lewis AM, Luxton JJ, Taylor LE, Altina N, Wu F, Du H, Kim J, Damle N, Overbey E, Meydan C, Grigorev K, Winer DA, Furman D, Mason CE, and Bailey SM
- Subjects
- Humans, Male, RNA, Long Noncoding genetics, RNA, Long Noncoding metabolism, Adult, Middle Aged, DNA Breaks, Double-Stranded, Female, DNA Damage, Mountaineering, Telomere Homeostasis, Altitude, Telomere metabolism, Telomere genetics, Space Flight
- Abstract
Telomeres are repetitive nucleoprotein complexes at chromosomal termini essential for maintaining genome stability. Telomeric RNA, or TERRA, is a previously presumed long noncoding RNA of heterogeneous lengths that contributes to end-capping structure and function, and facilitates telomeric recombination in tumors that maintain telomere length via the telomerase-independent Alternative Lengthening of Telomeres (ALT) pathway. Here, we investigated TERRA in the radiation-induced DNA damage response (DDR) across astronauts, high-altitude climbers, healthy donors, and cellular models. Similar to astronauts in the space radiation environment and climbers of Mt. Everest, in vitro radiation exposure prompted increased transcription of TERRA, while simulated microgravity did not. Data suggest a specific TERRA DDR to telomeric double-strand breaks (DSBs), and provide direct demonstration of hybridized TERRA at telomere-specific DSB sites, indicative of protective TERRA:telomeric DNA hybrid formation. Targeted telomeric DSBs also resulted in accumulation of TERRA foci in G2-phase, supportive of TERRA's role in facilitating recombination-mediated telomere elongation. Results have important implications for scenarios involving persistent telomeric DNA damage, such as those associated with chronic oxidative stress (e.g., aging, systemic inflammation, environmental and occupational radiation exposures), which can trigger transient ALT in normal human cells, as well as for targeting TERRA as a therapeutic strategy against ALT-positive tumors., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
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