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Liu X, Feng J, Guo M, Chen C, Zhao T, Sun X, Zhang Y. Resetting the aging clock through epigenetic reprogramming: Insights from natural products. Pharmacol Ther 2025; 270:108850. [PMID: 40221101 DOI: 10.1016/j.pharmthera.2025.108850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 12/04/2024] [Accepted: 04/07/2025] [Indexed: 04/14/2025]
Abstract
Epigenetic modifications play a critical role in regulating gene expression under various physiological and pathological conditions. Epigenetic modifications reprogramming is a recognized hallmark of aging and a key component of the aging clock used to differentiate between chronological and biological age. The potential for prospective diagnosis and regulatory capabilities position epigenetic modifications as an emerging drug target to extend longevity and alleviate age-related organ dysfunctions. In the past few decades, numerous preclinical studies have demonstrated the therapeutic potential of natural products in various human diseases, including aging, with some advancing to clinical trials and clinical application. This review highlights the discovery and recent advancements in the aging clock, as well as the potential use of natural products as anti-aging therapeutics by correcting disordered epigenetic reprogramming. Specifically, the focus is on the imbalance of histone modifications, alterations in DNA methylation patterns, disrupted ATP-dependent chromatin remodeling, and changes in RNA modifications. By exploring these areas, new insights can be gained into aging prediction and anti-aging interventions.
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Affiliation(s)
- Xin Liu
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, and Department of Cardiology, the Second Affiliated Hospital, Harbin Medical University, Harbin 150081, China; State Key Laboratory -Province Key Laboratories of Biomedicine-Pharmaceutics of China, and Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin 150081, China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China
| | - Jing Feng
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, and Department of Cardiology, the Second Affiliated Hospital, Harbin Medical University, Harbin 150081, China; State Key Laboratory -Province Key Laboratories of Biomedicine-Pharmaceutics of China, and Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin 150081, China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China
| | - Madi Guo
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, and Department of Cardiology, the Second Affiliated Hospital, Harbin Medical University, Harbin 150081, China; State Key Laboratory -Province Key Laboratories of Biomedicine-Pharmaceutics of China, and Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin 150081, China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China
| | - Chen Chen
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, and Department of Cardiology, the Second Affiliated Hospital, Harbin Medical University, Harbin 150081, China; State Key Laboratory -Province Key Laboratories of Biomedicine-Pharmaceutics of China, and Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin 150081, China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China
| | - Tong Zhao
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, and Department of Cardiology, the Second Affiliated Hospital, Harbin Medical University, Harbin 150081, China; State Key Laboratory -Province Key Laboratories of Biomedicine-Pharmaceutics of China, and Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin 150081, China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China
| | - Xiuxiu Sun
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, and Department of Cardiology, the Second Affiliated Hospital, Harbin Medical University, Harbin 150081, China; State Key Laboratory -Province Key Laboratories of Biomedicine-Pharmaceutics of China, and Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin 150081, China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China
| | - Yong Zhang
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, and Department of Cardiology, the Second Affiliated Hospital, Harbin Medical University, Harbin 150081, China; State Key Laboratory -Province Key Laboratories of Biomedicine-Pharmaceutics of China, and Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin 150081, China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China.
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Teschendorff AE, Horvath S. Epigenetic ageing clocks: statistical methods and emerging computational challenges. Nat Rev Genet 2025; 26:350-368. [PMID: 39806006 DOI: 10.1038/s41576-024-00807-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/20/2024] [Indexed: 01/16/2025]
Abstract
Over the past decade, epigenetic clocks have emerged as powerful machine learning tools, not only to estimate chronological and biological age but also to assess the efficacy of anti-ageing, cellular rejuvenation and disease-preventive interventions. However, many computational and statistical challenges remain that limit our understanding, interpretation and application of epigenetic clocks. Here, we review these computational challenges, focusing on interpretation, cell-type heterogeneity and emerging single-cell methods, aiming to provide guidelines for the rigorous construction of interpretable epigenetic clocks at cell-type and single-cell resolution.
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Affiliation(s)
- Andrew E Teschendorff
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
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3
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Du H, Zhang Y, Yu X, You X, Wu D, Du Z, Cai Y, Luo Z, Lu H, Liao Z, Ding BS, Zhao Y, Wang Y, Xiao K, Yang F, Gan F, Ning N, Zeng J, Shi P, Zhou Z, Huang S. Inhibition of KDM6B prevents osteoarthritis by blocking growth plate-like H3K27me3 loss in bivalent genes. SCIENCE CHINA. LIFE SCIENCES 2025; 68:1423-1436. [PMID: 39969745 DOI: 10.1007/s11427-024-2676-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 06/19/2024] [Indexed: 02/20/2025]
Abstract
Osteoarthritis (OA) is the most prevalent joint disorder occurring with articular cartilage degradation. It includes a switch from an articular to a growth plate chondrocyte phenotype. Here, we investigated the histone modification profiles and found significant H3K27me3 loss in OA, which led to disease-associated gene expression. Surprisingly, these genes were occupied by both H3K27me3 and H3K4me3 in normal chondrocytes, showing a poised bivalent state. Furthermore, we observed the derepression of similar bivalent genes in growth plate chondrocytes. Finally, a KDM6B inhibitor GSK-J4 prevented the H3K27me3 loss and cartilage damage in the rat OA model. Our results reveal an inherited bivalent epigenetic signature on developmental genes that makes articular chondrocytes prone to hypertrophy and contributes to a promising epigenetic therapy for OA.
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Affiliation(s)
- Hao Du
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yao Zhang
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xi Yu
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
- Rehabilitation Medicine Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xuanhe You
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Diwei Wu
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ze Du
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yongrui Cai
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhenyu Luo
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hanpeng Lu
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhixin Liao
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Bi-Sen Ding
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
| | - Ya Zhao
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, China
- Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou, 225001, China
| | - Yan Wang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, 611130, China
| | - Ke Xiao
- Department of Lower Limb Surgery of Sichuan Province Orthopedic Hospital, Central Laboratory of Sichuan Province Orthopedic Hospital, Chengdu, 610000, China
| | - Fan Yang
- Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, 518000, China
| | - Fangji Gan
- School of Mechanical Engineering, Sichuan University, Chengdu, 610065, China
| | - Ning Ning
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiancheng Zeng
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Peiliang Shi
- GemPharmatech (Chengdu) Co., Ltd., Chengdu, 610000, China
| | - Zongke Zhou
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Shishu Huang
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Ding F, Yu Y, Zhao J, Wei S, Zhang Y, Han JH, Li Z, Jiang HB, Ryu D, Cho M, Bae SJ, Park W, Ha KT, Gao B. The interplay of cellular senescence and reprogramming shapes the biological landscape of aging and cancer revealing novel therapeutic avenues. Front Cell Dev Biol 2025; 13:1593096. [PMID: 40356604 PMCID: PMC12066513 DOI: 10.3389/fcell.2025.1593096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Accepted: 04/17/2025] [Indexed: 05/15/2025] Open
Abstract
Cellular senescence and cellular reprogramming represent two fundamentally intertwined processes that profoundly influence aging and cancer. This paper explores how the permanent cell-cycle arrest of senescent cells and the identity-resetting capacity of reprogramming jointly shape biological outcomes in later life and tumor development. We synthesize recent findings to show that senescent cells, while halting the proliferation of damaged cells, can paradoxically promote tissue dysfunction and malignancy via their secretory phenotype. Conversely, induced reprogramming of somatic cells-exemplified by Yamanaka factors-resets cellular age and epigenetic marks, offering a potential to rejuvenate aged cells. Key findings highlight shared mechanisms (e.g., DNA damage responses and epigenetic remodeling) and bidirectional crosstalk between these processes: senescence signals can facilitate neighboring cell plasticity, whereas reprogramming attempts can trigger intrinsic senescence programs as a barrier. In aging tissues, transient (partial) reprogramming has been shown to erase senescence markers and restore cell function without inducing tumorigenesis, underlining a novel strategy to combat age-related degeneration. In cancer, we discuss how therapy-induced senescence of tumor cells may induce stem-cell-like traits in some cells and drive relapse, revealing a delicate balance between tumor suppression and tumor promotion. Understanding the interplay between senescence and reprogramming is crucial for developing innovative therapies. By targeting the senescence-reprogramming axis-for instance, via senolytic drugs, SASP inhibitors, or safe reprogramming techniques-there is significant therapeutic potential to ameliorate aging-related diseases and improve cancer treatment. Our findings underscore that carefully modulating cellular senescence and rejuvenation processes could pave the way for novel regenerative and anti-cancer strategies.
