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Rroji O, Mucignat C. Factors influencing brain recovery from stroke via possible epigenetic changes. Future Sci OA 2024; 10:2409609. [PMID: 39429231 PMCID: PMC11497982 DOI: 10.1080/20565623.2024.2409609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 09/24/2024] [Indexed: 10/22/2024] Open
Abstract
Aim: To examine epigenetic changes leading to functional repair after damage to the central motor system.Data sources: A literature search was conducted using medical and health science electronic databases (PubMed, MEDLINE, Scopus) up to July 2023.Study selection: Data were summarized for type of intervention, study design, findings including human and animal studies.Data extraction: Data were extracted and double-checked independently for methodological quality. By means of the influence of environmental (calorie restriction or physical exercise) and other factors, epigenetic instructions were found to increase levels of BDNF and enhance synaptic neurotransmission, possibly leading to larger scale changes in structural and functional assets, which may end up to cognitive and motor repair after stroke.
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Affiliation(s)
- Orjon Rroji
- Department of Radiology & Imaging techniques, European University of Tirana, Albania
| | - Carla Mucignat
- Department of Molecular Medicine, University of Padova, Italy
- National Institute for Biostructures & Biosystems, Rome, Italy
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2
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Tiwari V, Prajapati B, Asare Y, Damkou A, Ji H, Liu L, Naser N, Gouna G, Leszczyńska KB, Mieczkowski J, Dichgans M, Wang Q, Kawaguchi R, Shi Z, Swarup V, Geschwind DH, Prinz M, Gokce O, Simons M. Innate immune training restores pro-reparative myeloid functions to promote remyelination in the aged central nervous system. Immunity 2024; 57:2173-2190.e8. [PMID: 39053462 DOI: 10.1016/j.immuni.2024.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 11/21/2023] [Accepted: 07/01/2024] [Indexed: 07/27/2024]
Abstract
The reduced ability of the central nervous system to regenerate with increasing age limits functional recovery following demyelinating injury. Previous work has shown that myelin debris can overwhelm the metabolic capacity of microglia, thereby impeding tissue regeneration in aging, but the underlying mechanisms are unknown. In a model of demyelination, we found that a substantial number of genes that were not effectively activated in aged myeloid cells displayed epigenetic modifications associated with restricted chromatin accessibility. Ablation of two class I histone deacetylases in microglia was sufficient to restore the capacity of aged mice to remyelinate lesioned tissue. We used Bacillus Calmette-Guerin (BCG), a live-attenuated vaccine, to train the innate immune system and detected epigenetic reprogramming of brain-resident myeloid cells and functional restoration of myelin debris clearance and lesion recovery. Our results provide insight into aging-associated decline in myeloid function and how this decay can be prevented by innate immune reprogramming.
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Affiliation(s)
- Vini Tiwari
- Institute of Neuronal Cell Biology, Technical University Munich, 81377 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany
| | - Bharat Prajapati
- Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 41390 Gothenburg, Sweden
| | - Yaw Asare
- Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, 81377 Munich, Germany
| | - Alkmini Damkou
- Institute of Neuronal Cell Biology, Technical University Munich, 81377 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany
| | - Hao Ji
- Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, 81377 Munich, Germany
| | - Lu Liu
- German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany; Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, 81377 Munich, Germany
| | - Nawraa Naser
- Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, 81377 Munich, Germany
| | - Garyfallia Gouna
- Institute of Neuronal Cell Biology, Technical University Munich, 81377 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany
| | - Katarzyna B Leszczyńska
- Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology of the Polish Academy of Sciences, 02093 Warsaw, Poland
| | - Jakub Mieczkowski
- Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology of the Polish Academy of Sciences, 02093 Warsaw, Poland; 3P-Medicine Laboratory, Medical University of Gdańsk, 80211 Gdańsk, Poland
| | - Martin Dichgans
- German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany; Munich Cluster of Systems Neurology (SyNergy), 81377 Munich, Germany; Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, 81377 Munich, Germany
| | - Qing Wang
- Departments of Neurology and Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Riki Kawaguchi
- Departments of Neurology and Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Psychiatry, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Zechuan Shi
- Department of Neurobiology and Behavior, University of California, Irvine, CA, USA
| | - Vivek Swarup
- Department of Neurobiology and Behavior, University of California, Irvine, CA, USA
| | - Daniel H Geschwind
- Departments of Neurology and Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Marco Prinz
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79085 Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany
| | - Ozgun Gokce
- Munich Cluster of Systems Neurology (SyNergy), 81377 Munich, Germany; Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, 81377 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, 53127 Bonn, Germany
| | - Mikael Simons
- Institute of Neuronal Cell Biology, Technical University Munich, 81377 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany; Munich Cluster of Systems Neurology (SyNergy), 81377 Munich, Germany; Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, 81377 Munich, Germany.
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Lossi L, Castagna C, Merighi A. An Overview of the Epigenetic Modifications in the Brain under Normal and Pathological Conditions. Int J Mol Sci 2024; 25:3881. [PMID: 38612690 PMCID: PMC11011998 DOI: 10.3390/ijms25073881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 03/27/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024] Open
Abstract
Epigenetic changes are changes in gene expression that do not involve alterations to the DNA sequence. These changes lead to establishing a so-called epigenetic code that dictates which and when genes are activated, thus orchestrating gene regulation and playing a central role in development, health, and disease. The brain, being mostly formed by cells that do not undergo a renewal process throughout life, is highly prone to the risk of alterations leading to neuronal death and neurodegenerative disorders, mainly at a late age. Here, we review the main epigenetic modifications that have been described in the brain, with particular attention on those related to the onset of developmental anomalies or neurodegenerative conditions and/or occurring in old age. DNA methylation and several types of histone modifications (acetylation, methylation, phosphorylation, ubiquitination, sumoylation, lactylation, and crotonylation) are major players in these processes. They are directly or indirectly involved in the onset of neurodegeneration in Alzheimer's or Parkinson's disease. Therefore, this review briefly describes the roles of these epigenetic changes in the mechanisms of brain development, maturation, and aging and some of the most important factors dynamically regulating or contributing to these changes, such as oxidative stress, inflammation, and mitochondrial dysfunction.
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Affiliation(s)
| | | | - Adalberto Merighi
- Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2, 10095 Grugliasco, Italy; (L.L.); (C.C.)
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4
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Zhang C, Su H, Waight E, Poluektova LY, Gorantla S, Gendelman HE, Dash PK. Accelerated Neuroimmune Dysfunction in Aged HIV-1-Infected Humanized Mice. Pharmaceuticals (Basel) 2024; 17:149. [PMID: 38399364 PMCID: PMC10892358 DOI: 10.3390/ph17020149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 01/18/2024] [Accepted: 01/19/2024] [Indexed: 02/25/2024] Open
Abstract
Disordered immunity, aging, human immunodeficiency virus type one (HIV-1) infection, and responses to antiretroviral therapy are linked. However, how each factor is linked with the other(s) remains incompletely understood. It has been reported that accelerated aging, advanced HIV-1 infection, inflammation, and host genetic factors are associated with host cellular, mitochondrial, and metabolic alterations. However, the underlying mechanism remains elusive. With these questions in mind, we used chronically HIV-1-infected CD34-NSG humanized mice (hu-mice) to model older people living with HIV and uncover associations between HIV-1 infection and aging. Adult humanized mice were infected with HIV-1 at the age of 20 weeks and maintained for another 40 weeks before sacrifice. Animal brains were collected and subjected to transcriptomics, qPCR, and immunofluorescence assays to uncover immune disease-based biomarkers. CD4+ T cell decline was associated with viral level and age. Upregulated C1QA, CD163, and CXCL16 and downregulated LMNA and CLU were identified as age-associated genes tied to HIV-1 infection. Ingenuity pathway analysis affirmed links to innate immune activation, pyroptosis signaling, neuroinflammation, mitochondrial dysfunction, cellular senescence, and neuronal dysfunction. In summary, CD34-NSG humanized mice are identified as a valuable model for studying HIV-1-associated aging. Biomarkers of immune senescence and neuronal signaling are both age- and virus-associated. By exploring the underlying biological mechanisms that are linked to these biomarkers, interventions for next generation HIV-1-infected patients can be realized.
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Affiliation(s)
| | | | | | | | | | | | - Prasanta K. Dash
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
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Banerjee S, Paradkar MU, Ponde CK, Rajani RM, Pillai S, Ashavaid TF. Does epigenetic markers of HLA gene show association with coronary artery disease in Indian subjects? Mol Biol Rep 2024; 51:173. [PMID: 38252175 DOI: 10.1007/s11033-023-08974-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 10/23/2023] [Indexed: 01/23/2024]
Abstract
BACKGROUND DNA methylation, one of the most stable forms of epigenetic modification is associated with the development and progression of coronary artery disease (CAD). Our previously reported study on epigenome-wide microarray analysis showed significantly methylated CpG sites. Top 5 significant CpGs from HLA gene were selected and analysed by Pyrosequencing (PSQ) to determine their association with severity of CAD. METHODS Blood samples of 50-age matched angiographically CAD positive male cases with 50 angiographically CAD negative male controls were subjected to lipid profile estimation and PSQ for methylation level analysis. Findings and subgroup analysis were evaluated by Mann-Whitney U; Kruskal-Wallis' rank test and two-way ANOVA by MedCalc (v19.6). RESULTS Methylation levels in HLA-DQA1 for cg10217052 was 78.5 (37-85) and 76.5 (24-84); cg09411910 was 81 (72.0 to 93.0) and 81.5 (50.0 to 89.0) in cases and controls respectively. Levels in HLA-DQB1-cg03344051, were 28.88 + 9.41 for cases and 30.36 + 9.37 in controls. For HLA-DRB1-cg07889003, levels in cases and controls were 15.5 (5.00-39.00) and 10.5 (5.00-29.0); while in cg08269402 were 52 (16-65) and 42.5 (17-61) respectively. No association was observed between methylation levels and lipid profile. cg03344051, cg07889003 and cg08269402 were significantly differentiated in double or triple vessel disease (DVD or TVD) as compared to single vessel disease (SVD) suggesting an increase in the extent of methylation with the increase in CAD severity. CONCLUSION The present study shows significant increase in the extent of methylation in 3 CpG sites in DVD/TVD cases as compared to SVD cases. Additionally, a novel site, cg07889003 identified in our discovery phase has shown association with the severity of CAD.
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Affiliation(s)
- Shyamashree Banerjee
- Research Laboratories, P.D Hinduja Hospital & Medical Research Centre, Mumbai, India
| | - Minal U Paradkar
- Research Laboratories, P.D Hinduja Hospital & Medical Research Centre, Mumbai, India
- Department of Biochemistry, P.D Hinduja Hospital & Medical Research Centre, Mumbai, India
| | | | - Rajesh M Rajani
- Department of Cardiology, P.D Hinduja Hospital & Medical Research Centre, Mumbai, India
| | - Sudhir Pillai
- Department of Cardiology, P.D Hinduja Hospital & Medical Research Centre, Mumbai, India
| | - Tester F Ashavaid
- Research Laboratories, P.D Hinduja Hospital & Medical Research Centre, Mumbai, India.
- Department of Biochemistry, P.D Hinduja Hospital & Medical Research Centre, Mumbai, India.
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Jiraboonsri S, Hemvipat P, Kamolratanakul S, Bhummaphan N, Siritientong T, Kitkumthorn N, Mutirangura A, Meevassana J. CpG methylation changes in Alu repetitive sequences in normal aging due to diastolic hypertension in human dermal fibroblasts from the facial area. Biomed Rep 2024; 20:5. [PMID: 38222864 PMCID: PMC10784876 DOI: 10.3892/br.2023.1693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 11/02/2023] [Indexed: 01/16/2024] Open
Abstract
Aging fibroblasts, an important factor contributing to skin aging, are affected by numerous mechanisms, including alterations in DNA methylation and age-related diseases. The current study aimed to investigate the role of Alu methylation in aging fibroblasts and hypertension. The Alu methylation levels in dermal fibroblasts obtained from patients of different ages and blood pressure status were analyzed using the combined bisulfite restriction analysis technique. An inverse correlation was observed between Alu methylation in dermal fibroblasts and patient age. Dermal fibroblasts from the high-normal diastolic blood pressure group had higher Alu methylation levels compared with those from the normal group. The findings of the present study suggest that Alu methylation alterations can be observed with chronological aging and hypertension, and are a potential aging marker or therapeutic target.