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Affiliation(s)
- Fuan Ding
- Department of Vascular Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Ying Yu
- Department of Surgery, Changchun University of Chinese Medicine, Changchun, China
| | - Jiangqi Zhao
- Department of Dermatology, The Second Hospital of Jilin University, Changchun, China
| | - Shibo Wei
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea
| | - Yan Zhang
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea
| | - Jung Ho Han
- Korean Medicine Application Center, Korea Institute of Oriental Medicine, Daegu, Republic of Korea
| | - Zhuo Li
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Hong-Bo Jiang
- Department of Dermatology, Qingdao Women and Children’s Hospital, Qingdao University, Qingdao, Shandong, China
| | - Dongryeol Ryu
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea
| | - Minkyoung Cho
- Department of Parasitology and Tropical Medicine, and Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju, Republic of Korea
| | - Sung-Jin Bae
- Department of Molecular Biology and Immunology, Kosin University College of Medicine, Busan, Republic of Korea
| | - Wonyoung Park
- Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do, Republic of Korea
- Research Institute for Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do, Republic of Korea
| | - Ki-Tae Ha
- Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do, Republic of Korea
- Research Institute for Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do, Republic of Korea
| | - Bo Gao
- Department of Vascular Surgery, The Second Hospital of Jilin University, Changchun, China
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Hammer MJ, Conley YP, Henderson WA, Lukkahatai N, Miaskowski C, Starkweather A, Wesmiller SW. Breaking the code: Using the Precision Health Model to guide research and clinical care. Nurs Outlook 2025; 73:102396. [PMID: 40262402 DOI: 10.1016/j.outlook.2025.102396] [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: 12/03/2024] [Revised: 03/18/2025] [Accepted: 03/22/2025] [Indexed: 04/24/2025]
Abstract
BACKGROUND Precision health is a person-centered approach to health and well-being that is operationalized through evaluating omics-level profiles and their associations with the exposome. A precision health approach addresses the challenge that "one size does not fit all" in the management of an individual's health. PURPOSE The purpose of this white paper is to introduce a Precision Health Model and its application in research and clinical care. METHODS An expert panel reviewed and synthesized the extant literature related to precision health, the current state of omics' science, and common exposome factors that influence the health/illness continuum. A case study provides the framework for the application of the Precision Health Model. DISCUSSION Precision health and key domains are defined and serve as the platform for the development of the Precision Health Model. CONCLUSION Application of the Precision Health Model will provide inclusive, equitable, person-centered research and clinical care.
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Affiliation(s)
- Marilyn J Hammer
- Department of Nursing and Patient Care Services and Department of Medical Oncology, Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA.
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Schoepf IC, Haerry D, Esteban-Cantos A, Arribas JR, Tarr PE. Perspective: clinical relevance of epigenetic aging and HIV. Epigenomics 2025:1-5. [PMID: 40231671 DOI: 10.1080/17501911.2025.2491299] [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: 12/30/2024] [Accepted: 04/07/2025] [Indexed: 04/16/2025] Open
Abstract
Longitudinal studies now document how leukocyte telomere attrition and epigenetic aging may be accelerated in people with HIV (PWH), in particular, around the time of HIV acquisition, during primary HIV infection, and during untreated chronic HIV infection. Whether chronic low-level inflammation and epigenetic aging go hand in hand or may be partially independent continues to be investigated in PWH and other settings. Epigenetic age acceleration (EAA) in PWH has now clearly been shown to be potentially reversible during successful antiretroviral therapy (ART). These studies point to how the beneficial effects of modern ART also include EAA-decelerating effects that seem large enough to regard ART as a kind of epigenetic rejuvenation therapy. Progress in the field has been limited in part due to the high cost of assessing EAA based on DNA methylation measures ("epigenetic clocks"). Demonstration of the clinical relevance of EAA and its reversion by ART will depend on large studies associating EAA with cardiovascular events and other adverse aging-associated endpoints in PWH.
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Affiliation(s)
- Isabella C Schoepf
- University Department of Medicine and Infectious Diseases Service, Kantonsspital Baselland, University of Basel, Bruderholz, Switzerland
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | | | - Andrés Esteban-Cantos
- HIV/AIDS and Infectious Diseases Research Group, Hospital La Paz Institute for Health Research, Madrid, Spain
- CIBER of Infectious Diseases (CIBERINFEC), Madrid, Spain
| | - José R Arribas
- HIV/AIDS and Infectious Diseases Research Group, Hospital La Paz Institute for Health Research, Madrid, Spain
- CIBER of Infectious Diseases (CIBERINFEC), Madrid, Spain
| | - Philip E Tarr
- University Department of Medicine and Infectious Diseases Service, Kantonsspital Baselland, University of Basel, Bruderholz, Switzerland
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Brito KDNLD, Trentin AG. Role of mesenchymal stromal cell secretome on recovery from cellular senescence: an overview. Cytotherapy 2025; 27:422-437. [PMID: 39674933 DOI: 10.1016/j.jcyt.2024.11.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 11/13/2024] [Accepted: 11/14/2024] [Indexed: 12/17/2024]
Abstract
Cellular senescence is intricately linked with numerous changes observed in the aging process, including the depletion of the stem cell pool and the decline in tissue and organ functions. Over the past three decades, efforts to halt and reverse aging have intensified, bringing rejuvenation closer to reality. Current strategies involve treatments using stem cells or their derivatives, such as the secretome. This article aims to highlight key points and evaluate the utilization of secretome derived from mesenchymal stromal cells (MSCs) as an antisenescent approach. Employing a quasi-systematic research approach, the authors conducted a comprehensive analysis based on a search algorithm targeting the in vitro effects of MSC-derived secretome on rescuing cells from a senescent state. Reviewing 39 articles out of 687 hits retrieved from PubMed and Scopus without a time limit, the authors synthesized information and identified common types of MSC-tissue sources utilized (including bone marrow-MSCs, umbilical cord-MSCs, iPSC-derived MSCs, adipose tissue-MSCs, dental pulp-MSCs, amniotic membrane-MSCs, placenta-MSCs, gingival-MSCs, urine-MSCs, and commercially available MSC lineages) from both human and other species (such as mice and rats). The authors also examined the forms of secretome tested (including conditioned media and extracellular vesicles), the cell types treated (MSCs or other cell types), methods/biomarkers of monitoring senescence/rejuvenation, and the mechanisms involved. Ultimately, this review underscores the proof-of-principle of the beneficial effects of MSC-derived secretome in reversing cellular senescence across various cell types. Such insights might aid the scientific community in designing improved in vitro and in vivo assays for future research and clinical validation of this promising cell-free therapy.
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Affiliation(s)
- Karynne de Nazaré Lins de Brito
- Department of Cell Biology, Embryology, and Genetics, Federal University of Santa Catarina, Florianópolis, Brazil; Faculty of Medicine, Altamira Campus, Federal University of Pará, Altamira, Brazil.
| | - Andréa Gonçalves Trentin
- Department of Cell Biology, Embryology, and Genetics, Federal University of Santa Catarina, Florianópolis, Brazil; National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil.
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Antón-Fernández A, Ruiz de Alegría Á, Mariscal-Casero A, Roldán-Lázaro M, Peinado-Cauchola R, Ávila J, Hernández F. Partial reprogramming by cyclical overexpression of Yamanaka factors improves pathological phenotypes of tauopathy mouse model of human Alzheimer's disease. Prog Neurobiol 2025; 247:102743. [PMID: 40021076 DOI: 10.1016/j.pneurobio.2025.102743] [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: 10/01/2024] [Revised: 12/20/2024] [Accepted: 02/24/2025] [Indexed: 03/03/2025]
Abstract
Partial reprogramming induced by the controlled and cyclical overexpression of Yamanaka factors in the nervous system has so far succeeded in reversing some aging-associated phenotypes, such as improving memory function. These promising results suggest that partial reprogramming could be a potential strategy to prevent or mitigate aging-related pathologies like tauopathies, including Alzheimer's disease. Here, we explore the potential of this strategy in addressing tauopathy development in the P301S mouse model. To achieve this, a new transgenic animal was created that can inducibly overexpress Yamanaka factors upon doxycycline administration and carries the Tau-P301S mutation, which leads to tauopathy development. The results of this study show a significant improvement in key pathological features of tauopathies in the hippocampus, including reversed tauopathy, alleviated reactive astrogliosis, age-related reduction of the H3K9me3 epigenetic marker, along with improved spatial memory, which has been described as deteriorated in this model. These findings reinforce the potential of partial reprogramming as a therapeutic strategy to combat brain pathologies associated with aging.
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Affiliation(s)
- Alejandro Antón-Fernández
- Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Nicolás Cabrera, 1, Cantoblanco, Madrid 28049, Spain.
| | - Álvaro Ruiz de Alegría
- Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Nicolás Cabrera, 1, Cantoblanco, Madrid 28049, Spain
| | - Ana Mariscal-Casero
- Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Nicolás Cabrera, 1, Cantoblanco, Madrid 28049, Spain
| | - Marta Roldán-Lázaro
- Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Nicolás Cabrera, 1, Cantoblanco, Madrid 28049, Spain
| | - Rocío Peinado-Cauchola
- Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Nicolás Cabrera, 1, Cantoblanco, Madrid 28049, Spain
| | - Jesús Ávila
- Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Nicolás Cabrera, 1, Cantoblanco, Madrid 28049, Spain; Consejo Superior de Investigaciones Científicas (CSIC), Serrano 117, Madrid 28006, Spain
| | - Félix Hernández
- Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Nicolás Cabrera, 1, Cantoblanco, Madrid 28049, Spain.
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9
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Hu M, Fan Z. Role and mechanisms of histone methylation in osteogenic/odontogenic differentiation of dental mesenchymal stem cells. Int J Oral Sci 2025; 17:24. [PMID: 40133254 PMCID: PMC11937254 DOI: 10.1038/s41368-025-00353-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 01/01/2025] [Accepted: 02/11/2025] [Indexed: 03/27/2025] Open
Abstract
Dental mesenchymal stem cells (DMSCs) are pivotal for tooth development and periodontal tissue health and play an important role in tissue engineering and regenerative medicine because of their multidirectional differentiation potential and self-renewal ability. The cellular microenvironment regulates the fate of stem cells and can be modified using various optimization techniques. These methods can influence the cellular microenvironment, activate disparate signaling pathways, and induce different biological effects. "Epigenetic regulation" refers to the process of influencing gene expression and regulating cell fate without altering DNA sequences, such as histone methylation. Histone methylation modifications regulate pivotal transcription factors governing DMSCs differentiation into osteo-/odontogenic lineages. The most important sites of histone methylation in tooth organization were found to be H3K4, H3K9, and H3K27. Histone methylation affects gene expression and regulates stem cell differentiation by maintaining a delicate balance between major trimethylation sites, generating distinct chromatin structures associated with specific downstream transcriptional states. Several crucial signaling pathways associated with osteogenic differentiation are susceptible to modulation via histone methylation modifications. A deeper understanding of the regulatory mechanisms governing histone methylation modifications in osteo-/odontogenic differentiation and immune-inflammatory responses of DMSCs will facilitate further investigation of the epigenetic regulation of histone methylation in DMSC-mediated tissue regeneration and inflammation. Here is a concise overview of the pivotal functions of epigenetic histone methylation at H3K4, H3K9, and H3K27 in the regulation of osteo-/odontogenic differentiation and renewal of DMSCs in both non-inflammatory and inflammatory microenvironments. This review summarizes the current research on these processes in the context of tissue regeneration and therapeutic interventions.
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Affiliation(s)
- Meijun Hu
- Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Zhipeng Fan
- Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China.
- Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China.
- Research Unit of Tooth Development and Regeneration, Chinese Academy of Medical Sciences, Beijing, China.
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10
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Zhang H, Sun S, Izpisua Belmonte JC, Liu GH, Wang S, Zhang W, Qu J. Protocols for the application of human embryonic stem cell-derived neurons for aging modeling and gene manipulation. STAR Protoc 2025; 6:103633. [PMID: 39932849 PMCID: PMC11867521 DOI: 10.1016/j.xpro.2025.103633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 12/02/2024] [Accepted: 01/18/2025] [Indexed: 02/13/2025] Open
Abstract
In vitro models of neuronal aging and gene manipulation in human neurons (hNeurons) are valuable tools for investigating human brain aging and diseases. Here, we present a protocol for applying human embryonic stem cell (hESC)-derived neurons to model aging and the further application of small interfering RNA (siRNA)-mediated gene silencing for functional investigations. We describe steps for neuronal differentiation and culture, siRNA transfection, and technical considerations to ensure reproducibility. Our protocol enables investigations of the molecular mechanism underlying neuronal aging and facilitates drug evaluation. For complete details on the use and execution of this protocol, please refer to Zhang et al.1.
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Affiliation(s)
- Hui Zhang
- Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Shuhui Sun
- Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | | | - Guang-Hui Liu
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Aging Biomarker Consortium (ABC), Beijing 100101, China.
| | - Si Wang
- National Clinical Research Center for Geriatric Disorders, Aging Translational Medicine Center, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Biomarker Consortium (ABC), Beijing 100101, China.
| | - Weiqi Zhang
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; China National Center for Bioinformation, Beijing, China; Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China; Aging Biomarker Consortium (ABC), Beijing 100101, China.
| | - Jing Qu
- Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China; Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Aging Biomarker Consortium (ABC), Beijing 100101, China.
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11
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Li B, Ming H, Qin S, Nice EC, Dong J, Du Z, Huang C. Redox regulation: mechanisms, biology and therapeutic targets in diseases. Signal Transduct Target Ther 2025; 10:72. [PMID: 40050273 PMCID: PMC11885647 DOI: 10.1038/s41392-024-02095-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 10/09/2024] [Accepted: 11/21/2024] [Indexed: 03/09/2025] Open
Abstract
Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both the onset and progression of various diseases. Under physiological conditions, oxidative free radicals generated by the mitochondrial oxidative respiratory chain, endoplasmic reticulum, and NADPH oxidases can be effectively neutralized by NRF2-mediated antioxidant responses. These responses elevate the synthesis of superoxide dismutase (SOD), catalase, as well as key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption of this finely tuned equilibrium is closely linked to the pathogenesis of a wide range of diseases. Recent advances have broadened our understanding of the molecular mechanisms underpinning this dysregulation, highlighting the pivotal roles of genomic instability, epigenetic modifications, protein degradation, and metabolic reprogramming. These findings provide a foundation for exploring redox regulation as a mechanistic basis for improving therapeutic strategies. While antioxidant-based therapies have shown early promise in conditions where oxidative stress plays a primary pathological role, their efficacy in diseases characterized by complex, multifactorial etiologies remains controversial. A deeper, context-specific understanding of redox signaling, particularly the roles of redox-sensitive proteins, is critical for designing targeted therapies aimed at re-establishing redox balance. Emerging small molecule inhibitors that target specific cysteine residues in redox-sensitive proteins have demonstrated promising preclinical outcomes, setting the stage for forthcoming clinical trials. In this review, we summarize our current understanding of the intricate relationship between oxidative stress and disease pathogenesis and also discuss how these insights can be leveraged to optimize therapeutic strategies in clinical practice.
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Affiliation(s)
- Bowen Li
- Department of Biotherapy, Institute of Oxidative Stress Medicine, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, PR China
| | - Hui Ming
- Department of Biotherapy, Institute of Oxidative Stress Medicine, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, PR China
| | - Siyuan Qin
- Department of Biotherapy, Institute of Oxidative Stress Medicine, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, PR China
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, PR China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Jingsi Dong
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Zhongyan Du
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
- Key Laboratory of Blood-stasis-toxin Syndrome of Zhejiang Province, Hangzhou, China.
| | - Canhua Huang
- Department of Biotherapy, Institute of Oxidative Stress Medicine, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, PR China.
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, PR China.
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12
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Sun Z, Li L, Zhang L. Apigenin enhancing oxidative resistance and proteostasis to extend lifespan via PTEN-mediated AKT signalling pathway. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167670. [PMID: 39826849 DOI: 10.1016/j.bbadis.2025.167670] [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: 11/11/2024] [Revised: 12/27/2024] [Accepted: 01/10/2025] [Indexed: 01/22/2025]
Abstract
Aging is a complicated process, featuring the progressive deterioration of physiological functions and a heightened susceptibility to diseases including neurodegenerative disorders, cardiovascular diseases, and cancer. Apigenin, a flavonoid existing in various plants, has attracted attention due to its potential role in anti-aging. In this investigation, the potential effect of apigenin on extending lifespan in Saccharomyces cerevisiae (yeast) and Drosophila melanogaster (flies) was explored. The results indicate that apigenin significantly extends both replicative and chronological life duration in yeast, as well as longevity in male and female flies. Apigenin treatment also improves resistance to oxidative stress in both organisms, as manifested by enhanced survival, decreased reactive oxygen species (ROS) levels and upregulation of antioxidant enzymes. Furthermore, apigenin activates crucial elements of the proteostasis network (PN), such as upregulation of proteostasis-related enzymes activity and genes expression. Network analysis revealed that apigenin affects aging conserved in the longevity-regulating pathway. Notably, Pten is a hub target in flies. Apigenin regulated DmPten at both mRNA and protein expression level while modulating downstream targets, including the phosphorylation of AKT and associated signalling pathways. In a high-sucrose diet (HSD) model, Apigenin treatment extended lifespan, reduced hemolymph glucose levels, enhanced Pten expression, suppressed AKT phosphorylation, and modulated the phosphorylation status of S6K and expression of DmFoxo. These results demonstrate that apigenin could serve as a longevity research object and potential therapeutic drug for promoting health and longevity through its antioxidant and proteostatic properties.
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Affiliation(s)
- Zhengqiong Sun
- State Key Laboratory of Subtropical Silviculture, Zhejiang A & F University, Hangzhou 311300, China
| | - Lei Li
- Department of Pharmaceutical Botany, School of Pharmacy, Naval Medical University, Shanghai 200433, China
| | - Lei Zhang
- State Key Laboratory of Subtropical Silviculture, Zhejiang A & F University, Hangzhou 311300, China; Department of Pharmaceutical Botany, School of Pharmacy, Naval Medical University, Shanghai 200433, China.
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13
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Wu Z, Wang Z, Chen T, Wang D, Zhou F, Zhang G, Wei S, Wu Y. Dermal white adipose tissue: A new modulator in wound healing and regeneration. Regen Ther 2025; 28:115-125. [PMID: 39717110 PMCID: PMC11665542 DOI: 10.1016/j.reth.2024.11.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 11/06/2024] [Accepted: 11/20/2024] [Indexed: 12/25/2024] Open
Abstract
Dermal white adipose tissue (dWAT), distinguished by its origin from cells within the dermis and independence from subcutaneous fat tissue, has garnered significant attention for its non-metabolic functions. Characterized by strong communication with other components of the skin, dWAT mediates the proliferation and recruitment of various cell types by releasing adipogenic and inflammatory factors. Here, we focus on the modulatory role of dWAT at different stages during wound healing, highlighting its ability to mediate the adipocyte-to-myofibroblast transition which plays a pivotal role in the physiology and pathology processes of skin fibrosis, scarring, and aging. This review highlights the regulatory potential of dWAT in modulating wound healing processes and presents it as a target for developing therapeutic strategies aimed at reducing scarring and enhancing regenerative outcomes in skin-related disorders.