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Affiliation(s)
- Suvinai Jiraboonsri
- Center of Excellence in Burn and Wound Care, Chulalongkorn University, Bangkok 10330, Thailand
| | - Panicha Hemvipat
- Center of Excellence in Burn and Wound Care, Chulalongkorn University, Bangkok 10330, Thailand
| | - Supitcha Kamolratanakul
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Narumol Bhummaphan
- College of Public Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Tippawan Siritientong
- Center of Excellence in Burn and Wound Care, Chulalongkorn University, Bangkok 10330, Thailand
| | - Nakarin Kitkumthorn
- Department of Oral Biology, Faculty of Dentistry, Mahidol University, Bangkok 10400, Thailand
| | - Apiwat Mutirangura
- Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Jiraroch Meevassana
- Center of Excellence in Burn and Wound Care, Chulalongkorn University, Bangkok 10330, Thailand
- Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
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7
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Ramezani M, Zobeiry M, Abdolahi S, Hatami B, Zali MR, Baghaei K. A crosstalk between epigenetic modulations and non-alcoholic fatty liver disease progression. Pathol Res Pract 2023; 251:154809. [PMID: 37797383 DOI: 10.1016/j.prp.2023.154809] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 09/08/2023] [Accepted: 09/08/2023] [Indexed: 10/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has recently emerged as a major public health concern worldwide due to its rapidly rising prevalence and its potential to progress into end-stage liver disease. While the precise pathophysiology underlying NAFLD remains incompletely understood, it is strongly associated with various environmental triggers and other metabolic disorders. Epigenetics examines changes in gene expression that are not caused by alterations in the DNA sequence itself. There is accumulating evidence that epigenetics plays a key role in linking environmental cues to the onset and progression of NAFLD. Our understanding of how epigenetic mechanisms contribute to NAFLD pathophysiology has expanded considerably in recent years as research on the epigenetics of NAFLD has developed. This review summarizes recent insights into major epigenetic processes that have been implicated in NAFLD pathogenesis including DNA methylation, histone acetylation, and microRNAs that have emerged as promising targets for further investigation. Elucidating epigenetic mechanisms in NAFLD may uncover novel diagnostic biomarkers and therapeutic targets for this disease. However, many questions have remained unanswered regarding how epigenetics promotes NAFLD onset and progression. Additional studies are needed to further characterize the epigenetic landscape of NAFLD and validate the potential of epigenetic markers as clinical tools. Nevertheless, an enhanced understanding of the epigenetic underpinnings of NAFLD promises to provide key insights into disease mechanisms and pave the way for novel prognostic and therapeutic approaches.
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Affiliation(s)
- Meysam Ramezani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Shahrokh Abdolahi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Behzad Hatami
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Gastroenterology and Liver Diseases Research center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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8
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Shin MS, Park HJ, Young J, Kang I. Implication of IL-7 receptor alpha chain expression by CD8 + T cells and its signature in defining biomarkers in aging. Immun Ageing 2022; 19:66. [PMID: 36544153 PMCID: PMC9768896 DOI: 10.1186/s12979-022-00324-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 12/10/2022] [Indexed: 12/24/2022]
Abstract
CD8+ T cells play an important role in host defense against infections and malignancies as well as contribute to the development of inflammatory disorders. Alterations in the frequency of naïve and memory CD8+ T cells are one of the most significant changes in the immune system with age. As the world population rapidly ages, a better understanding of aging immune function or immunosenescence could become a basis for discovering treatments of illnesses that commonly occur in older adults. In particular, biomarkers for immune aging could be utilized to identify individuals at high risk of developing age-associated conditions and help monitor the efficacy of therapeutic interventions targeting such conditions. This review details the possible role of CD8+ T cell subsets expressing different levels of the cytokine receptor IL-7 receptor alpha chain (IL-7Rα) and the gene signature associated with IL-7Rα as potential biomarkers for immune aging given the association of CD8+ T cells in host defense, inflammation, and immunosenescence.
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Affiliation(s)
- Min Sun Shin
- Departments of Internal Medicine, Section of Rheumatology, Allergy & Immunology, Yale University School of Medicine, S525C TAC, 300 Cedar Street, New Haven, CT, 06520, USA
| | - Hong-Jai Park
- Departments of Internal Medicine, Section of Rheumatology, Allergy & Immunology, Yale University School of Medicine, S525C TAC, 300 Cedar Street, New Haven, CT, 06520, USA
| | - Juan Young
- Departments of Psychiatry, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Insoo Kang
- Departments of Internal Medicine, Section of Rheumatology, Allergy & Immunology, Yale University School of Medicine, S525C TAC, 300 Cedar Street, New Haven, CT, 06520, USA.
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Li X, Delerue T, Schöttker B, Holleczek B, Grill E, Peters A, Waldenberger M, Thorand B, Brenner H. Derivation and validation of an epigenetic frailty risk score in population-based cohorts of older adults. Nat Commun 2022; 13:5269. [PMID: 36071044 PMCID: PMC9450828 DOI: 10.1038/s41467-022-32893-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 08/23/2022] [Indexed: 11/09/2022] Open
Abstract
DNA methylation (DNAm) patterns in peripheral blood have been shown to be associated with aging related health outcomes. We perform an epigenome-wide screening to identify CpGs related to frailty, defined by a frailty index (FI), in a large population-based cohort of older adults from Germany, the ESTHER study. Sixty-five CpGs are identified as frailty related methylation loci. Using LASSO regression, 20 CpGs are selected to derive a DNAm based algorithm for predicting frailty, the epigenetic frailty risk score (eFRS). The eFRS exhibits strong associations with frailty at baseline and after up to five-years of follow-up independently of established frailty risk factors. These associations are confirmed in another independent population-based cohort study, the KORA-Age study, conducted in older adults. In conclusion, we identify 65 CpGs as frailty-related loci, of which 20 CpGs are used to calculate the eFRS with predictive performance for frailty over long-term follow-up.
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Affiliation(s)
- Xiangwei Li
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.,Medical Faculty Heidelberg, University of Heidelberg, Im Neuenheimer Feld 672, 69120, Heidelberg, Germany
| | - Thomas Delerue
- Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764, Neuherberg, Bavaria, Germany
| | - Ben Schöttker
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.,Network Aging Research, University of Heidelberg, Bergheimer Straße 20, 69115, Heidelberg, Germany
| | - Bernd Holleczek
- Saarland Cancer Registry, Krebsregister Saarland, Neugeländstraße 9, 66117, Saarbrücken, Germany
| | - Eva Grill
- Institute for Medical Information Processing, Biometry and Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany.,German Center for Vertigo and Balance Disorders, Klinikum der Universität München, Munich, Germany
| | - Annette Peters
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764, Neuherberg, Bavaria, Germany.,Institute for Medical Informatics, Biometrics and Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - Melanie Waldenberger
- Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764, Neuherberg, Bavaria, Germany.,Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764, Neuherberg, Bavaria, Germany
| | - Barbara Thorand
- Institute for Medical Information Processing, Biometry and Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany. .,Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120, Heidelberg, Germany. .,German Cancer Consortium, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
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10
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Alimohammadi M, Makaremi S, Rahimi A, Asghariazar V, Taghadosi M, Safarzadeh E. DNA methylation changes and inflammaging in aging-associated diseases. Epigenomics 2022; 14:965-986. [PMID: 36043685 DOI: 10.2217/epi-2022-0143] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aging as an inevitable phenomenon is associated with pervasive changes in physiological functions. There is a relationship between aging and the increase of several chronic diseases. Most age-related disorders are accompanied by an underlying chronic inflammatory state, as demonstrated by local infiltration of inflammatory cells and greater levels of proinflammatory cytokines in the bloodstream. Within inflammaging, many epigenetic events, especially DNA methylation, change. During the aging process, due to aberrations of DNA methylation, biological processes are disrupted, leading to the emergence or progression of a variety of human diseases, including cancer, neurodegenerative disorders, cardiovascular disease and diabetes. The focus of this review is on DNA methylation, which is involved in inflammaging-related activities, and how its dysregulation leads to human disorders.
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Affiliation(s)
- Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1983969411, Iran
| | - Shima Makaremi
- School of Medicine & Allied Medical Sciences, Ardabil University of Medical Sciences, Ardabil, 5618985991, Iran
| | - Ali Rahimi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, 5618985991, Iran
| | - Vahid Asghariazar
- Deputy of Research & Technology, Ardabil University of Medical Sciences, Ardabil, 5618985991, Iran
| | - Mahdi Taghadosi
- Department of Immunology, Kermanshah University of Medical Sciences, Kermanshah, 6714869914, Iran
| | - Elham Safarzadeh
- Department of Microbiology, Parasitology, & Immunology, Ardabil University of Medical Sciences, Ardabil, 5618985991, Iran
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11
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Beal AP, Hackerott S, Feldheim K, Gruber SH, Eirin‐Lopez JM. Age group DNA methylation differences in lemon sharks ( Negaprion brevirostris): Implications for future age estimation tools. Ecol Evol 2022; 12:e9226. [PMID: 36052296 PMCID: PMC9425014 DOI: 10.1002/ece3.9226] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/05/2022] [Accepted: 07/05/2022] [Indexed: 11/11/2022] Open
Abstract
Age information is often non-existent for most shark populations due to a lack of measurable physiological and morphological traits that can be used to estimate age. Recently, epigenetic clocks have been found to accurately estimate age for mammals, birds, and fish. However, since these clocks rely, among other things, on the availability of reference genomes, their application is hampered in non-traditional model organisms lacking such molecular resources. The technique known as Methyl-Sensitive Amplified Polymorphism (MSAP) has emerged as a valid alternative for studying DNA methylation biomarkers when reference genome information is missing, and large numbers of samples need to be processed. Accordingly, the MSAP technique was used in the present study to characterize global DNA methylation patterns in lemon sharks from three different age groups (juveniles, subadults, and adults). The obtained results reveal that, while MSAP analyses lack enough resolution as a standalone approach to infer age in these organisms, the global DNA methylation patterns observed using this technique displayed significant differences between age groups. Overall, these results confer that DNA methylation does change with age in sharks like what has been seen for other vertebrates and that MSAP could be useful as part of an epigenetics pipeline to infer the broad range of ages found in large samples sizes.
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Affiliation(s)
- Andria Paige Beal
- Environmental Epigenetics Laboratory, Institute of EnvironmentFlorida International UniversityMiamiFloridaUSA
| | - Serena Hackerott
- Environmental Epigenetics Laboratory, Institute of EnvironmentFlorida International UniversityMiamiFloridaUSA
| | - Kevin Feldheim
- Pritzker Laboratory for Molecular Systematics and EvolutionField Museum of Natural HistoryChicagoIllinoisUSA
| | | | - Jose M. Eirin‐Lopez
- Environmental Epigenetics Laboratory, Institute of EnvironmentFlorida International UniversityMiamiFloridaUSA
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12
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Xu Y, Zhong L, Wei H, Li Y, Xie J, Xie L, Chen X, Guo X, Yin P, Li S, Zeng J, Li XJ, Lin L. Brain Region- and Age-Dependent 5-Hydroxymethylcytosine Activity in the Non-Human Primate. Front Aging Neurosci 2022; 14:934224. [PMID: 35912074 PMCID: PMC9326314 DOI: 10.3389/fnagi.2022.934224] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 06/15/2022] [Indexed: 11/24/2022] Open
Abstract
Because of the difficulty in collecting fresh brains of humans at different ages, it remains unknown how epigenetic regulation occurs in the primate brains during aging. In the present study, we examined the genomic distribution of 5hmC, an indicator of DNA methylation, in the brain regions of non-human primates (rhesus monkey) at the ages of 2 (juvenile), 8 (young adult), and 17 (old) years. We found that genomic 5hmC distribution was accumulated in the monkey brain as age increased and displayed unique patterns in the cerebellum and striatum in an age-dependent manner. We also observed a correlation between differentially hydroxymethylated regions (DhMRs) and genes that contribute to brain region-related functions and diseases. Our studies revealed, for the first time, the brain-region and age-dependent 5hmC modifications in the non-human primate and the association of these 5hmC modifications with brain region-specific function and potentially aging-related brain diseases.
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Affiliation(s)
- Yanru Xu
- Guangdong Key Laboratory of Nonhuman Primate Models of Human Diseases, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Liying Zhong
- Guangdong Key Laboratory of Nonhuman Primate Models of Human Diseases, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Huixian Wei
- Guangdong Key Laboratory of Nonhuman Primate Models of Human Diseases, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Yuwei Li
- Guangdong Key Laboratory of Nonhuman Primate Models of Human Diseases, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Jiaxiang Xie
- Guangdong Key Laboratory of Nonhuman Primate Models of Human Diseases, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Leijie Xie
- Guangdong Key Laboratory of Nonhuman Primate Models of Human Diseases, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Xiusheng Chen
- Guangdong Key Laboratory of Nonhuman Primate Models of Human Diseases, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Xiangyu Guo
- Guangdong Key Laboratory of Nonhuman Primate Models of Human Diseases, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Peng Yin
- Guangdong Key Laboratory of Nonhuman Primate Models of Human Diseases, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Shihua Li
- Guangdong Key Laboratory of Nonhuman Primate Models of Human Diseases, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Junwei Zeng
- Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xiao-Jiang Li
- Guangdong Key Laboratory of Nonhuman Primate Models of Human Diseases, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Li Lin
- Guangdong Key Laboratory of Nonhuman Primate Models of Human Diseases, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
- *Correspondence: Li Lin
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13
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Pharmacological Approaches to Decelerate Aging: A Promising Path. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4201533. [PMID: 35860429 PMCID: PMC9293537 DOI: 10.1155/2022/4201533] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 05/24/2022] [Accepted: 06/26/2022] [Indexed: 11/17/2022]
Abstract
Biological aging or senescence is a course in which cellular function decreases over a period of time and is a consequence of altered signaling mechanisms that are triggered in stressed cells leading to cell damage. Aging is among the principal risk factors for many chronic illnesses such as cancer, cardiovascular disorders, and neurodegenerative diseases. Taking this into account, targeting fundamental aging mechanisms therapeutically may effectively impact numerous chronic illnesses. Selecting ideal therapeutic options in order to hinder the process of aging and decelerate the progression of age-related diseases is valuable. Along therapeutic options, life style modifications may well render the process of aging. The process of aging is affected by alteration in many cellular and signaling pathways amid which mTOR, SIRT1, and AMPK pathways are the most emphasized. Herein, we have discussed the mechanisms of aging focusing mainly on the mentioned pathways as well as the role of inflammation and autophagy in aging. Moreover, drugs and natural products with antiaging properties are discussed in detail.