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Affiliation(s)
- Zhongyu Wu
- Department of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, PR China
| | - Zhanqi Wang
- Department of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, PR China
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, National Clinical Research Center for Oral Diseases, Beijing Key Laboratory of Digital Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081, PR China
| | - Tao Chen
- Department of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, PR China
| | - Dongyang Wang
- Department of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, PR China
| | - Feng Zhou
- Department of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, PR China
| | - Guorui Zhang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, PR China
| | - Shan Wei
- Huizhou Health Sciences Polytechnic, Huizhou 516025, Guangdong, PR China
| | - Yingying Wu
- Department of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, PR China
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14
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Li G, Li D, Li Y, Liu B. CircXYLT1 suppresses oxidative stress and promotes vascular remodeling in aging mice carotid artery injury model of atherosclerosis via PTBP1. Exp Gerontol 2025; 201:112690. [PMID: 39863188 DOI: 10.1016/j.exger.2025.112690] [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: 11/09/2024] [Revised: 12/30/2024] [Accepted: 01/22/2025] [Indexed: 01/27/2025]
Abstract
Atherosclerosis and aortic aneurysms are prevalent cardiovascular diseases in the elderly, characterized by chronic inflammation and oxidative stress. This study explores the role of CircXYLT1 in regulating oxidative stress and vascular remodeling in age-related vascular diseases. RNA sequencing revealed a significant upregulation of CircXYLT1 in the vascular tissues of aged mice, highlighting its potential role in age-related vascular diseases. Using a carotid artery wire injury model, we performed adeno-associated virus (AAV)-mediated knockdown and overexpression of CircXYLT1. Key oxidative stress markers, including reactive oxygen species (ROS) and malondialdehyde (MDA), were measured. Knockdown of CircXYLT1 increased oxidative stress and reduced antioxidant protein expression (SOD, GPX), while overexpression led to decreased oxidative damage and enhanced vascular smooth muscle cell (VSMC) proliferation. Mechanistically, CircXYLT1 interacted with PTBP1, reducing its nuclear localization and modulating downstream chemokine signaling pathways. These findings suggest that CircXYLT1 plays a critical role in vascular remodeling and oxidative stress regulation, offering potential as a therapeutic target for managing cardiovascular diseases in aging populations.
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Affiliation(s)
- Gang Li
- Department of Vascular Surgery, Shandong Provincial Hospital affiliated to Shandong First Medical University
| | - Donghui Li
- Department of Anesthesiology, Shandong Provincial Hospital affiliated to Shandong First Medical University
| | - Yajing Li
- Department of Vascular Surgery, Shandong Provincial Hospital affiliated to Shandong First Medical University
| | - Bingqi Liu
- Department of Vascular Surgery, Shandong Provincial Hospital affiliated to Shandong First Medical University.
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15
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Mandelblatt JS, Antoni MH, Bethea TN, Cole S, Hudson BI, Penedo FJ, Ramirez AG, Rebeck GW, Sarkar S, Schwartz AG, Sloan EK, Zheng YL, Carroll JE, Sedrak MS. Gerotherapeutics: aging mechanism-based pharmaceutical and behavioral interventions to reduce cancer racial and ethnic disparities. J Natl Cancer Inst 2025; 117:406-422. [PMID: 39196709 PMCID: PMC11884862 DOI: 10.1093/jnci/djae211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 07/31/2024] [Accepted: 08/26/2024] [Indexed: 08/30/2024] Open
Abstract
The central premise of this article is that a portion of the established relationships between social determinants of health and racial and ethnic disparities in cancer morbidity and mortality is mediated through differences in rates of biological aging processes. We further posit that using knowledge about aging could enable discovery and testing of new mechanism-based pharmaceutical and behavioral interventions ("gerotherapeutics") to differentially improve the health of cancer survivors from minority populations and reduce cancer disparities. These hypotheses are based on evidence that lifelong differences in adverse social determinants of health contribute to disparities in rates of biological aging ("social determinants of aging"), with individuals from minoritized groups experiencing accelerated aging (ie, a steeper slope or trajectory of biological aging over time relative to chronological age) more often than individuals from nonminoritized groups. Acceleration of biological aging can increase the risk, age of onset, aggressiveness, and stage of many adult cancers. There are also documented negative feedback loops whereby the cellular damage caused by cancer and its therapies act as drivers of additional biological aging. Together, these dynamic intersectional forces can contribute to differences in cancer outcomes between survivors from minoritized vs nonminoritized populations. We highlight key targetable biological aging mechanisms with potential applications to reducing cancer disparities and discuss methodological considerations for preclinical and clinical testing of the impact of gerotherapeutics on cancer outcomes in minoritized populations. Ultimately, the promise of reducing cancer disparities will require broad societal policy changes that address the structural causes of accelerated biological aging and ensure equitable access to all new cancer control paradigms.
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Affiliation(s)
- Jeanne S Mandelblatt
- Georgetown Lombardi Institute for Cancer and Aging Research, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
- Department of Oncology, Georgetown University Medical Center, Georgetown University, Washington, DC, USA
| | - Michael H Antoni
- Health Division, Department of Psychology and Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Traci N Bethea
- Department of Oncology, Georgetown University Medical Center, Georgetown University, Washington, DC, USA
| | - Steve Cole
- Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, USA
- Cousins Center for Psychoneuroimmunology, University of California Los Angeles, Los Angeles, CA, USA
| | - Barry I Hudson
- Department of Oncology, Georgetown University Medical Center, Georgetown University, Washington, DC, USA
| | - Frank J Penedo
- Health Division, Department of Psychology and Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Amelie G Ramirez
- Department of Population Health Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - G William Rebeck
- Department of Neuroscience, Georgetown University Medical Center, Georgetown University, Washington, DC, USA
| | - Swarnavo Sarkar
- Department of Oncology, Georgetown University Medical Center, Georgetown University, Washington, DC, USA
| | - Ann G Schwartz
- Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Erica K Sloan
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia
| | - Yun-Ling Zheng
- Department of Oncology, Georgetown University Medical Center, Georgetown University, Washington, DC, USA
| | - Judith E Carroll
- Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, USA
- Cousins Center for Psychoneuroimmunology, University of California Los Angeles, Los Angeles, CA, USA
- Cancer Prevention and Control Program, Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
| | - Mina S Sedrak
- Cancer Prevention and Control Program, Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
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16
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Hu Y, Horlbeck MA, Zhang R, Ma S, Shrestha R, Kartha VK, Duarte FM, Hock C, Savage RE, Labade A, Kletzien H, Meliki A, Castillo A, Durand NC, Mattei E, Anderson LJ, Tay T, Earl AS, Shoresh N, Epstein CB, Wagers AJ, Buenrostro JD. Multiscale footprints reveal the organization of cis-regulatory elements. Nature 2025; 638:779-786. [PMID: 39843737 PMCID: PMC11839466 DOI: 10.1038/s41586-024-08443-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 11/22/2024] [Indexed: 01/24/2025]
Abstract
Cis-regulatory elements (CREs) control gene expression and are dynamic in their structure and function, reflecting changes in the composition of diverse effector proteins over time1. However, methods for measuring the organization of effector proteins at CREs across the genome are limited, hampering efforts to connect CRE structure to their function in cell fate and disease. Here we developed PRINT, a computational method that identifies footprints of DNA-protein interactions from bulk and single-cell chromatin accessibility data across multiple scales of protein size. Using these multiscale footprints, we created the seq2PRINT framework, which uses deep learning to allow precise inference of transcription factor and nucleosome binding and interprets regulatory logic at CREs. Applying seq2PRINT to single-cell chromatin accessibility data from human bone marrow, we observe sequential establishment and widening of CREs centred on pioneer factors across haematopoiesis. We further discover age-associated alterations in the structure of CREs in murine haematopoietic stem cells, including widespread reduction of nucleosome footprints and gain of de novo identified Ets composite motifs. Collectively, we establish a method for obtaining rich insights into DNA-binding protein dynamics from chromatin accessibility data, and reveal the architecture of regulatory elements across differentiation and ageing.
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Affiliation(s)
- Yan Hu
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Max A Horlbeck
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
- Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA
| | - Ruochi Zhang
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
- Eric and Wendy Schmidt Center, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Sai Ma
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Rojesh Shrestha
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Vinay K Kartha
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Fabiana M Duarte
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Conrad Hock
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Rachel E Savage
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Ajay Labade
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Heidi Kletzien
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
- Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA, USA
| | - Alia Meliki
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Andrew Castillo
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Neva C Durand
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Eugenio Mattei
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Lauren J Anderson
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Tristan Tay
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Andrew S Earl
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Noam Shoresh
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Charles B Epstein
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Amy J Wagers
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
- Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA, USA
| | - Jason D Buenrostro
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
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17
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Wu H, Wang M, Zheng Y, Xie XS. Droplet-based high-throughput 3D genome structure mapping of single cells with simultaneous transcriptomics. Cell Discov 2025; 11:8. [PMID: 39837831 PMCID: PMC11751028 DOI: 10.1038/s41421-025-00770-8] [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: 11/20/2024] [Accepted: 12/30/2024] [Indexed: 01/23/2025] Open
Abstract
Single-cell three-dimensional (3D) genome techniques have advanced our understanding of cell-type-specific chromatin structures in complex tissues, yet current methodologies are limited in cell throughput. Here we introduce a high-throughput single-cell Hi-C (dscHi-C) approach and its transcriptome co-assay (dscHi-C-multiome) using droplet microfluidics. Using dscHi-C, we investigate chromatin structural changes during mouse brain aging by profiling 32,777 single cells across three developmental stages (3 months, 12 months, and 23 months), yielding a median of 78,220 unique contacts. Our results show that genes with significant structural changes are enriched in pathways related to metabolic process and morphology change in neurons, and innate immune response in glial cells, highlighting the role of 3D genome organization in physiological brain aging. Furthermore, our multi-omics joint assay, dscHi-C-multiome, enables precise cell type identification in the adult mouse brain and uncovers the intricate relationship between genome architecture and gene expression. Collectively, we developed the sensitive, high-throughput dscHi-C and its multi-omics derivative, dscHi-C-multiome, demonstrating their potential for large-scale cell atlas studies in development and disease.