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14
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Oxysterols are potential physiological regulators of ageing. Ageing Res Rev 2022; 77:101615. [PMID: 35351610 DOI: 10.1016/j.arr.2022.101615] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 02/18/2022] [Accepted: 03/24/2022] [Indexed: 12/24/2022]
Abstract
Delaying and even reversing ageing is a major public health challenge with a tremendous potential to postpone a plethora of diseases including cancer, metabolic syndromes and neurodegenerative disorders. A better understanding of ageing as well as the development of innovative anti-ageing strategies are therefore an increasingly important field of research. Several biological processes including inflammation, proteostasis, epigenetic, oxidative stress, stem cell exhaustion, senescence and stress adaptive response have been reported for their key role in ageing. In this review, we describe the relationships that have been established between cholesterol homeostasis, in particular at the level of oxysterols, and ageing. Initially considered as harmful pro-inflammatory and cytotoxic metabolites, oxysterols are currently emerging as an expanding family of fine regulators of various biological processes involved in ageing. Indeed, depending of their chemical structure and their concentration, oxysterols exhibit deleterious or beneficial effects on inflammation, oxidative stress and cell survival. In addition, stem cell differentiation, epigenetics, cellular senescence and proteostasis are also modulated by oxysterols. Altogether, these data support the fact that ageing is influenced by an oxysterol profile. Further studies are thus required to explore more deeply the impact of the "oxysterome" on ageing and therefore this cholesterol metabolic pathway constitutes a promising target for future anti-ageing interventions.
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15
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Levy G, Levin B. An Evolution-Based Model of Causation for Aging-Related Diseases and Intrinsic Mortality: Explanatory Properties and Implications for Healthy Aging. Front Public Health 2022; 10:774668. [PMID: 35252084 PMCID: PMC8894190 DOI: 10.3389/fpubh.2022.774668] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 01/10/2022] [Indexed: 01/07/2023] Open
Abstract
Aging-related diseases are the most prevalent diseases in advanced countries nowadays, accounting for a substantial proportion of mortality. We describe the explanatory properties of an evolution-based model of causation (EBMC) applicable to aging-related diseases and intrinsic mortality. The EBMC takes the sufficient and component causes model of causation as a starting point and develops it using evolutionary and statistical theories. Genetic component causes are classified as “early-onset” or “late-onset” and environmental component causes as “evolutionarily conserved” or “evolutionarily recent.” Genetic and environmental component causes are considered to occur as random events following time-to-event distributions, and sufficient causes are classified according to whether or not their time-to-event distributions are “molded” by the declining force of natural selection with increasing age. We obtain for each of these two groups different time-to-event distributions for disease incidence or intrinsic mortality asymptotically (i.e., for a large number of sufficient causes). The EBMC provides explanations for observations about aging-related diseases concerning the penetrance of genetic risk variants, the age of onset of monogenic vs. sporadic forms, the meaning of “age as a risk factor,” the relation between frequency and age of onset, and the emergence of diseases associated with the modern Western lifestyle. The EBMC also provides an explanation of the Gompertz mortality model at the fundamental level of genetic causes and involving evolutionary biology. Implications for healthy aging are examined under the scenarios of health promotion and postponed aging. Most importantly from a public health standpoint, the EBMC implies that primary prevention through changes in lifestyle and reduction of environmental exposures is paramount in promoting healthy aging.
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Affiliation(s)
- Gilberto Levy
- Independent Researcher, Rio de Janeiro, Brazil
- *Correspondence: Gilberto Levy
| | - Bruce Levin
- Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, United States
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16
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Capparelli R, Iannelli D. Role of Epigenetics in Type 2 Diabetes and Obesity. Biomedicines 2021; 9:977. [PMID: 34440181 PMCID: PMC8393970 DOI: 10.3390/biomedicines9080977] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 07/30/2021] [Accepted: 08/06/2021] [Indexed: 12/23/2022] Open
Abstract
Epigenetic marks the genome by DNA methylation, histone modification or non-coding RNAs. Epigenetic marks instruct cells to respond reversibly to environmental cues and keep the specific gene expression stable throughout life. In this review, we concentrate on DNA methylation, the mechanism often associated with transgenerational persistence and for this reason frequently used in the clinic. A large study that included data from 10,000 blood samples detected 187 methylated sites associated with body mass index (BMI). The same study demonstrates that altered methylation results from obesity (OB). In another study the combined genetic and epigenetic analysis allowed us to understand the mechanism associating hepatic insulin resistance and non-alcoholic disease in Type 2 Diabetes (T2D) patients. The study underlines the therapeutic potential of epigenetic studies. We also account for seemingly contradictory results associated with epigenetics.
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Affiliation(s)
- Rosanna Capparelli
- Department of Agriculture Sciences, University of Naples “Federico II”, Via Università, 100-Portici, 80055 Naples, Italy
| | - Domenico Iannelli
- Department of Agriculture Sciences, University of Naples “Federico II”, Via Università, 100-Portici, 80055 Naples, Italy
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17
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Milošević M, Arsić A, Cvetković Z, Vučić V. Memorable Food: Fighting Age-Related Neurodegeneration by Precision Nutrition. Front Nutr 2021; 8:688086. [PMID: 34422879 PMCID: PMC8374314 DOI: 10.3389/fnut.2021.688086] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 07/13/2021] [Indexed: 12/13/2022] Open
Abstract
Healthcare systems worldwide are seriously challenged by a rising prevalence of neurodegenerative diseases (NDDs), which mostly, but not exclusively, affect the ever-growing population of the elderly. The most known neurodegenerative diseases are Alzheimer's (AD) and Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, but some viral infections of the brain and traumatic brain injury may also cause NDD. Typical for NDD are the malfunctioning of neurons and their irreversible loss, which often progress irreversibly to dementia and ultimately to death. Numerous factors are involved in the pathogenesis of NDD: genetic variability, epigenetic changes, extent of oxidative/nitrosative stress, mitochondrial dysfunction, and DNA damage. The complex interplay of all the above-mentioned factors may be a fingerprint of neurodegeneration, with different diseases being affected to different extents by particular factors. There is a voluminous body of evidence showing the benefits of regular exercise to brain health and cognitive functions. Moreover, the importance of a healthy diet, balanced in macro- and micro-nutrients, in preventing neurodegeneration and slowing down a progression to full-blown disease is evident. Individuals affected by NDD almost inevitably have low-grade inflammation and anomalies in lipid metabolism. Metabolic and lipid profiles in NDD can be improved by the Mediterranean diet. Many studies have associated the Mediterranean diet with a decreased risk of dementia and AD, but a cause-and-effect relationship has not been deduced. Studies with caloric restriction showed neuroprotective effects in animal models, but the results in humans are inconsistent. The pathologies of NDD are complex and there is a great inter-individual (epi)genetic variance within any population. Furthermore, the gut microbiome, being deeply involved in nutrient uptake and lipid metabolism, also represents a pillar of the gut microbiome-brain axis and is linked with the pathogenesis of NDD. Numerous studies on the role of different micronutrients (omega-3 fatty acids, bioactive polyphenols from fruit and medicinal plants) in the prevention, prediction, and treatment of NDD have been conducted, but we are still far away from a personalized diet plan for individual NDD patients. For this to be realized, large-scale cohorts that would include the precise monitoring of food intake, mapping of genetic variants, epigenetic data, microbiome studies, and metabolome, lipidome, and transcriptome data are needed.
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Affiliation(s)
- Maja Milošević
- Department of Neuroendocrinology, Institute for Medical Research, University of Belgrade, Belgrade, Serbia
| | - Aleksandra Arsić
- Department of Nutritional Biochemistry and Dietology, Centre of Research Excellence in Nutrition and Metabolism, Institute for Medical Research, University of Belgrade, Belgrade, Serbia
| | - Zorica Cvetković
- Department of Hematology, Clinical Hospital Center Zemun, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Vesna Vučić
- Department of Nutritional Biochemistry and Dietology, Centre of Research Excellence in Nutrition and Metabolism, Institute for Medical Research, University of Belgrade, Belgrade, Serbia
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18
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Ramasamy D, Deva Magendhra Rao AK, Rajkumar T, Mani S. Non-CpG methylation-a key epigenetic modification in cancer. Brief Funct Genomics 2021; 20:304-311. [PMID: 34318313 DOI: 10.1093/bfgp/elab035] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/28/2021] [Accepted: 07/02/2021] [Indexed: 12/17/2022] Open
Abstract
The methylation of cytosine residues that precede adenine/thymine or other cytosine nucleotides instead of guanine in DNA is known as non-CpG methylation. It is a pronounced epigenetic modification with a central role in gene regulation similar to CpG methylation. Due to technological limitations, the locus-specific role of non-CpG methylation was scarcely understood. At present, high-throughput analyses and improved enrichment methods can elucidate the role of genome-wide non-CpG methylation distributions. Although the functional basis of non-CpG methylation in regulating gene expression control is known, its role in cancer development is yet to be ascertained. This review sheds light on the possible mechanism of non-CpG methylation in embryos and developed tissues with a special focus on cancer development and progression. In particular, the maintenance and alteration of non-CpG methylation levels and the crucial factors that determine this level of non-CpG methylation and its functional role in cancer are discussed.
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19
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Ribeiro ACR, Jahr FM, Hawkins E, Kronfol MM, Younis RM, McClay JL, Deshpande LS. Epigenetic histone acetylation and Bdnf dysregulation in the hippocampus of rats exposed to repeated, low-dose diisopropylfluorophosphate. Life Sci 2021; 281:119765. [PMID: 34186043 DOI: 10.1016/j.lfs.2021.119765] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 06/08/2021] [Accepted: 06/21/2021] [Indexed: 10/21/2022]
Abstract
AIMS Deployment-related exposures to organophosphate (OP) compounds are implicated for Gulf War Illness (GWI) development in First GW veterans. However, reasons for the persistence of GWI are not fully understood. Epigenetic modifications to chromatin are regulatory mechanisms that can adaptively or maladaptively respond to external stimuli. These include DNA methylation and histone acetylation. DNA methylation changes have been reported in GWI but the role of histone acetylation in GWI has been less explored, despite its importance as an epigenetic mechanism for neurological disorders. MAIN METHODS Male Sprague-Dawley rats were exposed to OP diisopropyl fluorophosphate (DFP, 0.5 mg/kg s.c., 5-d) and 6-m later brains were dissected for hippocampus. Western blotting, activity assays and chromatin immunoprecipitation (ChIP) were utilized for epigenetic analyses. Behavior was assessed using the Forced Swim Test (FST) and the Elevated Plus Maze (EPM). KEY FINDINGS We observed a significant upregulation in HDAC1 protein along with a significant increase in HDAC enzyme activity in the hippocampus of DFP rats. A locus-specific ChIP study revealed decreases in H3K9ac at the brain derived neurotrophic factor (Bdnf) promoter IV coupled with a significant decrease in BDNF protein in DFP rat hippocampus. Treatment with HDAC inhibitor valproic acid reduced HDAC activity and decreased the FST immobility time in DFP rats. SIGNIFICANCE Our research suggests that epigenetic alterations to histone acetylation pathways and decreased BDNF expression could represent novel mechanisms for GWI symptomatology and may provide new targets for developing effective drugs for GWI treatment.
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Affiliation(s)
- Ana C R Ribeiro
- Department of Neurology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Fay M Jahr
- Department of Pharmacotherapy & Outcome Sciences, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA
| | - Elisa Hawkins
- Department of Neurology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Mohamad M Kronfol
- Department of Pharmacotherapy & Outcome Sciences, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA
| | - Rabha M Younis
- Department of Pharmacotherapy & Outcome Sciences, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA
| | - Joseph L McClay
- Department of Pharmacotherapy & Outcome Sciences, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA
| | - Laxmikant S Deshpande
- Department of Neurology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
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20
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Dobrowolny G, Barbiera A, Sica G, Scicchitano BM. Age-Related Alterations at Neuromuscular Junction: Role of Oxidative Stress and Epigenetic Modifications. Cells 2021; 10:1307. [PMID: 34074012 PMCID: PMC8225025 DOI: 10.3390/cells10061307] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/19/2021] [Accepted: 05/22/2021] [Indexed: 12/11/2022] Open
Abstract
With advancing aging, a decline in physical abilities occurs, leading to reduced mobility and loss of independence. Although many factors contribute to the physio-pathological effects of aging, an important event seems to be related to the compromised integrity of the neuromuscular system, which connects the brain and skeletal muscles via motoneurons and the neuromuscular junctions (NMJs). NMJs undergo severe functional, morphological, and molecular alterations during aging and ultimately degenerate. The effect of this decline is an inexorable decrease in skeletal muscle mass and strength, a condition generally known as sarcopenia. Moreover, several studies have highlighted how the age-related alteration of reactive oxygen species (ROS) homeostasis can contribute to changes in the neuromuscular junction morphology and stability, leading to the reduction in fiber number and innervation. Increasing evidence supports the involvement of epigenetic modifications in age-dependent alterations of the NMJ. In particular, DNA methylation, histone modifications, and miRNA-dependent gene expression represent the major epigenetic mechanisms that play a crucial role in NMJ remodeling. It is established that environmental and lifestyle factors, such as physical exercise and nutrition that are susceptible to change during aging, can modulate epigenetic phenomena and attenuate the age-related NMJs changes. This review aims to highlight the recent epigenetic findings related to the NMJ dysregulation during aging and the role of physical activity and nutrition as possible interventions to attenuate or delay the age-related decline in the neuromuscular system.
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Affiliation(s)
- Gabriella Dobrowolny
- Department of Anatomy, Histology, Forensic Medicine and Orthopaedics (DAHFMO)-Unit of Histology and Medical Embryology, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy;
| | - Alessandra Barbiera
- Department of Life Sciences and Public Health, Histology and Embryology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (A.B.); (G.S.)
| | - Gigliola Sica
- Department of Life Sciences and Public Health, Histology and Embryology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (A.B.); (G.S.)
| | - Bianca Maria Scicchitano
- Department of Life Sciences and Public Health, Histology and Embryology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (A.B.); (G.S.)
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21
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Abstract
Fasting potentials are the most interesting topics in the Nutritional Era. Fasting consists of the catabolism of lipids, proteins, and carbohydrates to maintain blood glucose levels in a normal range. The action mechanisms of fasting were firstly understood in minor organisms and later in humans. Nutritional interventions of caloric restriction could attenuate age-associated epigenetic alterations and could have a protective effect against cellular alterations, promoting longevity and health span. While most fasting studies point out the weight and fat mass decreases, it is important to define specific guidelines for fasting and non-fasting days to enhance adherence, minimize the dropout rates of the interventions, and maximize body composition improvement. Although the panorama of evidence on fasting and caloric restriction is wide, there is a lack of a safe fasting protocol to guide physicians in its prescription. The main goal is to identify a how to use guide, a major posology of fasting, inserted within a huge dietetic personalized strategy leading to an optimal and healthy nutritional status.
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22
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Kundu P, Torres ERS, Stagaman K, Kasschau K, Okhovat M, Holden S, Ward S, Nevonen KA, Davis BA, Saito T, Saido TC, Carbone L, Sharpton TJ, Raber J. Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in App NL-G-F, App NL-F, and wild type mice. Sci Rep 2021; 11:4678. [PMID: 33633159 PMCID: PMC7907263 DOI: 10.1038/s41598-021-83851-4] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 02/09/2021] [Indexed: 12/19/2022] Open
Abstract
Epigenetic mechanisms occurring in the brain as well as alterations in the gut microbiome composition might contribute to Alzheimer’s disease (AD). Human amyloid precursor protein knock-in (KI) mice contain the Swedish and Iberian mutations (AppNL-F) or those two and also the Arctic mutation (AppNL-G-F). In this study, we assessed whether behavioral and cognitive performance in 6-month-old AppNL-F, AppNL-G-F, and C57BL/6J wild-type (WT) mice was associated with the gut microbiome, and whether the genotype modulates this association. The genotype effects observed in behavioral tests were test-dependent. The biodiversity and composition of the gut microbiome linked to various aspects of mouse behavioral and cognitive performance but differences in genotype modulated these relationships. These genotype-dependent associations include members of the Lachnospiraceae and Ruminococcaceae families. In a subset of female mice, we assessed DNA methylation in the hippocampus and investigated whether alterations in hippocampal DNA methylation were associated with the gut microbiome. Among other differentially methylated regions, we identified a 1 Kb region that overlapped ing 3′UTR of the Tomm40 gene and the promoter region of the Apoe gene that and was significantly more methylated in the hippocampus of AppNL-G-F than WT mice. The integrated gut microbiome hippocampal DNA methylation analysis revealed a positive relationship between amplicon sequence variants (ASVs) within the Lachnospiraceae family and methylation at the Apoe gene. Hence, these microbes may elicit an impact on AD-relevant behavioral and cognitive performance via epigenetic changes in AD-susceptibility genes in neural tissue or that such changes in the epigenome can elicit alterations in intestinal physiology that affect the growth of these taxa in the gut microbiome.
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Affiliation(s)
- Payel Kundu
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Eileen Ruth S Torres
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Keaton Stagaman
- Department of Microbiology, Oregon State University, Corvallis, OR, 97331, USA
| | - Kristin Kasschau
- Department of Microbiology, Oregon State University, Corvallis, OR, 97331, USA
| | - Mariam Okhovat
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Sarah Holden
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Samantha Ward
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Kimberly A Nevonen
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Brett A Davis
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Takashi Saito
- Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, 467-8601, Japan
| | - Takaomi C Saido
- Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, 351-0198, Japan
| | - Lucia Carbone
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, 97239, USA.,Departments of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, 97239, USA.,Departments of Medical Informatics and Clinical Epidemiology, Portland, OR, 97239, USA.,Division of Genetics, Oregon National Primate Research Center, Beaverton, OR, 97006, USA
| | - Thomas J Sharpton
- Department of Microbiology, Oregon State University, Corvallis, OR, 97331, USA.,Department of Statistics, Oregon State University, Corvallis, OR, 97331, USA
| | - Jacob Raber
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239, USA. .,Departments of Neurology, Psychiatry, and Radiation Medicine, Division of Neuroscience ONPRC, Oregon Health & Science University, Portland, OR, 97239, USA. .,College of Pharmacy, Oregon State University, Corvallis, OR, 97331, USA. .,Department of Behavioral Neuroscience, L470, Oregon Health & Science University, 3181SW Sam Jackson Park Road, Portland, OR, 97239, USA.
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23
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Chen T, Cai C, Wang L, Li S, Chen L. Farnesyl Transferase Inhibitor Lonafarnib Enhances α7nAChR Expression Through Inhibiting DNA Methylation of CHRNA7 and Increases α7nAChR Membrane Trafficking. Front Pharmacol 2021; 11:589780. [PMID: 33447242 PMCID: PMC7801264 DOI: 10.3389/fphar.2020.589780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 10/15/2020] [Indexed: 11/25/2022] Open
Abstract
Inhibition of Ras farnesylation in acute has been found to upregulate the α7 nicotinic acetylcholine receptor (α7nAChR) activity. This study was carried out to investigate the effect of chronic administration for 7 days of farnesyl transferase inhibitor lonafarnib (50 mg/kg, intraperitoneally injected) to male mice on the expression and activity of α7nAChR in hippocampal CA1 pyramidal cells. Herein, we show that lonafarnib dose dependently enhances the amplitude of ACh-evoked inward currents (IACh), owning to the increased α7nAChR expression and membrane trafficking. Lonafarnib inhibited phosphorylation of c-Jun and JNK, which was related to DNA methylation. In addition, reduced DNA methyltransferase 1 (DNMT1) expression was observed in lonafarnib-treated mice, which was reversed by JNK activator. Lonafarnib-upregulated expression of α7nAChR was mimicked by DNMT inhibitor, and repressed by JNK activator. However, only inhibited DNA methylation did not affect IACh, and the JNK activator partially decreased the lonafarnib-upregulated IACh. On the other hand, lonafarnib also increased the membrane expression of α7nAChR, which was partially inhibited by JNK activator or CaMKII inhibitor, without changes in the α7nAChR phosphorylation. CaMKII inhibitor had no effect on the expression of α7nAChR. Lonafarnib-enhanced spatial memory of mice was also partially blocked by JNK activator or CaMKII inhibitor. These results suggest that Ras inhibition increases α7nAChR expression through depressed DNA methylation of CHRNA7 via Ras-c-Jun-JNK pathway, increases the membrane expression of α7nAChR resulting in part from the enhanced CaMKII pathway and total expression of this receptor, and consequently enhances the spatial memory.
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Affiliation(s)
- Tingting Chen
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, China.,Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, China
| | - Chengyun Cai
- School of Life Science, Nantong University, Nantong, China
| | - Lifeng Wang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, China.,Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, China
| | - Shixin Li
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, China.,Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, China
| | - Ling Chen
- Department of Physiology, Nanjing Medical University, Nanjing, China
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Maugeri A, Barchitta M, Magnano San Lio R, Li Destri G, Agodi A, Basile G. Epigenetic Aging and Colorectal Cancer: State of the Art and Perspectives for Future Research. Int J Mol Sci 2020; 22:ijms22010200. [PMID: 33379143 PMCID: PMC7795459 DOI: 10.3390/ijms22010200] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 12/22/2020] [Accepted: 12/24/2020] [Indexed: 12/13/2022] Open
Abstract
Although translational research has identified a large number of potential biomarkers involved in colorectal cancer (CRC) carcinogenesis, a better understanding of the molecular pathways associated with biological aging in colorectal cells and tissues is needed. Here, we aim to summarize the state of the art about the role of age acceleration, defined as the difference between epigenetic age and chronological age, in the development and progression of CRC. Some studies have shown that accelerated biological aging is positively associated with the risk of cancer and death in general. In line with these findings, other studies have shown how the assessment of epigenetic age in people at risk for CRC could be helpful for monitoring the molecular response to preventive interventions. Moreover, it would be interesting to investigate whether aberrant epigenetic aging could help identify CRC patients with a high risk of recurrence and a worst prognosis, as well as those who respond poorly to treatment. Yet, the application of this novel concept is still in its infancy, and further research should be encouraged in anticipation of future applications in clinical practice.
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Affiliation(s)
- Andrea Maugeri
- Department of Medical and Surgical Sciences and Advanced Technologies “GF Ingrassia”, University of Catania, via S. Sofia, 87, 95123 Catania, Italy; (A.M.); (R.M.S.L.); (G.L.D.); (A.A.)
| | - Martina Barchitta
- Department of Medical and Surgical Sciences and Advanced Technologies “GF Ingrassia”, University of Catania, via S. Sofia, 87, 95123 Catania, Italy; (A.M.); (R.M.S.L.); (G.L.D.); (A.A.)
- Correspondence:
| | - Roberta Magnano San Lio
- Department of Medical and Surgical Sciences and Advanced Technologies “GF Ingrassia”, University of Catania, via S. Sofia, 87, 95123 Catania, Italy; (A.M.); (R.M.S.L.); (G.L.D.); (A.A.)
| | - Giovanni Li Destri
- Department of Medical and Surgical Sciences and Advanced Technologies “GF Ingrassia”, University of Catania, via S. Sofia, 87, 95123 Catania, Italy; (A.M.); (R.M.S.L.); (G.L.D.); (A.A.)
| | - Antonella Agodi
- Department of Medical and Surgical Sciences and Advanced Technologies “GF Ingrassia”, University of Catania, via S. Sofia, 87, 95123 Catania, Italy; (A.M.); (R.M.S.L.); (G.L.D.); (A.A.)
| | - Guido Basile
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, via S. Sofia, 78, 95123 Catania, Italy;
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25
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Rahman MA, Rahman MS, Uddin MJ, Mamum-Or-Rashid ANM, Pang MG, Rhim H. Emerging risk of environmental factors: insight mechanisms of Alzheimer's diseases. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2020; 27:44659-44672. [PMID: 32201908 DOI: 10.1007/s11356-020-08243-z] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 02/25/2020] [Indexed: 06/10/2023]
Abstract
Neurodegenerative disorders are typically sporadic in nature in addition to usually influenced through an extensive range of environmental factors, lifestyle, and genetic elements. Latest observations have hypothesized that exposure of environmental factors may increase the prospective risk of Alzheimer's diseases (AD). However, the role of environmental factors as a possible dangerous issue has extended importance concerned in AD pathology, although actual etiology of the disorder is still not yet clear. Thus, the aim of this review is to highlight the possible correlation between environmental factors and AD, based on the present literature view. Environmental risk factors might play an important role in decelerating or accelerating AD progression. Among well-known environmental risk factors, prolonged exposure to several heavy metals, for example, aluminum, arsenic, cadmium, lead, and mercury; particulate air, and some pesticides as well as metal-containing nanoparticles have been participated to cause AD. These heavy metals have the capacity to enhance amyloid β (Aβ) peptide along with tau phosphorylation, initiating amyloid/senile plaques, as well as neurofibrillary tangle formation; therefore, neuronal cell death has been observed. Furthermore, particulate air, pesticides, and heavy metal exposure have been recommended to lead AD susceptibility and phenotypic diversity though epigenetic mechanisms. Therefore, this review deliberates recent findings detailing the mechanisms for a better understanding the relationship between AD and environmental risk factors along with their mechanisms of action on the brain functions.