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Affiliation(s)
- Honggui Wu
- Biomedical Pioneering Innovation Center (BIOPIC), and School of Life Sciences, Peking University, Beijing, China
- Changping Laboratory, Beijing, China
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Maoxu Wang
- Biomedical Pioneering Innovation Center (BIOPIC), and School of Life Sciences, Peking University, Beijing, China
- Changping Laboratory, Beijing, China
| | - Yinghui Zheng
- Biomedical Pioneering Innovation Center (BIOPIC), and School of Life Sciences, Peking University, Beijing, China
- Changping Laboratory, Beijing, China
| | - X Sunney Xie
- Biomedical Pioneering Innovation Center (BIOPIC), and School of Life Sciences, Peking University, Beijing, China.
- Changping Laboratory, Beijing, China.
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18
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Chen C, He J, Huang W, Xu D, Li Z, Yang A. PLK3 weakens antioxidant defense and inhibits proliferation of porcine Leydig cells under oxidative stress. Sci Rep 2025; 15:2612. [PMID: 39837970 PMCID: PMC11751325 DOI: 10.1038/s41598-025-86867-2] [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: 09/24/2024] [Accepted: 01/14/2025] [Indexed: 01/23/2025] Open
Abstract
Aging is characterized by cellular degeneration and impaired physiological functions, leading to a decline in male sexual desire and reproductive capacity. Oxidative stress (OS) lead to testicular aging by impairing the male reproductive system, but the potential mechanisms remain unclear. In the present study, the functional status of testicular tissues from young and aged boars was compared, and the transcriptional responses of Leydig cells (LCs) to hydrogen peroxide (H2O2)-induced senescence were explored, revealing the role of OS in promoting aging of the male reproductive system. 601 differentially expressed genes (DEGs) associated with OS, cell cycle regulation, and intracellular processes were identified. These DEGs were significantly enriched in critical aging pathways, including the p53 signaling pathway, autophagy, and cellular senescence. Protein-protein interaction (PPI) network analysis unveiled 15 key genes related to cell cycle and DNA replication, with polo-like kinase 3 (PLK3) exhibiting increased expression under OS. In vitro, PLK3 knockdown significantly enhanced the viability and antioxidant capacity of LCs under OS. This study deepens our understanding of how LCs respond to OS and provides new therapeutic targets for enhancing cellular resistance to oxidative damage and promoting tissue health.
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Affiliation(s)
- Chujie Chen
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- College of Life Sciences and Resource Environment, Yichun university, Yichun, Jiangxi, China
| | - Jinyan He
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Weixian Huang
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Dong Xu
- Department of Biological and Environmental Engineering, Yueyang Vocational Technical College, Yueyang, Hunan, China
| | - Zhaohui Li
- Xiangtan Livestock Breeding Station, Xiangtan, Hunan, China
| | - Anqi Yang
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
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19
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Xing Y, Ma C, Guan H, Shen J, Shen Y, Li G, Sun G, Tian Y, Kang X, Liu X, Li H, Tian W. Multi-Omics Insights into Regulatory Mechanisms Underlying Differential Deposition of Intramuscular and Abdominal Fat in Chickens. Biomolecules 2025; 15:134. [PMID: 39858528 PMCID: PMC11763713 DOI: 10.3390/biom15010134] [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: 12/11/2024] [Revised: 01/09/2025] [Accepted: 01/14/2025] [Indexed: 01/27/2025] Open
Abstract
Excessive abdominal fat deposition in chickens disadvantages feed conversion, meat production, and reproductive performance. Intramuscular fat contributes to meat texture, tenderness, and flavor, serving as a vital indicator of overall meat quality. Therefore, a comprehensive analysis of the regulatory mechanisms governing differential deposition of abdominal versus intramuscular fat is essential in breeding higher-quality chickens with ideal fat distribution. This review systematically summarizes the regulatory mechanisms underlying intramuscular and abdominal fat traits at chromatin, genomic, transcriptional, post-transcriptional, translational, and epigenetic-modification scales. Additionally, we summarize the role of non-coding RNAs and protein-coding genes in governing intramuscular and abdominal fat deposition. These insights provide a valuable theoretical foundation for the genetic engineering of high-quality and high-yielding chicken breeds.
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Affiliation(s)
- Yuxin Xing
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; (Y.X.); (C.M.); (H.G.); (J.S.); (Y.S.); (G.L.); (G.S.); (Y.T.); (X.K.); (X.L.)
| | - Chenglin Ma
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; (Y.X.); (C.M.); (H.G.); (J.S.); (Y.S.); (G.L.); (G.S.); (Y.T.); (X.K.); (X.L.)
| | - Hongbo Guan
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; (Y.X.); (C.M.); (H.G.); (J.S.); (Y.S.); (G.L.); (G.S.); (Y.T.); (X.K.); (X.L.)
| | - Jianing Shen
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; (Y.X.); (C.M.); (H.G.); (J.S.); (Y.S.); (G.L.); (G.S.); (Y.T.); (X.K.); (X.L.)
| | - Ying Shen
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; (Y.X.); (C.M.); (H.G.); (J.S.); (Y.S.); (G.L.); (G.S.); (Y.T.); (X.K.); (X.L.)
| | - Guoxi Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; (Y.X.); (C.M.); (H.G.); (J.S.); (Y.S.); (G.L.); (G.S.); (Y.T.); (X.K.); (X.L.)
- Key Laboratory of Livestock and Poultry Resources (Poultry) Evaluation and Utilization of Ministry of Agriculture and Rural Affairs, Henan Agricultural University, Zhengzhou 450046, China
- Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450046, China
| | - Guirong Sun
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; (Y.X.); (C.M.); (H.G.); (J.S.); (Y.S.); (G.L.); (G.S.); (Y.T.); (X.K.); (X.L.)
- Key Laboratory of Livestock and Poultry Resources (Poultry) Evaluation and Utilization of Ministry of Agriculture and Rural Affairs, Henan Agricultural University, Zhengzhou 450046, China
- Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450046, China
| | - Yadong Tian
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; (Y.X.); (C.M.); (H.G.); (J.S.); (Y.S.); (G.L.); (G.S.); (Y.T.); (X.K.); (X.L.)
- Key Laboratory of Livestock and Poultry Resources (Poultry) Evaluation and Utilization of Ministry of Agriculture and Rural Affairs, Henan Agricultural University, Zhengzhou 450046, China
- Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450046, China
| | - Xiangtao Kang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; (Y.X.); (C.M.); (H.G.); (J.S.); (Y.S.); (G.L.); (G.S.); (Y.T.); (X.K.); (X.L.)
- Key Laboratory of Livestock and Poultry Resources (Poultry) Evaluation and Utilization of Ministry of Agriculture and Rural Affairs, Henan Agricultural University, Zhengzhou 450046, China
- Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450046, China
| | - Xiaojun Liu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; (Y.X.); (C.M.); (H.G.); (J.S.); (Y.S.); (G.L.); (G.S.); (Y.T.); (X.K.); (X.L.)
- Key Laboratory of Livestock and Poultry Resources (Poultry) Evaluation and Utilization of Ministry of Agriculture and Rural Affairs, Henan Agricultural University, Zhengzhou 450046, China
- Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450046, China
| | - Hong Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; (Y.X.); (C.M.); (H.G.); (J.S.); (Y.S.); (G.L.); (G.S.); (Y.T.); (X.K.); (X.L.)
- Key Laboratory of Livestock and Poultry Resources (Poultry) Evaluation and Utilization of Ministry of Agriculture and Rural Affairs, Henan Agricultural University, Zhengzhou 450046, China
- Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450046, China
| | - Weihua Tian
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; (Y.X.); (C.M.); (H.G.); (J.S.); (Y.S.); (G.L.); (G.S.); (Y.T.); (X.K.); (X.L.)
- Key Laboratory of Livestock and Poultry Resources (Poultry) Evaluation and Utilization of Ministry of Agriculture and Rural Affairs, Henan Agricultural University, Zhengzhou 450046, China
- Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450046, China
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Wang W, Li Y, Zhang C, Zhou H, Li C, Cheng R, Chen X, Pu Y, Chen Y. Small Extracellular Vesicles from Young Healthy Human Plasma Inhibit Cardiac Fibrosis After Myocardial Infarction via miR-664a-3p Targeting SMAD4. Int J Nanomedicine 2025; 20:557-579. [PMID: 39830157 PMCID: PMC11740580 DOI: 10.2147/ijn.s488368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 01/05/2025] [Indexed: 01/22/2025] Open
Abstract
Purpose Cardiac fibrosis, a key contributor to ventricular pathologic remodeling and heart failure, currently lacks effective therapeutic approaches. Patients and Methods Small extracellular vesicles from young healthy human plasma (Young-sEVs) were characterized via protein marker, transmission electron microscopy, and nanoparticle tracking analysis, then applied in cellular models and mouse models of cardiac fibrosis. Western blotting and qRT-PCR were used to identify protective signaling pathways in cardiac fibroblasts (CFs). Results Young-sEVs significantly inhibited cardiac fibrosis and subsequent cardiac dysfunction post-myocardial infarction (MI) in mice. The main findings included that echocardiographic assessments four weeks post-MI indicated that Young-sEVs improved left ventricular ejection fraction (LVEF) and fractional shortening (LVFS), and reduced left ventricular internal diameter in diastole (LVIDd) and systole (LVIDs). Treatment with Young-sEVs also decreased Masson-positive fibroblast areas and collagen synthesis in cardiac tissue. However, sEVs from the old control group did not achieve the above effect. Consistent with in vivo results, Young-sEVs could also inhibit the proliferation, migration, and collagen synthesis of CFs in the TGF-β1-induced cellular fibrosis model. High-throughput microRNA (miRNA) sequencing and qRT-PCR analysis revealed that miR-664a-3p was abundant in Young-sEVs. The high expression of miR-664a-3p significantly inhibited the proliferation, migration, and collagen synthesis of TGF-β1-induced CFs. However, suppressing the expression of miR-664a-3p in Young-sEVs eliminated their therapeutic effect on cardiac fibrosis in mice. Further studies confirmed SMAD4 as a direct downstream target of miR-664a-3p, whose overexpression could reverse the anti-fibrotic effects of miR-664a-3p. Conclusion In summary, these findings firstly revealed that Young-sEVs could directly bind to the 3'-untranslated region of SMAD4 mRNA through miR-664a-3p, thereby inhibiting the TGF-β/SMAD4 signaling pathway to protect heart from fibrosis and improve cardiac function. Considering the ease of obtaining plasma-derived sEVs, our study offers a promising therapeutic strategy for heart failure, with the potential for rapid clinical translation in the near future.
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Affiliation(s)
- Weiwei Wang
- Department of Emergency and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China
| | - Ying Li
- Department of Emergency and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China
| | - Cheng Zhang
- Long Jiang Central Laboratory, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, People’s Republic of China
| | - Haoyang Zhou
- Department of Emergency and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China
| | - Chunyu Li
- Long Jiang Intensive Care Unit, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China
| | - Rong Cheng
- Department of Emergency and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China
| | - Xufeng Chen
- Department of Emergency and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China
| | - Yanan Pu
- Department of Clinical Laboratory, Nanjing Chest Hospital, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, People’s Republic of China
| | - Yan Chen
- Department of Emergency and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China
- Department of Emergency and Critical Care Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, 215000, People’s Republic of China
- Department of Emergency Management, School of Health Policy & Management, Nanjing Medical University, Nanjing, 211166, People’s Republic of China
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21
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Sun T, Zhong Q, Yu X, Luo H, Ren F, Liu C, Chen P, Flores-Borja F, Sun H, An Z. Molecular dynamics of chemotactic signalling orchestrates dental pulp stem cell fibrosis during aging. Front Cell Dev Biol 2025; 12:1530644. [PMID: 39866843 PMCID: PMC11760607 DOI: 10.3389/fcell.2024.1530644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 12/19/2024] [Indexed: 01/28/2025] Open
Abstract
Aging often triggers dental pulp fibrosis, resulting in clinical repercussions such as increased susceptibility to dental infections, compromised tooth vitality, and reduced responsiveness to dental interventions. Despite its prevalence, the precise molecular mechanisms underlying this condition remains unclear. Leveraging single-cell transcriptome analysis from both our own and publicly available datasets, we identified Ccrl2+ macrophages as particularly vulnerable during the early stages of aging. Notably, dental pulp progenitors with high expression of RARRES2, a unique ligand for CCRL2, facilitate the selective recruitment of a specific macrophage population to the stem cell niches. This process culminates in the formation of the ligand-receptor complex that engages CMKLR1, a receptor broadly expressed across macrophage populations. This interaction drives macrophage activation and expansion through the RARRES2/CCRL2/CMKLR1 axis. Through rigorous experimental validation, we demonstrated that macrophage activation and expansion within stem cell niches lead to increased secretion of proinflammatory factors, promoting dental pulp fibrosis during aging. Our findings uncover the intricate molecular dynamics of dental pulp aging, emphasizing immune microenvironment interactions. This study provides a novel perspective on potential therapeutic strategies for age-related pulp diseases by targeting macrophages and modulating the immune microenvironment.
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Affiliation(s)
- Tianmeng Sun
- Department of Oral Biology, School and Hospital of Stomatology, Jilin University, Changchun, China
- Key Laboratory of Tooth Development and Bone Remodeling of Jilin Province, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Qing Zhong
- Department of Oral Biology, School and Hospital of Stomatology, Jilin University, Changchun, China
- Key Laboratory of Tooth Development and Bone Remodeling of Jilin Province, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Xiaoyi Yu
- Department of Oral Biology, School and Hospital of Stomatology, Jilin University, Changchun, China
- Key Laboratory of Tooth Development and Bone Remodeling of Jilin Province, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Huanyu Luo
- Department of Oral Biology, School and Hospital of Stomatology, Jilin University, Changchun, China
- Key Laboratory of Tooth Development and Bone Remodeling of Jilin Province, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Feilong Ren
- Department of Oral Biology, School and Hospital of Stomatology, Jilin University, Changchun, China
- Key Laboratory of Tooth Development and Bone Remodeling of Jilin Province, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Cangwei Liu
- Department of Oral Pathology, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Peng Chen
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Fabian Flores-Borja
- Centre for Oral Immunobiology and Regenerative Medicine, Barts and the London School of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, United Kingdom
| | - Hongchen Sun
- Department of Oral Pathology, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Zhengwen An
- Department of Oral Biology, School and Hospital of Stomatology, Jilin University, Changchun, China
- Key Laboratory of Tooth Development and Bone Remodeling of Jilin Province, School and Hospital of Stomatology, Jilin University, Changchun, China
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Richardson M, Brandt C, Jain N, Li JL, Demanelis K, Jasmine F, Kibriya MG, Tong L, Pierce BL. Characterization of DNA methylation clock algorithms applied to diverse tissue types. Aging (Albany NY) 2025; 17:67-96. [PMID: 39754638 PMCID: PMC11810061 DOI: 10.18632/aging.206182] [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: 12/05/2023] [Accepted: 12/12/2024] [Indexed: 01/06/2025]
Abstract
BACKGROUND DNA methylation (DNAm) data from human samples has been leveraged to develop "epigenetic clock" algorithms that predict age and other aging-related phenotypes. Some DNAm clocks were trained using DNAm obtained from blood cells, while other clocks were trained using data from diverse tissue/cell types. To assess how DNAm clocks perform across non-blood tissue types, we applied DNAm algorithms to DNAm data generated from 9 different human tissue types. METHODS We generated array-based DNAm measurements for 973 samples from deceased tissue donors from the GTEx (Genotype Tissue Expression) project representing nine distinct tissue types: lung, colon, prostate, ovary, breast, kidney, testis, skeletal muscle, and whole blood. For all samples, we generated DNAm clock estimates for 8 epigenetic clocks and characterized these tissue-specific clock estimates in terms of their distributions, correlations with chronological age, correlations of clock estimates between tissue types, and association with participant characteristics. RESULTS For each clock, the mean DNAm age estimate varied substantially across tissue types, and the mean values for the different clocks varied substantially within tissue types. For most clocks, the correlation with chronological age varied across tissue types, with blood often showing the strongest correlation. Each clock showed strong correlation across tissues, with some evidence of some residual correlation after adjusting for chronological age. In lung tissue, smoking generally had a positive association with epigenetic age. CONCLUSIONS This work demonstrates how differences in epigenetic aging among tissue types leads to clear differences in DNAm clock characteristics across tissue types. Tissue or cell-type specific epigenetic clocks are needed to optimize predictive performance of DNAm clocks in non-blood tissues and cell types.
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Affiliation(s)
- Mark Richardson
- Department of Public Health Sciences, University of Chicago, Chicago, IL 60615, USA
| | - Courtney Brandt
- Department of Public Health Sciences, University of Chicago, Chicago, IL 60615, USA
| | - Niyati Jain
- Department of Public Health Sciences, University of Chicago, Chicago, IL 60615, USA
| | - James L. Li
- Department of Public Health Sciences, University of Chicago, Chicago, IL 60615, USA
| | - Kathryn Demanelis
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Farzana Jasmine
- Department of Public Health Sciences, University of Chicago, Chicago, IL 60615, USA
| | - Muhammad G. Kibriya
- Department of Public Health Sciences, University of Chicago, Chicago, IL 60615, USA
| | - Lin Tong
- Department of Public Health Sciences, University of Chicago, Chicago, IL 60615, USA
| | - Brandon L. Pierce
- Department of Public Health Sciences, University of Chicago, Chicago, IL 60615, USA
- Department of Human Genetics, University of Chicago, Chicago, IL 60615, USA
- Comprehensive Cancer Center, University of Chicago, Chicago, IL 60615, USA
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Zhong L, Yang J, Syed JN, Zhang Y, Tian Y, Fu X. Alpha-Glucosidase Inhibitors in Aging and Aging-Related Diseases: Clinical Applications and Relevant Mechanisms. Aging Dis 2025:AD.2024.1477. [PMID: 39751859 DOI: 10.14336/ad.2024.1477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 12/19/2024] [Indexed: 01/04/2025] Open
Abstract
Aging is a complex and universal process marked by gradual functional declines at the cellular and tissue levels, often leading to a range of aging-related diseases such as diabetes, cardiovascular diseases, and cancer. Delaying the aging process can help prevent, slow down, and alleviate the severity of these various conditions, enhancing overall health and well-being. Alpha-glucosidase inhibitors (AGIs) are a class of widely used antidiabetic drugs that inhibit alpha-glucosidase in the small intestinal mucosa, delaying carbohydrate absorption and reducing postprandial hyperglycemia. Beyond their roles in diabetes treatment, AGIs have shown potential in extending lifespan and effectively treating aging-related diseases by modulating oxidative stress, gut microbiota, inflammatory responses, and nutrient-sensing pathways. This review summarizes recent advancements in the application of AGIs for preventing and treating aging and aging-related diseases, with a focus on their mechanisms and roles in these processes.