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Affiliation(s)
- Md Ataur Rahman
- Center for Neuroscience, Korea Institute of Science and Technology (KIST), 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul, 02792, Republic of Korea.
- Department of Biotechnology and Genetic Engineering, Global Biotechnology & Biomedical Research Network (GBBRN), Faculty of Biological Sciences, Islamic University, Kushtia, 7003, Bangladesh.
| | - Md Saidur Rahman
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, 456-756, Republic of Korea
| | - Md Jamal Uddin
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, 03760, Republic of Korea
- ABEx Bio-Research Center, East Azampur, Dhaka, 1230, Bangladesh
| | - A N M Mamum-Or-Rashid
- Anti-Aging Medical Research Center and Glycation Stress Research Center, Graduate School of Life and Medical Sciences, Doshisha University, Kyoto, Japan
| | - Myung-Geol Pang
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, 456-756, Republic of Korea
| | - Hyewhon Rhim
- Center for Neuroscience, Korea Institute of Science and Technology (KIST), 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul, 02792, Republic of Korea.
- Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology (UST), Seoul, 02792, Republic of Korea.
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26
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Hodjat M, Khan F, Saadat KA. Epigenetic alterations in aging tooth and the reprogramming potential. Ageing Res Rev 2020; 63:101140. [PMID: 32795505 DOI: 10.1016/j.arr.2020.101140] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 07/27/2020] [Accepted: 08/04/2020] [Indexed: 02/07/2023]
Abstract
Tooth compartments and associated supportive tissues exhibit significant alterations during aging, leading to their impaired functioning. Aging not only affects the structure and function of dental tissue but also reduces its capacity to maintain physiological homeostasis and the healing process. Decreased cementocyte viability; diminished regenerative potential of stem cells residing in the pulp, alveolar bone and periodontal ligament; and impaired osteogenic and odontogenic differentiation capacity of progenitor cells are among the cellular impacts associated with oral aging. Various physiological and pathological phenomena are regulated by the epigenome, and hence, changes in epigenetic markers due to external stimuli have been reported in aging oral tissues and are considered a possible molecular mechanism underlying dental aging. The role of nutri-epigenetics in aging has emerged as an attractive research area. Thus far, various nutrients and bioactive compounds have been identified to have a modulatory effect on the epigenetic machinery, showing a promising response in dental aging. The human microbiota is another key player in aging and can be a target for anti-aging interventions in dental tissue. Considering the reversible characteristics of epigenetic markers and the potential for environmental factors to manipulate the epigenome, to minimize the deteriorative effects of aging, it is important to evaluate the linkage between external stimuli and their effects in terms of age-related epigenetic modifications.
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27
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Ding Q, Shao C, Rose P, Zhu YZ. Epigenetics and Vascular Senescence-Potential New Therapeutic Targets? Front Pharmacol 2020; 11:535395. [PMID: 33101015 PMCID: PMC7556287 DOI: 10.3389/fphar.2020.535395] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 08/31/2020] [Indexed: 12/14/2022] Open
Abstract
Epigenetics is defined as the heritable alterations of gene expression without changes to the coding sequence of DNA. These alterations are mediated by processes including DNA methylation, histone modifications, and non-coding RNAs mechanisms. Vascular aging consists of both structural and functional changes in the vasculature including pathological processes that drive progression such as vascular cell senescence, inflammation, oxidation stress, and calcification. As humans age, these pathological conditions gradually accumulate, driven by epigenetic alterations, and are linked to various aging-related diseases. The development of drugs targeting a spectrum of epigenetic processes therefore offers novel treatment strategies for the targeting of age-related diseases. In our previous studies, we identified HDAC4, JMJD3, Fra-1, and GATA4 as potential pharmacological targets for regulating vascular inflammation, injury, and senescence.
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Affiliation(s)
- Qian Ding
- State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China.,School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Chunhong Shao
- Department of Psychiatry, Huashan Hospital, Fudan University, Shanghai, China
| | - Peter Rose
- School of Biosciences, University of Nottingham, Loughborough, United Kingdom
| | - Yi Zhun Zhu
- State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China
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28
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Arora I, Sharma M, Sun LY, Tollefsbol TO. The Epigenetic Link between Polyphenols, Aging and Age-Related Diseases. Genes (Basel) 2020; 11:genes11091094. [PMID: 32962067 PMCID: PMC7565986 DOI: 10.3390/genes11091094] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 08/15/2020] [Accepted: 09/16/2020] [Indexed: 12/21/2022] Open
Abstract
Aging is a complex process mainly categorized by a decline in tissue, cells and organ function and an increased risk of mortality. Recent studies have provided evidence that suggests a strong association between epigenetic mechanisms throughout an organism’s lifespan and age-related disease progression. Epigenetics is considered an evolving field and regulates the genetic code at several levels. Among these are DNA changes, which include modifications to DNA methylation state, histone changes, which include modifications of methylation, acetylation, ubiquitination and phosphorylation of histones, and non-coding RNA changes. As a result, these epigenetic modifications are vital targets for potential therapeutic interventions against age-related deterioration and disease progression. Dietary polyphenols play a key role in modulating these modifications thereby delaying aging and extending longevity. In this review, we summarize recent advancements linking epigenetics, polyphenols and aging as well as critical findings related to the various dietary polyphenols in different fruits and vegetables. In addition, we cover studies that relate polyphenols and their epigenetic effects to various aging-related diseases such as cardiovascular diseases, neurodegenerative diseases, autoimmune disorders, diabetes, osteoporosis and cancer.
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Affiliation(s)
- Itika Arora
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (I.A.); (M.S.); (L.Y.S.)
| | - Manvi Sharma
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (I.A.); (M.S.); (L.Y.S.)
| | - Liou Y. Sun
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (I.A.); (M.S.); (L.Y.S.)
- Comprehensive Center for Healthy Aging, University of Alabama Birmingham, 1530 3rd Avenue South, Birmingham, AL 35294, USA
| | - Trygve O. Tollefsbol
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (I.A.); (M.S.); (L.Y.S.)
- Comprehensive Center for Healthy Aging, University of Alabama Birmingham, 1530 3rd Avenue South, Birmingham, AL 35294, USA
- Comprehensive Cancer Center, University of Alabama Birmingham, 1802 6th Avenue South, Birmingham, AL 35294, USA
- Nutrition Obesity Research Center, University of Alabama Birmingham, 1675 University Boulevard, Birmingham, AL 35294, USA
- Comprehensive Diabetes Center, University of Alabama Birmingham, Birmingham, AL 35294, USA
- Correspondence: ; Tel.: +1-205-934-4573; Fax: +1-205-975-6097
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29
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Park JW, Han SB, Hah J, Lee G, Kim JK, Kim SH, Kim DH. Biological Aging Modulates Cell Migration via Lamin A/C-Dependent Nuclear Motion. MICROMACHINES 2020; 11:E801. [PMID: 32847135 PMCID: PMC7570206 DOI: 10.3390/mi11090801] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 08/20/2020] [Accepted: 08/22/2020] [Indexed: 12/13/2022]
Abstract
Aging is a progressive functional decline in organs and tissues over time and typically represents the accumulation of psychological and social changes in a human being. Diverse diseases, such as cardiovascular, musculoskeletal, and neurodegenerative disorders, are now understood to be caused by aging. While biological assessment of aging mainly focuses on the gradual changes that occur either on the molecular scale, for example, alteration of gene expression and epigenetic modification, or on larger scales, for example, changes in muscle strength and cardiac function, the mechanics that regulates the behavior of individual cells and interactions between the internal elements of cells, are largely missing. In this study, we show that the dynamic features of migrating cells across different human ages could help to establish the underlying mechanism of biological age-dependent cellular functional decline. To determine the relationship between cellular dynamics and human age, we identify the characteristic relationship between cell migration and nuclear motion which is tightly regulated by nucleus-bound cytoskeletal organization. This analysis demonstrates that actomyosin contractility-dependent nuclear motion plays a key role in cell migration. We anticipate this study to provide noble biophysical insights on biological aging in order to precisely diagnose age-related chronic diseases.
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Affiliation(s)
- Jung-Won Park
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Korea; (J.-W.P.); (S.-B.H.); (J.H.); (G.L.); (J.-K.K.); (S.H.K.)
| | - Seong-Beom Han
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Korea; (J.-W.P.); (S.-B.H.); (J.H.); (G.L.); (J.-K.K.); (S.H.K.)
| | - Jungwon Hah
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Korea; (J.-W.P.); (S.-B.H.); (J.H.); (G.L.); (J.-K.K.); (S.H.K.)
| | - Geonhui Lee
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Korea; (J.-W.P.); (S.-B.H.); (J.H.); (G.L.); (J.-K.K.); (S.H.K.)
| | - Jeong-Ki Kim
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Korea; (J.-W.P.); (S.-B.H.); (J.H.); (G.L.); (J.-K.K.); (S.H.K.)
| | - Soo Hyun Kim
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Korea; (J.-W.P.); (S.-B.H.); (J.H.); (G.L.); (J.-K.K.); (S.H.K.)
- Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792, Korea
| | - Dong-Hwee Kim
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Korea; (J.-W.P.); (S.-B.H.); (J.H.); (G.L.); (J.-K.K.); (S.H.K.)
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30
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Interplay between Metabolism, Nutrition and Epigenetics in Shaping Brain DNA Methylation, Neural Function and Behavior. Genes (Basel) 2020; 11:genes11070742. [PMID: 32635190 PMCID: PMC7397264 DOI: 10.3390/genes11070742] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 06/25/2020] [Accepted: 07/02/2020] [Indexed: 12/14/2022] Open
Abstract
Gene expression in the brain is dramatically regulated by a variety of stimuli. While the role of neural activity has been extensively studied, less is known about the effects of metabolism and nutrition on transcriptional control mechanisms in the brain. Extracellular signals are integrated at the chromatin level through dynamic modifications of epigenetic marks, which in turn fine-tune gene transcription. In the last twenty years, it has become clear that epigenetics plays a crucial role in modulating central nervous system functions and finally behavior. Here, we will focus on the effect of metabolic signals in shaping brain DNA methylation, both during development and adulthood. We will provide an overview of maternal nutrition effects on brain methylation and behavior in offspring. In addition, the impact of different diet challenges on cytosine methylation dynamics in the adult brain will be discussed. Finally, the possible role played by the metabolic status in modulating DNA hydroxymethylation, which is particularly abundant in neural tissue, will be considered.
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31
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Ladomersky E, Zhai L, Lauing KL, Bell A, Xu J, Kocherginsky M, Zhang B, Wu JD, Podojil JR, Platanias LC, Mochizuki AY, Prins RM, Kumthekar P, Raizer JJ, Dixit K, Lukas RV, Horbinski C, Wei M, Zhou C, Pawelec G, Campisi J, Grohmann U, Prendergast GC, Munn DH, Wainwright DA. Advanced Age Increases Immunosuppression in the Brain and Decreases Immunotherapeutic Efficacy in Subjects with Glioblastoma. Clin Cancer Res 2020; 26:5232-5245. [PMID: 32546647 DOI: 10.1158/1078-0432.ccr-19-3874] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 05/04/2020] [Accepted: 06/11/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE Wild-type isocitrate dehydrogenase-expressing glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median age at diagnosis of ≥65 years. It accounts for approximately 90% of all GBMs and has a median overall survival (OS) of <15 months. Although immune checkpoint blockade (ICB) therapy has achieved remarkable survival benefits in a variety of aggressive malignancies, similar success has yet to be achieved for GBM among phase III clinical trials to date. Our study aimed to understand the relationship between subject age and immunotherapeutic efficacy as it relates to survival from glioma. EXPERIMENTAL DESIGN (i) Clinical data: GBM patient datasets from The Cancer Genome Atlas, Northwestern Medicine Enterprise Data Warehouse, and clinical studies evaluating ICB were stratified by age and compared for OS. (ii) Animal models: young, middle-aged, and older adult wild-type and indoleamine 2,3 dioxygenase (IDO)-knockout syngeneic mice were intracranially engrafted with CT-2A or GL261 glioma cell lines and treated with or without CTLA-4/PD-L1 mAbs, or radiation, anti-PD-1 mAb, and/or a pharmacologic IDO enzyme inhibitor. RESULTS Advanced age was associated with decreased GBM patient survival regardless of treatment with ICB. The advanced age-associated increase of brain IDO expression was linked to the suppression of immunotherapeutic efficacy and was not reversed by IDO enzyme inhibitor treatment. CONCLUSIONS Immunosuppression increases in the brain during advanced age and inhibits antiglioma immunity in older adults. Going forward, it will be important to fully understand the factors and mechanisms in the elderly brain that contribute to the decreased survival of older patients with GBM during treatment with ICB.