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Affiliation(s)
- Ling Zhong
- Department of Endocrinology and Metabolism, Department of Biotherapy, Laboratory of Diabetes and Metabolism Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Jielin Yang
- Department of Translational Medicine, The Hospital for Sick Children, Toronto, ON M5S 1A1, Canada
| | - Jibran Nehal Syed
- Department of Translational Medicine, The Hospital for Sick Children, Toronto, ON M5S 1A1, Canada
| | - Yuwei Zhang
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Yan Tian
- Department of Endocrinology and Metabolism, Department of Biotherapy, Laboratory of Diabetes and Metabolism Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xianghui Fu
- Department of Endocrinology and Metabolism, Department of Biotherapy, Laboratory of Diabetes and Metabolism Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
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24
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Smith ZD, Hetzel S, Meissner A. DNA methylation in mammalian development and disease. Nat Rev Genet 2025; 26:7-30. [PMID: 39134824 DOI: 10.1038/s41576-024-00760-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/24/2024] [Indexed: 12/15/2024]
Abstract
The DNA methylation field has matured from a phase of discovery and genomic characterization to one seeking deeper functional understanding of how this modification contributes to development, ageing and disease. In particular, the past decade has seen many exciting mechanistic discoveries that have substantially expanded our appreciation for how this generic, evolutionarily ancient modification can be incorporated into robust epigenetic codes. Here, we summarize the current understanding of the distinct DNA methylation landscapes that emerge over the mammalian lifespan and discuss how they interact with other regulatory layers to support diverse genomic functions. We then review the rising interest in alternative patterns found during senescence and the somatic transition to cancer. Alongside advancements in single-cell and long-read sequencing technologies, the collective insights made across these fields offer new opportunities to connect the biochemical and genetic features of DNA methylation to cell physiology, developmental potential and phenotype.
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Affiliation(s)
- Zachary D Smith
- Department of Genetics, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, USA.
| | - Sara Hetzel
- Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Alexander Meissner
- Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany.
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25
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Guelfi G, Capaccia C, Tedeschi M, Bufalari A, Leonardi L, Cenci-Goga B, Maranesi M. Dog Aging: A Comprehensive Review of Molecular, Cellular, and Physiological Processes. Cells 2024; 13:2101. [PMID: 39768192 PMCID: PMC11675035 DOI: 10.3390/cells13242101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 01/11/2025] Open
Abstract
The aging process is a multifactorial biological phenomenon starting at birth and persisting throughout life, characterized by a decline in physiological functions and adaptability. This decline results in the diminished capacity of aging organisms to respond to environmental changes and stressors, leading to reduced efficiency in metabolic, immune, and hormonal functions. As behavioral flexibility wanes, older individuals face longer recovery times and increased vulnerability to diseases. While early research proposed nine core hallmarks of mammalian aging, recent studies have expanded this framework to twelve key characteristics: epigenetic changes, genomic instability, telomere shortening, loss of proteostasis, altered metabolism, mitochondrial dysfunction, cellular senescence, disrupted intercellular communication, stem cell depletion, immune system dysfunction, accumulation of toxic metabolites, and dysbiosis. Given the growing interest in the aging area, we propose to add a new hallmark: impaired water homeostasis. This potential hallmark could play a critical role in aging processes and might open new directions for future research in the field. This review enhances our understanding of the physiological aspects of aging in dogs, suggesting new clinical intervention strategies to prevent and control issues that may arise from the pathological degeneration of these hallmarks.
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Affiliation(s)
- Gabriella Guelfi
- Department of Veterinary Medicine, University of Perugia, Via San Costanzo 4, 06126 Perugia, Italy; (C.C.); (M.T.); (L.L.); (B.C.-G.); (M.M.)
| | | | | | - Antonello Bufalari
- Department of Veterinary Medicine, University of Perugia, Via San Costanzo 4, 06126 Perugia, Italy; (C.C.); (M.T.); (L.L.); (B.C.-G.); (M.M.)
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Fu Z, Wang W, Gao Y. Understanding the impact of ER stress on lung physiology. Front Cell Dev Biol 2024; 12:1466997. [PMID: 39744015 PMCID: PMC11688383 DOI: 10.3389/fcell.2024.1466997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 11/22/2024] [Indexed: 01/04/2025] Open
Abstract
Human lungs consist of a distinctive array of cell types, which are subjected to persistent challenges from chemical, mechanical, biological, immunological, and xenobiotic stress throughout life. The disruption of endoplasmic reticulum (ER) homeostatic function, triggered by various factors, can induce ER stress. To overcome the elevated ER stress, an adaptive mechanism known as the unfolded protein response (UPR) is activated in cells. However, persistent ER stress and maladaptive UPR can lead to defects in proteostasis at the cellular level and are typical features of the lung aging. The aging lung and associated lung diseases exhibit signs of ER stress-related disruption in cellular homeostasis. Dysfunction resulting from ER stress and maladaptive UPR can compromise various cellular and molecular processes associated with aging. Hence, comprehending the mechanisms of ER stress and UPR components implicated in aging and associated lung diseases could enable to develop appropriate therapeutic strategies for the vulnerable population.
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Affiliation(s)
- Zhiling Fu
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Wei Wang
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yuan Gao
- Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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27
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Borrego-Ruiz A, Borrego JJ. Epigenetic Mechanisms in Aging: Extrinsic Factors and Gut Microbiome. Genes (Basel) 2024; 15:1599. [PMID: 39766866 PMCID: PMC11675900 DOI: 10.3390/genes15121599] [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: 11/23/2024] [Revised: 12/03/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND/OBJECTIVES Aging is a natural physiological process involving biological and genetic pathways. Growing evidence suggests that alterations in the epigenome during aging result in transcriptional changes, which play a significant role in the onset of age-related diseases, including cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. For this reason, the epigenetic alterations in aging and age-related diseases have been reviewed, and the major extrinsic factors influencing these epigenetic alterations have been identified. In addition, the role of the gut microbiome and its metabolites as epigenetic modifiers has been addressed. RESULTS Long-term exposure to extrinsic factors such as air pollution, diet, drug use, environmental chemicals, microbial infections, physical activity, radiation, and stress provoke epigenetic changes in the host through several endocrine and immune pathways, potentially accelerating the aging process. Diverse studies have reported that the gut microbiome plays a critical role in regulating brain cell functions through DNA methylation and histone modifications. The interaction between genes and the gut microbiome serves as a source of adaptive variation, contributing to phenotypic plasticity. However, the molecular mechanisms and signaling pathways driving this process are still not fully understood. CONCLUSIONS Extrinsic factors are potential inducers of epigenetic alterations, which may have important implications for longevity. The gut microbiome serves as an epigenetic effector influencing host gene expression through histone and DNA modifications, while bidirectional interactions with the host and the underexplored roles of microbial metabolites and non-bacterial microorganisms such as fungi and viruses highlight the need for further research.
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Affiliation(s)
- Alejandro Borrego-Ruiz
- Departamento de Psicología Social y de las Organizaciones, Universidad Nacional de Educación a Distancia (UNED), 28040 Madrid, Spain;
| | - Juan J. Borrego
- Departamento de Microbiología, Universidad de Málaga, 29071 Málaga, Spain
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28
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Li Q. Correlation between lipid accumulation product and epigenetic age acceleration in American adults: a cross-sectional analysis using NHANES data. Eur J Med Res 2024; 29:575. [PMID: 39623450 PMCID: PMC11613462 DOI: 10.1186/s40001-024-02174-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 11/25/2024] [Indexed: 12/06/2024] Open
Abstract
BACKGROUND The risks of obesity and epigenetic age acceleration (EAA) have drawn widespread attention. Lipid accumulation product (LAP) is a simple and reliable indicator of obesity; however, the relationship between LAP and EAA remains unclear. METHODS Data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002 were used. The EAA was assessed using a self-administered questionnaire in the database. LAP was calculated based on triglycerides and waist circumference. The association between LAP and EAA was analyzed using logistic regression models, subgroup analysis, and smooth curve fitting. RESULTS A total of 1796 participants were included in the study, of whom 1055 had EAA. After adjusting for relevant covariates, participants with EAA generally had higher LAP levels than those without EAA (258.1 vs. 244.6). Logistic regression analysis showed that individuals in the highest LAP quartile (Q4) were more likely to have EAA than those in the lowest quartile (Q1) (OR = 1.77; 95% CI 1.31-2.39; P < 0.001). The area under the curve of the adjusted logistic regression analysis was 0.706. CONCLUSION This research indicates that elevated LAP levels are independently linked to an increased risk of EAA, and early intervention to reduce high LAP levels is necessary to mitigate the progression of EAA.