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Affiliation(s)
- Erik Ladomersky
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Lijie Zhai
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Kristen L Lauing
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - April Bell
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Jiahui Xu
- Department of Preventive Medicine-Biostatistics, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Masha Kocherginsky
- Department of Preventive Medicine-Biostatistics, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Bin Zhang
- Department of Medicine-Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.,Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Jennifer D Wu
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Joseph R Podojil
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Leonidas C Platanias
- Department of Medicine-Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.,Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Aaron Y Mochizuki
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, California
| | - Robert M Prins
- Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, California
| | - Priya Kumthekar
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Jeffrey J Raizer
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Karan Dixit
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Rimas V Lukas
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Craig Horbinski
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.,Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Min Wei
- BeiGene, Zhong-Guan-Cun Life Science Park, Changping District, Beijing, China
| | - Changyou Zhou
- BeiGene, Zhong-Guan-Cun Life Science Park, Changping District, Beijing, China
| | - Graham Pawelec
- Department of Immunology, University of Tübingen, Tübingen, Germany
| | - Judith Campisi
- Buck Institute for Research on Aging, Novato, California.,Lawrence Berkeley National Laboratory, Berkeley, California
| | - Ursula Grohmann
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | | | | | - Derek A Wainwright
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois. .,Department of Medicine-Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.,Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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Mavrogonatou E, Pratsinis H, Kletsas D. The role of senescence in cancer development. Semin Cancer Biol 2020; 62:182-191. [DOI: 10.1016/j.semcancer.2019.06.018] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 06/24/2019] [Accepted: 06/27/2019] [Indexed: 02/07/2023]
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33
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Andrawus M, Sharvit L, Shekhidem HA, Roichman A, Cohen HY, Atzmon G. The effects of environmental stressors on candidate aging associated genes. Exp Gerontol 2020; 137:110952. [PMID: 32344118 DOI: 10.1016/j.exger.2020.110952] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 03/29/2020] [Accepted: 04/09/2020] [Indexed: 01/15/2023]
Abstract
BACKGROUND Aging is defined as a biological and physical complex process that is characterized by the increase in susceptibility to diseases and eventually death. Aging may occur at different rates between and within species, especially or (it varies) among the long-lived ones. Here, we ask whether this diversity (e.g. aging phenotype) stems from genetic or environmental factors or as a combination between the two (epigenetics). Epigenetics play a central role in controlling changes in gene expression during aging. DNA methylation is the most abundant epigenetic modification among vertebrates and is essential to mammalian development. MATERIALS AND METHODS In this study, we utilized the HELPtag assay to identify five candidate genes that were significantly hyper- or hypo-methylated across four different age groups in mice. The candidate genes were annotated using ensemble and their expression was further tested in vitro using the murine RAW 264.7 cell line to examine the effect of three environmental stressors (UV radiation, Hypoxia and fasting) on their expression. RNA was extracted at different time points followed by cDNA synthesis. Changes in gene expression were evaluated using qRT-PCR. RESULTS We show that fasting and UV radiation reduced the viability of RAW264.7 cells. We also found a significant change in three candidate genes' expression levels during fasting (TOP2B, RNF13 and MRPL4). Furthermore, we found a significant change in the four candidate genes' expression levels following UVC treatment (TOP2B, RNF13, PKNOX1 and CREB5) and yet no changes were recorded in hypoxic conditions. CONCLUSION Our results suggest that the model we used was a fitting model for the assessment of environmental stressors on candidate gene expression. In addition, we established a cellular response to the environment via changes in gene expression.
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Affiliation(s)
- Mariana Andrawus
- Department of Human Biology, University of Haifa, Haifa 3498838, Israel
| | - Lital Sharvit
- Department of Human Biology, University of Haifa, Haifa 3498838, Israel
| | | | - Asael Roichman
- Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel
| | - Haim Y Cohen
- Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel
| | - Gil Atzmon
- Department of Human Biology, University of Haifa, Haifa 3498838, Israel.
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Dompe C, Janowicz K, Hutchings G, Moncrieff L, Jankowski M, Nawrocki MJ, Józkowiak M, Mozdziak P, Petitte J, Shibli JA, Dyszkiewicz-Konwińska M, Bruska M, Piotrowska-Kempisty H, Kempisty B, Nowicki M. Epigenetic Research in Stem Cell Bioengineering-Anti-Cancer Therapy, Regenerative and Reconstructive Medicine in Human Clinical Trials. Cancers (Basel) 2020; 12:E1016. [PMID: 32326172 PMCID: PMC7226111 DOI: 10.3390/cancers12041016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 04/14/2020] [Accepted: 04/15/2020] [Indexed: 12/12/2022] Open
Abstract
The epigenome denotes all the information related to gene expression that is not contained in the DNA sequence but rather results from chemical changes to histones and DNA. Epigenetic modifications act in a cooperative way towards the regulation of gene expression, working at the transcriptional or post-transcriptional level, and play a key role in the determination of phenotypic variations in cells containing the same genotype. Epigenetic modifications are important considerations in relation to anti-cancer therapy and regenerative/reconstructive medicine. Moreover, a range of clinical trials have been performed, exploiting the potential of epigenetics in stem cell engineering towards application in disease treatments and diagnostics. Epigenetic studies will most likely be the basis of future cancer therapies, as epigenetic modifications play major roles in tumour formation, malignancy and metastasis. In fact, a large number of currently designed or tested clinical approaches, based on compounds regulating epigenetic pathways in various types of tumours, employ these mechanisms in stem cell bioengineering.
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Affiliation(s)
- Claudia Dompe
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (C.D.); (L.M.); (M.N.)
- The School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (K.J.); (G.H.)
| | - Krzysztof Janowicz
- The School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (K.J.); (G.H.)
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.); (M.J.N.); (M.D.-K.); (M.B.)
| | - Greg Hutchings
- The School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (K.J.); (G.H.)
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.); (M.J.N.); (M.D.-K.); (M.B.)
| | - Lisa Moncrieff
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (C.D.); (L.M.); (M.N.)
- The School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (K.J.); (G.H.)
| | - Maurycy Jankowski
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.); (M.J.N.); (M.D.-K.); (M.B.)
| | - Mariusz J. Nawrocki
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.); (M.J.N.); (M.D.-K.); (M.B.)
| | - Małgorzata Józkowiak
- Department of Toxicology, Poznan University of Medical Sciences, 61-631 Poznan, Poland; (M.J.); (H.P.-K.)
| | - Paul Mozdziak
- Physiology Graduate Program, North Carolina State University, Raleigh, NC 27695, USA;
| | - Jim Petitte
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA;
| | - Jamil A. Shibli
- Department of Periodontology and Oral Implantology, Dental Research Division, University of Guarulhos, São Paulo 07023-070, Brazil;
| | - Marta Dyszkiewicz-Konwińska
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.); (M.J.N.); (M.D.-K.); (M.B.)
- Department of Biomaterials and Experimental Dentistry, Poznan University of Medical Sciences, 61 701 Poznan, Poland
| | - Małgorzata Bruska
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.); (M.J.N.); (M.D.-K.); (M.B.)
| | - Hanna Piotrowska-Kempisty
- Department of Toxicology, Poznan University of Medical Sciences, 61-631 Poznan, Poland; (M.J.); (H.P.-K.)
| | - Bartosz Kempisty
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (C.D.); (L.M.); (M.N.)
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.); (M.J.N.); (M.D.-K.); (M.B.)
- Department of Obstetrics and Gynaecology, University Hospital and Masaryk University, 602 00 Brno, Czech Republic
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87 100 Torun, Poland
| | - Michał Nowicki
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (C.D.); (L.M.); (M.N.)
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Pretsch G, Sanadgol N, Smidak R, Lubec J, Korz V, Höger H, Zappe K, Cichna‑Markl M, Lubec G. Doublecortin and IGF-1R protein levels are reduced in spite of unchanged DNA methylation in the hippocampus of aged rats. Amino Acids 2020; 52:543-553. [DOI: 10.1007/s00726-020-02834-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 03/04/2020] [Indexed: 11/24/2022]
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Guo XJ, Yang D, Zhang XY. Epigenetics recording varied environment and complex cell events represents the origin of cellular aging. J Zhejiang Univ Sci B 2020; 20:550-562. [PMID: 31168969 DOI: 10.1631/jzus.b1800507] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Although a relationship between epigenetics and aging phenotypic changes has been established, a theoretical explanation of the intrinsic connection between the epigenetics and aging is lacking. In this essay, we propose that epigenetic recording of varied cell environment and complex history could be an origin of cellular aging. Through epigenetic modifications, the environment and historical events can induce the chromatin template into an activated or repressive accessible structure, thereby shaping the DNA template into a spectrum of chromatin states. The inner nature of diversity and conflicts born by the cell environment and its historical events are hence recorded into the chromatin template. This could result in a dissipated spectrum of the chromatin state and chaos in overall gene expression. An unavoidable degradation of epigenome entropy, similar to Shannon entropy, would be consequently induced. The resultant disorder in epigenome, characterized by corrosion of epigenome entropy as reflected in chromatin template, can be stably memorized and propagated through cell division. Furthermore, the hysteretic nature of epigenetics responding to the emerging environment could exacerbate the degradation of epigenome entropy. As well as stochastic errors, we propose that outside entropy (or chaos) derived from the varied environment and complex cell history, gradually input and imprinted into the chromatin via epigenetic modifications, would lead inevitably to cellular aging, the extent of which could be aggravated by hysteresis of epigenetics without error erasing and correction.
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Affiliation(s)
- Xue-Jun Guo
- State Key Laboratory of Environment Simulation, School of Environment, Beijing Normal University, Beijing 100875, China
| | - Dong Yang
- Gene Engineering and Biotechnology Beijing Key Laboratory, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Xiang-Yuan Zhang
- State Key Laboratory of Environment Simulation, School of Environment, Beijing Normal University, Beijing 100875, China
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Wang T, Maden SK, Luebeck GE, Li CI, Newcomb PA, Ulrich CM, Joo JHE, Buchanan DD, Milne RL, Southey MC, Carter KT, Willbanks AR, Luo Y, Yu M, Grady WM. Dysfunctional epigenetic aging of the normal colon and colorectal cancer risk. Clin Epigenetics 2020; 12:5. [PMID: 31900199 PMCID: PMC6942339 DOI: 10.1186/s13148-019-0801-3] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Accepted: 12/23/2019] [Indexed: 12/12/2022] Open
Abstract
Background Chronological age is a prominent risk factor for many types of cancers including colorectal cancer (CRC). Yet, the risk of CRC varies substantially between individuals, even within the same age group, which may reflect heterogeneity in biological tissue aging between people. Epigenetic clocks based on DNA methylation are a useful measure of the biological aging process with the potential to serve as a biomarker of an individual’s susceptibility to age-related diseases such as CRC. Methods We conducted a genome-wide DNA methylation study on samples of normal colon mucosa (N = 334). Subjects were assigned to three cancer risk groups (low, medium, and high) based on their personal adenoma or cancer history. Using previously established epigenetic clocks (Hannum, Horvath, PhenoAge, and EpiTOC), we estimated the biological age of each sample and assessed for epigenetic age acceleration in the samples by regressing the estimated biological age on the individual’s chronological age. We compared the epigenetic age acceleration between different risk groups using a multivariate linear regression model with the adjustment for gender and cell-type fractions for each epigenetic clock. An epigenome-wide association study (EWAS) was performed to identify differential methylation changes associated with CRC risk. Results Each epigenetic clock was significantly correlated with the chronological age of the subjects, and the Horvath clock exhibited the strongest correlation in all risk groups (r > 0.8, p < 1 × 10−30). The PhenoAge clock (p = 0.0012) revealed epigenetic age deceleration in the high-risk group compared to the low-risk group. Conclusions Among the four DNA methylation-based measures of biological age, the Horvath clock is the most accurate for estimating the chronological age of individuals. Individuals with a high risk for CRC have epigenetic age deceleration in their normal colons measured by the PhenoAge clock, which may reflect a dysfunctional epigenetic aging process.
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Affiliation(s)
- Ting Wang
- Clinical Research Division, Fred Hutchinson Cancer Research Center, D4-100, 1100 Fairview Ave N, Seattle, WA, 98109, USA
| | - Sean K Maden
- Clinical Research Division, Fred Hutchinson Cancer Research Center, D4-100, 1100 Fairview Ave N, Seattle, WA, 98109, USA.,Computational Biology Program, Oregon Health & Science University, Portland, OR, USA.,Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA
| | - Georg E Luebeck
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Christopher I Li
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Cornelia M Ulrich
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,Huntsman Cancer Institute and Department of Population Health Sciences, Salt Lake City, UT, USA
| | - Ji-Hoon E Joo
- Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia
| | - Daniel D Buchanan
- Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia
| | - Roger L Milne
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.,Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.,Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Melissa C Southey
- Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia.,Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.,Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Kelly T Carter
- Clinical Research Division, Fred Hutchinson Cancer Research Center, D4-100, 1100 Fairview Ave N, Seattle, WA, 98109, USA
| | - Amber R Willbanks
- Clinical Research Division, Fred Hutchinson Cancer Research Center, D4-100, 1100 Fairview Ave N, Seattle, WA, 98109, USA
| | - Yanxin Luo
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Ming Yu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, D4-100, 1100 Fairview Ave N, Seattle, WA, 98109, USA.
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, D4-100, 1100 Fairview Ave N, Seattle, WA, 98109, USA. .,Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. .,Department of Internal Medicine, University of Washington School of Medicine, Seattle, WA, USA.
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Brivio P, Paladini MS, Racagni G, Riva MA, Calabrese F, Molteni R. From Healthy Aging to Frailty: In Search of the Underlying Mechanisms. Curr Med Chem 2019; 26:3685-3701. [PMID: 31333079 DOI: 10.2174/0929867326666190717152739] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 12/14/2018] [Accepted: 03/08/2019] [Indexed: 11/22/2022]
Abstract
Population aging is accelerating rapidly worldwide, from 461 million people older than 65 years in 2004 to an estimated 2 billion people by 2050, leading to critical implications for the planning and delivery of health and social care. The most problematic expression of population aging is the clinical condition of frailty, which is a state of increased vulnerability that develops as a consequence of the accumulation of microscopic damages in many physiological systems that lead to a striking and disproportionate change in health state, even after an apparently small insult. Since little is known about the biology of frailty, an important perspective to understand this phenomenon is to establish how the alterations that physiologically occur during a condition of healthy aging may instead promote cumulative decline with subsequent depletion of homoeostatic reserve and increase the vulnerability also after minor stressor events. In this context, the present review aims to provide a description of the molecular mechanisms that, by having a critical impact on behavior and neuronal function in aging, might be relevant for the development of frailty. Moreover, since these biological systems are also involved in the coping strategies set in motion to respond to environmental challenges, we propose a role for lifestyle stress as an important player to drive frailty in aging.
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Affiliation(s)
- Paola Brivio
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Maria Serena Paladini
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Giorgio Racagni
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.,Associazione di Psicofarmacologia, Milan, Italy
| | - Marco Andrea Riva
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Francesca Calabrese
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Raffaella Molteni
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
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39
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Sándor S, Kubinyi E. Genetic Pathways of Aging and Their Relevance in the Dog as a Natural Model of Human Aging. Front Genet 2019; 10:948. [PMID: 31681409 PMCID: PMC6813227 DOI: 10.3389/fgene.2019.00948] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Accepted: 09/05/2019] [Indexed: 12/15/2022] Open
Abstract
Aging research has experienced a burst of scientific efforts in the last decades as the growing ratio of elderly people has begun to pose an increased burden on the healthcare and pension systems of developed countries. Although many breakthroughs have been reported in understanding the cellular mechanisms of aging, the intrinsic and extrinsic factors that contribute to senescence on higher biological levels are still barely understood. The dog, Canis familiaris, has already served as a valuable model of human physiology and disease. The possible role the dog could play in aging research is still an open question, although utilization of dogs may hold great promises as they naturally develop age-related cognitive decline, with behavioral and histological characteristics very similar to those of humans. In this regard, family dogs may possess unmatched potentials as models for investigations on the complex interactions between environmental, behavioral, and genetic factors that determine the course of aging. In this review, we summarize the known genetic pathways in aging and their relevance in dogs, putting emphasis on the yet barely described nature of certain aging pathways in canines. Reasons for highlighting the dog as a future aging and gerontology model are also discussed, ranging from its unique evolutionary path shared with humans, its social skills, and the fact that family dogs live together with their owners, and are being exposed to the same environmental effects.
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Affiliation(s)
- Sára Sándor
- Department of Ethology, Eötvös Loránd University, Budapest, Hungary
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40
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Tiane A, Schepers M, Rombaut B, Hupperts R, Prickaerts J, Hellings N, van den Hove D, Vanmierlo T. From OPC to Oligodendrocyte: An Epigenetic Journey. Cells 2019; 8:E1236. [PMID: 31614602 PMCID: PMC6830107 DOI: 10.3390/cells8101236] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 10/08/2019] [Accepted: 10/10/2019] [Indexed: 12/15/2022] Open
Abstract
Oligodendrocytes provide metabolic and functional support to neuronal cells, rendering them key players in the functioning of the central nervous system. Oligodendrocytes need to be newly formed from a pool of oligodendrocyte precursor cells (OPCs). The differentiation of OPCs into mature and myelinating cells is a multistep process, tightly controlled by spatiotemporal activation and repression of specific growth and transcription factors. While oligodendrocyte turnover is rather slow under physiological conditions, a disruption in this balanced differentiation process, for example in case of a differentiation block, could have devastating consequences during ageing and in pathological conditions, such as multiple sclerosis. Over the recent years, increasing evidence has shown that epigenetic mechanisms, such as DNA methylation, histone modifications, and microRNAs, are major contributors to OPC differentiation. In this review, we discuss how these epigenetic mechanisms orchestrate and influence oligodendrocyte maturation. These insights are a crucial starting point for studies that aim to identify the contribution of epigenetics in demyelinating diseases and may thus provide new therapeutic targets to induce myelin repair in the long run.
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Affiliation(s)
- Assia Tiane
- Department of Immunology, Biomedical Research Institute, Hasselt University, Hasselt 3500, Belgium.
- Department Psychiatry and Neuropsychology, European Graduate School of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht 6200 MD, The Netherlands.
| | - Melissa Schepers
- Department of Immunology, Biomedical Research Institute, Hasselt University, Hasselt 3500, Belgium.
- Department Psychiatry and Neuropsychology, European Graduate School of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht 6200 MD, The Netherlands.
| | - Ben Rombaut
- Department of Immunology, Biomedical Research Institute, Hasselt University, Hasselt 3500, Belgium.
- Department Psychiatry and Neuropsychology, European Graduate School of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht 6200 MD, The Netherlands.
| | - Raymond Hupperts
- Department of Neurology, Zuyderland Medical Center, Sittard-Geleen 6130 MB, The Netherlands.
- Department Psychiatry and Neuropsychology, European Graduate School of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht 6200 MD, The Netherlands.
| | - Jos Prickaerts
- Department Psychiatry and Neuropsychology, European Graduate School of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht 6200 MD, The Netherlands.
| | - Niels Hellings
- Department of Immunology, Biomedical Research Institute, Hasselt University, Hasselt 3500, Belgium.
| | - Daniel van den Hove
- Department Psychiatry and Neuropsychology, European Graduate School of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht 6200 MD, The Netherlands.
- Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg 97080, Germany.
| | - Tim Vanmierlo
- Department of Immunology, Biomedical Research Institute, Hasselt University, Hasselt 3500, Belgium.
- Department Psychiatry and Neuropsychology, European Graduate School of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht 6200 MD, The Netherlands.
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41
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Starr JM. Ageing and epigenetics: linking neurodevelopmental and neurodegenerative disorders. Dev Med Child Neurol 2019; 61:1134-1138. [PMID: 30883719 DOI: 10.1111/dmcn.14210] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/30/2019] [Indexed: 12/18/2022]
Abstract
Epigenetics has classically been recognized as crucial to neurodevelopment and neurodevelopmental disorders. More recently its role in ageing processes, including neurodegenerative disorders has emerged, although far more research is required in this area, particularly in humans. Epigenetic processes that regulate gene expression comprise strata of DNA modification (e.g. methylation), histone modification (e.g. histone acetylation), and mRNA translation (e.g. by microRNAs). These strata are progressively more fluid whereby changes in DNA methylation may persist for many years whilst expression of microRNAs fluctuates over short periods. There is considerable 'cross-talk' between these epigenetic strata. Epigenetic mechanisms are open to parental imprinting and thus they are candidates for linking diseases, not just over the life course, but also intergenerationally. There is a genetic overlap between intellectual disability and cognitive ageing. Epigenetic pathways may strengthen the links between neurodevelopmental disorders and neurodegenerative diseases. WHAT THIS PAPER ADDS: DNA methylation has relevance to both neurological development and neurodegeneration. Links between epigenetics, genotype and phenotype are emerging.
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Affiliation(s)
- John M Starr
- Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK
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42
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Gensous N, Bacalini MG, Franceschi C, Meskers CGM, Maier AB, Garagnani P. Age-Related DNA Methylation Changes: Potential Impact on Skeletal Muscle Aging in Humans. Front Physiol 2019; 10:996. [PMID: 31427991 PMCID: PMC6688482 DOI: 10.3389/fphys.2019.00996] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 07/18/2019] [Indexed: 12/27/2022] Open
Abstract
Human aging is accompanied by a decline in muscle mass and muscle function, which is commonly referred to as sarcopenia. Sarcopenia is associated with detrimental clinical outcomes, such as a reduced quality of life, frailty, an increased risk of falls, fractures, hospitalization, and mortality. The exact underlying mechanisms of sarcopenia are poorly delineated and the molecular mechanisms driving the development and progression of this disorder remain to be uncovered. Previous studies have described age-related differences in gene expression, with one study identifying an age-specific expression signature of sarcopenia, but little is known about the influence of epigenetics, and specially of DNA methylation, in its pathogenesis. In this review, we will focus on the available knowledge in literature on the characterization of DNA methylation profiles during skeletal muscle aging and the possible impact of physical activity and nutrition. We will consider the possible use of the recently developed DNA methylation-based biomarkers of aging called epigenetic clocks in the assessment of physical performance in older individuals. Finally, we will discuss limitations and future directions of this field.
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Affiliation(s)
- Noémie Gensous
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | | | - Claudio Franceschi
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.,Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
| | - Carel G M Meskers
- Amsterdam UMC, Department of Rehabilitation Medicine, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Andrea B Maier
- Department of Human Movement Sciences, @AgeAmsterdam, Faculty of Behavioural and Movement Sciences, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.,Department of Medicine and Aged Care, @AgeMelbourne, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia
| | - Paolo Garagnani
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.,Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.,Applied Biomedical Research Center (CRBA), Policlinico S.Orsola-Malpighi Polyclinic, Bologna, Italy.,CNR Institute of Molecular Genetics, Unit of Bologna, Bologna, Italy
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DNA Methylation Age-Environmental Influences, Health Impacts, and Its Role in Environmental Epidemiology. Curr Environ Health Rep 2019; 5:317-327. [PMID: 30047075 DOI: 10.1007/s40572-018-0203-2] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW DNA methylation-based aging biomarkers are valuable tools for evaluating the aging process from a molecular perspective. These epigenetic aging biomarkers can be evaluated across the lifespan and are tissue specific. This review examines the literature relating environmental exposures to DNA methylation-based aging biomarkers and also the literature evaluating these biomarkers as predictors of health outcomes. RECENT FINDINGS Multiple studies evaluated the association between air pollution and DNA methylation age and consistently observed that higher exposures are associated with elevated DNA methylation age. Psychosocial exposures, e.g., traumas and adolescent adversity, and infections are also associated with epigenetic aging. DNA methylation age has been repeatedly associated with mortality, cancer, and cognitive impairment. DNA methylation age is responsive to the environment and predictive of health outcomes. Studies are still needed to evaluate whether DNA methylation age acts as a mediator or modifier of environmental health effects and to understand the impact of factors such as race, gender, and genetics.
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Müller L, Di Benedetto S, Pawelec G. The Immune System and Its Dysregulation with Aging. Subcell Biochem 2019; 91:21-43. [PMID: 30888648 DOI: 10.1007/978-981-13-3681-2_2] [Citation(s) in RCA: 140] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Aging leads to numerous changes that affect all physiological systems of the body including the immune system, causing greater susceptibility to infectious disease and contributing to the cardiovascular, metabolic, autoimmune, and neurodegenerative diseases of aging. The immune system is itself also influenced by age-associated changes occurring in such physiological systems as the endocrine, nervous, digestive, cardio-vascular and muscle-skeletal systems. This chapter describes the multidimensional effects of aging on the most important components of the immune system. It considers the age-related changes in immune cells and molecules of innate and adaptive immunity and consequent impairments in their ability to communicate with each other and with their aged environment. The contribution of age-related dysregulation of hematopoiesis, required for continuous replenishment of immune cells throughout life, is discussed in this context, as is the developmentally-programmed phenomenon of thymic involution that limits the output of naïve T cells and markedly contributes to differences between younger and older people in the distribution of peripheral blood T-cell types. How all these changes may contribute to low-grade inflammation, sometimes dubbed "inflammaging", is considered. Due to findings implicating elevated inflammatory immuno-mediators in age-associated chronic autoimmune and neurodegenerative processes, evidence for their possible contribution to neuroinflammation is reviewed.
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Affiliation(s)
- Ludmila Müller
- Max Planck Institute for Human Development, Berlin, Germany.
| | - Svetlana Di Benedetto
- Max Planck Institute for Human Development, Berlin, Germany.,Center for Medical Research, University of Tübingen, Tübingen, Germany
| | - Graham Pawelec
- Center for Medical Research, University of Tübingen, Tübingen, Germany.,Health Sciences North Research Institute, Sudbury, ON, Canada
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45
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The Impact of Caloric Restriction on the Epigenetic Signatures of Aging. Int J Mol Sci 2019; 20:ijms20082022. [PMID: 31022953 PMCID: PMC6515465 DOI: 10.3390/ijms20082022] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 04/19/2019] [Accepted: 04/23/2019] [Indexed: 12/14/2022] Open
Abstract
Aging is characterized by an extensive remodeling of epigenetic patterns, which has been implicated in the physiopathology of age-related diseases. Nutrition plays a significant role in modulating the epigenome, and a growing amount of data indicate that dietary changes can modify the epigenetic marks associated with aging. In this review, we will assess the current advances in the relationship between caloric restriction, a proven anti-aging intervention, and epigenetic signatures of aging. We will specifically discuss the impact of caloric restriction on epigenetic regulation and how some of the favorable effects of caloric restriction on lifespan and healthspan could be mediated by epigenetic modifications.
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Zhou J, Wu YC, Xiao BJ, Guo XD, Zheng QX, Wu B. Age-related Changes in the Global DNA Methylation Profile of Oligodendrocyte Progenitor Cells Derived from Rat Spinal Cords. Curr Med Sci 2019; 39:67-74. [PMID: 30868493 DOI: 10.1007/s11596-019-2001-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 12/27/2018] [Indexed: 01/12/2023]
Abstract
Demyelination of axons plays an important role in the pathology of many spinal cord diseases and injuries. Remyelination in demyelinated lesions is primarily performed by oligodendrocyte progenitor cells (OPCs), which generate oligodendrocytes in the developing and mature central nervous system. The efficiency of remyelination decreases with age. Many reports suggest that this decline in remyelination results from impaired OPC recruitment and differentiation during aging. Of the various molecular mechanisms involved in aging, changes in epigenetic modifications have received particular attention. Global DNA methylation is a major epigenetic modification that plays important roles in cellular senescence and organismal aging. Thus, we aimed to evaluate the dynamic changes in the global DNA methylation profiles of OPCs derived from rat spinal cords during the aging process. We separated and cultured OPCs from the spinal cords of neonatal, 4-month-old, and 16-month-old rats and investigated the age-related alterations of genomic DNA methylation levels by using quantitative colorimetric analysis. To determine the potential cause of dynamic changes in global DNA methylation, we further analyzed the activity of DNA methyltransferases (DNMTs) and the expression of DNMT1, DNMT3a, DNMT3b, TET1, TET2, TET3, MBD2, and MeCP2 in the OPCs from each group. Our results showed the genomic DNA methylation level and the activity of DNMTs from OPCs derived from rat spinal cords decreased gradually during aging, and OPCs from 16-month-old rats were characterized by global hypomethylation. During OPC aging, the mRNA and protein expression levels of DNMT3a, DNMT3b, and MeCP2 were significantly elevated; those of DNMT1 were significantly down-regulated; and no significant changes were observed in those for TET1, TET2, TET3, or MBD2. Our results indicated that global DNA hypomethylation in aged OPCs is correlated with DNMT1 downregulation. Together, these data provide important evidence for partly elucidating the mechanism of age-related impaired OPC recruitment and differentiation and assist in the development of new treatments for promoting efficient remyelination.
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Affiliation(s)
- Jing Zhou
- Department of General Surgery, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yong-Chao Wu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Bao-Jun Xiao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiao-Dong Guo
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Qi-Xin Zheng
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Bin Wu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Kim S, Wyckoff J, Morris AT, Succop A, Avery A, Duncan GE, Jazwinski SM. DNA methylation associated with healthy aging of elderly twins. GeroScience 2018; 40:469-484. [PMID: 30136078 PMCID: PMC6294724 DOI: 10.1007/s11357-018-0040-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 08/09/2018] [Indexed: 12/21/2022] Open
Abstract
Variation in healthy aging and lifespan is ascribed more to various non-genetic factors than to inherited genetic determinants, and a major goal in aging research is to reveal the epigenetic basis of aging. One approach to this goal is to find genomic sites or regions where DNA methylation correlates with biological age. Using health data from 134 elderly twins, we calculated a frailty index as a quantitative indicator of biological age, and by applying the Infinium HumanMethylation450K BeadChip technology to their leukocyte DNA samples, we obtained quantitative DNA methylation data on genome-wide CpG sites. We analyzed the health and epigenome data by taking two independent associative approaches: the parametric regression-based approach and a non-parametric machine learning approach followed by GO ontology analysis. Our results indicate that DNA methylation at CpG sites in the promoter region of PCDHGA3 is associated with biological age. PCDHGA3 belongs to clustered protocadherin genes, which are all located in a single locus on chromosome 5 in human. Previous studies of the clustered protocadherin genes showed that (1) DNA methylation is associated with age or age-related phenotypes; (2) DNA methylation can modulate gene expression; (3) dysregulated gene expression is associated with various pathologies; and (4) DNA methylation patterns at this locus are associated with adverse lifetime experiences. All these observations suggest that DNA methylation at the clustered protocadherin genes, including PCDHGA3, is a key mediator of healthy aging.
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Affiliation(s)
- Sangkyu Kim
- Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA.
| | - Jennifer Wyckoff
- Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA
| | - Anne-T Morris
- Virginia Commonwealth University, Mid-Atlantic Twin Registry, Richmond, VA, USA
| | | | - Ally Avery
- University of Washington Twin Registry, Seattle, WA, USA
- Washington State Twin Registry, Washington State University - Health Sciences Spokane, Spokane, WA, USA
| | - Glen E Duncan
- University of Washington Twin Registry, Seattle, WA, USA
- Washington State Twin Registry, Washington State University - Health Sciences Spokane, Spokane, WA, USA
| | - S Michal Jazwinski
- Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA
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Xiao FH, Chen XQ, He YH, Kong QP. Accelerated DNA methylation changes in middle-aged men define sexual dimorphism in human lifespans. Clin Epigenetics 2018; 10:133. [PMID: 30373676 PMCID: PMC6206726 DOI: 10.1186/s13148-018-0573-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 10/21/2018] [Indexed: 12/26/2022] Open
Abstract
Background Accelerated age-associated DNA methylation changes in males may explain the earlier onset of age-related diseases (e.g., cardiovascular disease (CVD)) and thus contribute to sexually dimorphic morbidity and lifespan. However, the details regarding the emergence of this sex-biased methylation pattern remain unclear. Results To address these issues, we collected publicly available peripheral blood methylation datasets detected by Illumina HumanMethylation450 BeadChip platform from four studies that contain age and gender information of samples. We analyzed peripheral blood methylation data screened from 708 subjects of European ancestry. Results revealed a significant methylation change acceleration in middle-aged males (40–50 years old), which was further supported by another cohort containing 2711 subjects with Indian ancestry. Additional analyses suggested that these sexually dimorphic methylation changes were significantly overrepresented in genes associated with CVD, which may impact the potential activation of disease expression. Furthermore, we showed that higher prevalence of drinking and smoking in the males has some contribution to the sex-based methylation patterns during aging. Conclusion Our results indicated that the sex-biased methylation changes occurred in middle-aged men in an acceleration manner and likely contribute to the sexual dimorphism observed in human lifespan by promoting the occurrence of CVD. As drinking and smoking were also found to be associated with this accelerated methylation change in men, it is possible that male lifespan may be prolonged by improving unhealthy lifestyles at or before middle age. Electronic supplementary material The online version of this article (10.1186/s13148-018-0573-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Fu-Hui Xiao
- State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.,Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China.,Kunming Key Laboratory of Healthy Aging Study, Kunming, 650223, China.,KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming, 650223, China
| | - Xiao-Qiong Chen
- State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.,Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China.,Kunming Key Laboratory of Healthy Aging Study, Kunming, 650223, China.,KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming, 650223, China
| | - Yong-Han He
- State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.,Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China.,Kunming Key Laboratory of Healthy Aging Study, Kunming, 650223, China.,KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming, 650223, China
| | - Qing-Peng Kong
- State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China. .,Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China. .,Kunming Key Laboratory of Healthy Aging Study, Kunming, 650223, China. .,KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming, 650223, China.
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Abstract
Objective: The objective of the study was to summarize the role of DNA methylation in the development and metastasis of uveal melanoma (UM). Data Sources: The relevant studies in MEDLINE were searched. Study Selection: In this review, we performed a comprehensive literature search in MEDLINE using “uveal melanoma” AND (“DNA methylation” OR “epigenetics”) for original research/review articles published before February 2018 on the relationship between DNA methylation and UM. References of the retrieved studies were also examined to search for potentially relevant papers. Results: Previous studies on the relationship between DNA methylation and UM covered many genes including tumor suppressor genes (TSGs), cyclin-dependent kinase genes, and other genes. Among them, the TSG genes such as RASSF1A and p16INK4a, which encodes a cyclin-dependent kinase inhibitor, are relatively well-studied genes. Specifically, a high percentage of promoter methylation of RASSF1A was observed in UM cell lines and/or patients with UM. Promoter methylation of RASSF1A was also associated with the development of metastasis. Similarly, a high percentage of promoter hypermethylation of p16INK4a was found in UM cell lines. DNA promoter methylation can control the expression of p16INK4a, which affect cell growth, migration, and invasion in UM. Many other genes might also be involved in the pathogenesis of UM such as the Ras and EF-hand domain containing (RASEF) gene, RAB31, hTERT, embryonal fyn-associated substrate, and deleted in split-hand/split-foot 1. Conclusions: Our review reveals the complex mechanisms underlying the tumorigenesis of UM and highlights the great needs of future studies to discover more genes/5’-C-phosphate-G-3’ sites contributing to the development/metastasis of UM and explore the mechanisms through which epigenetic changes exert their function in UM.
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Affiliation(s)
- Zhi-Kun Yang
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Jing-Yun Yang
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA
| | - Zhuo-Zai Xu
- Department of Ophthalmology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Wei-Hong Yu
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
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Tresserra-Rimbau A, Lamuela-Raventos RM, Moreno JJ. Polyphenols, food and pharma. Current knowledge and directions for future research. Biochem Pharmacol 2018; 156:186-195. [PMID: 30086286 DOI: 10.1016/j.bcp.2018.07.050] [Citation(s) in RCA: 168] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 07/31/2018] [Indexed: 12/19/2022]
Abstract
Polyphenols are a large family of phytochemicals with great chemical diversity, known to be bioactive compounds of foods, species, medicinal plants and nutraceuticals. These compounds are ingested through the diet in significant amounts, around 1 g per day, an amount that be may be increased through supplements. The in vitro action of many representative polyphenols has been reported. However, their beneficial effects and their role in modulating the risk of high-prevalence diseases are difficult to demonstrate due to the wide variability of polyphenol structures and bioactive actions; the complexity of estimating the polyphenol content of food as a result of their variability in foods and cooked dishes; the potential modulation of the effects of polyphenols by food matrices; the addition of polyphenols and their synergistic interactions with each other and with other dietary bioactive components; the modulation of polyphenol bioavailability as a consequence of food composition and culinary techniques; their metabolism by the human body and the polyphenol gut microbiota metabolism in each metabotypes. Computational strategies, including virtual screening, shape-similarity-screening and molecular docking, were recently used to identify potential targets of polyphenols and thus gain a better understanding of the therapeutic effects exerted of polyphenols and modify natural polyphenol structures to potentiate specific activities. Here, we present the most relevant current knowledge and propose directions for future research in these fields, from the culinary world to the clinical setting. We hope this commentary will prompt scientists and clinicians to consider the therapeutic value of bioactive polyphenols and help shed some light on how much scientific truth lies in Hippocrates' famous quote: "Let your food be your medicine".
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Affiliation(s)
- Anna Tresserra-Rimbau
- Human Nutrition Unit, University Hospital of Sant Joan de Reus, Department of Biochemistry and Biotechnology, Faculty of Medicine and Health Sciences, Pere Virgili Health Research Center, University Rovira i Virgili, Reus, Spain; CIBER Fisiopatologia de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Rosa M Lamuela-Raventos
- CIBER Fisiopatologia de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain; Department of Nutrition, Food Sciences and Gastronomy, University of Barcelona, Barcelona, Spain; Institute of Nutrition and Food Safety, University of Barcelona, Barcelona, Spain
| | - Juan J Moreno
- CIBER Fisiopatologia de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain; Department of Nutrition, Food Sciences and Gastronomy, University of Barcelona, Barcelona, Spain; Institute of Nutrition and Food Safety, University of Barcelona, Barcelona, Spain.
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