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Affiliation(s)
- Qiqiang Li
- General Practice Department, Fuyong People's Hospital of Baoan District, Shenzhen, 518103, China.
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Wu Z, Qu J, Liu GH. Roles of chromatin and genome instability in cellular senescence and their relevance to ageing and related diseases. Nat Rev Mol Cell Biol 2024; 25:979-1000. [PMID: 39363000 DOI: 10.1038/s41580-024-00775-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/12/2024] [Indexed: 10/05/2024]
Abstract
Ageing is a complex biological process in which a gradual decline in physiological fitness increases susceptibility to diseases such as neurodegenerative disorders and cancer. Cellular senescence, a state of irreversible cell-growth arrest accompanied by functional deterioration, has emerged as a pivotal driver of ageing. In this Review, we discuss how heterochromatin loss, telomere attrition and DNA damage contribute to cellular senescence, ageing and age-related diseases by eliciting genome instability, innate immunity and inflammation. We also discuss how emerging therapeutic strategies could restore heterochromatin stability, maintain telomere integrity and boost the DNA repair capacity, and thus counteract cellular senescence and ageing-associated pathologies. Finally, we outline current research challenges and future directions aimed at better comprehending and delaying ageing.
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Affiliation(s)
- Zeming Wu
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Jing Qu
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.
- University of Chinese Academy of Sciences, Beijing, China.
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
- Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
- Aging Biomarker Consortium, Beijing, China.
| | - Guang-Hui Liu
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.
- University of Chinese Academy of Sciences, Beijing, China.
- Aging Biomarker Consortium, Beijing, China.
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, China.
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Jin W, Chen G, Chen W, Qiao G, Deng Y, Li K, Cai W. Poly-L-Lactic Acid Reduces the Volume of Dermal Adipose Tissue Through its Metabolite Lactate. Aesthetic Plast Surg 2024; 48:5136-5146. [PMID: 39060798 DOI: 10.1007/s00266-024-04265-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024]
Abstract
Poly-L-lactic acid (PLLA), a well-established biostimulator that induces collagenases, is widely used among clinical practice to treat skin aging. However, the precise regulatory effect of PLLA on different dermal cell subsets beyond fibroblast has not been fully elucidated. In this study, we constructed in vivo PLLA injection and in vitro PLLA-adipocyte co-culture models to analyze the regulatory effects of PLLA on the volume, differentiation, lipolysis, and thermogenic capacity of dermal adipocyte. We found that PLLA injection significantly reduced the thickness of dermal fat in mice. In co-culture assay, PLLA showed no effect on adipogenesis, but stimulated the lipolysis activity. Interestingly, PLLA also enhanced the differentiation of fat cells into beige fat cells, which possess higher thermogenic capacity. In mechanical study, we blocked adipocyte lactate uptake with a monocarboxylate transporter (MCT1/4) inhibitor and found that the regulatory effect of PLLA on dermal adipocyte relies on its metabolite lactate. In summary, our results suggest that PLLA has complex regulatory effects on the dermal cells, and its ability to improve skin aging is not fully attributed to stimulating collagen synthesis, but also partially involves adipocytes.No Level Assigned This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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Affiliation(s)
- Wen Jin
- Department of Pathology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211100, China
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Wei Chen
- Department of Plastic Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210003, China
| | - Guanqun Qiao
- Department of Plastic Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210003, China
| | - Yuequ Deng
- Department of Plastic Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210003, China
| | - Kai Li
- Department of Endocrinology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, 225300, China.
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 211166, China.
| | - Wei Cai
- Department of Plastic Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210003, China.
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Huang W, Lin C, Liu M. Bidirectional causal associations between aging and major mental disorders: A population-based study using the two-sample mendelian randomization method from the UK biobank (AM-SRNMA 002). Arch Gerontol Geriatr 2024; 127:105578. [PMID: 39029346 DOI: 10.1016/j.archger.2024.105578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 06/18/2024] [Accepted: 07/13/2024] [Indexed: 07/21/2024]
Abstract
AIMS While observational studies have suggested associations linking aging and mental disorders, the question of causality has remained unclear. This study aimed to explore the causal relationship between aging level and major mental disorders. METHODS We utilized Two-Sample Mendelian randomization (2SMR) with mental disorders data and aging indicators information from an extensive genome-wide association study (GWAS) database. The GWAS database is a comprehensive resource that compiles genetic association data, encompassing a sample size of over 450,000 individuals. We employed five methods for 2SMR and single nucleotide polymorphisms were chosen as instrumental variables. RESULTS Our analyses consistently supported a bidirectional causal association between the Frailty Index (FI) and Major Depressive Disorder (MDD). Furthermore, our findings indicated potential influences, such as Attention-Deficit/Hyperactivity Disorder (ADHD) and Bipolar Disorder (BD) affecting GrimAge, and Anxiety Disorder (AD) impacting Left Hand Grip Strength (LHGS). In contrast, we observed no significant correlations for other mental disorders on FI, Telomere Length (TL), GrimAge, Appendicular Lean Mass (ALM), and LHGS. In the reverse direction, FI showed a significant impact on the risk of MDD, AD, and ADHD, while LHGS affected the risk of MDD. Importantly, no significant associations were found between other factors and the risk of MDD, BD, AD, Schizophrenia (SZ), and ADHD. CONCLUSIONS This 2SMR analysis has presented evidence for a bidirectional causal relationship between FI and MDD, while the relationship between ADHD, BD, and GrimAge should be more considered. Our study provides genetic evidence supporting a causal link between aging indicators and several mental illnesses.
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Affiliation(s)
- Wenbo Huang
- Beijing Municipal Welfare Medical Research Institute Ltd, Beijing, China.
| | - Cheng Lin
- Department of Orthopaedic Surgery, Hirosaki University, Graduate School of Medicine, Hirosaki, Japan
| | - Mingxin Liu
- Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Hidaoui D, Porquet A, Chelbi R, Bohm M, Polyzou A, Alcazer V, Depil S, Imanci A, Morabito M, Renneville A, Selimoglu-Buet D, Thépot S, Itzykson R, Laplane L, Droin N, Trompouki E, Elvira-Matelot E, Solary E, Porteu F. Targeting heterochromatin eliminates chronic myelomonocytic leukemia malignant stem cells through reactivation of retroelements and immune pathways. Commun Biol 2024; 7:1555. [PMID: 39578583 PMCID: PMC11584673 DOI: 10.1038/s42003-024-07214-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 11/05/2024] [Indexed: 11/24/2024] Open
Abstract
Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy affecting the elderly, for which therapeutic options are limited. DNA hypomethylating agents (HMAs) provide transient responses, failing to eradicate the malignant clone. Hematopoietic stem cell (HSC) aging involves heterochromatin reorganization, evidenced by alterations in histone marks H3K9me2 and H3K9me3. These repressive marks together with DNA methylation are essential for suppressing transposable elements (TEs). In solid cancers, the antitumor efficacy of HMAs involves the derepression of TEs, mimicking a state of viral infection. In this study, we demonstrate a significant disorganization of heterochromatin in CMML HSCs and progenitors (HSPCs) characterized by an increase in the repressive mark H3K9me2, mainly at the level of TEs, and a repression of immune and age-associated transcripts. Combining HMAs with G9A/GLP H3K9me2 methyltransferase inhibitors reactivates these pathways, selectively targeting mutated cells while preserving wild-type HSCs, thus offering new therapeutic avenues for this severe myeloid malignancy.
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MESH Headings
- Leukemia, Myelomonocytic, Chronic/genetics
- Leukemia, Myelomonocytic, Chronic/metabolism
- Leukemia, Myelomonocytic, Chronic/drug therapy
- Leukemia, Myelomonocytic, Chronic/immunology
- Leukemia, Myelomonocytic, Chronic/pathology
- Heterochromatin/metabolism
- Heterochromatin/genetics
- Humans
- Neoplastic Stem Cells/metabolism
- Retroelements/genetics
- Histone-Lysine N-Methyltransferase/genetics
- Histone-Lysine N-Methyltransferase/metabolism
- Hematopoietic Stem Cells/metabolism
- DNA Methylation
- Animals
- Mice
- Male
- Histones/metabolism
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Affiliation(s)
- Donia Hidaoui
- INSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-Saclay, 94805, Villejuif, France
| | - Audrey Porquet
- INSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-Saclay, 94805, Villejuif, France
| | - Rabie Chelbi
- INSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-Saclay, 94805, Villejuif, France
- Inovarion, 75005, Paris, France
| | - Mathieu Bohm
- INSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-Saclay, 94805, Villejuif, France
- Inovarion, 75005, Paris, France
| | - Aikaterini Polyzou
- IRCAN Institute for Research on Cancer and Aging, INSERM U1081, CNRS UMR 7284, Université Côte d'Azur, Nice, France
| | - Vincent Alcazer
- Centre International de Recherche en Infectiologie, INSERM U1111 CNRS UMR530, Lyon, France
- Service d'hématologie Clinique, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France
| | - Stéphane Depil
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM U1052 CNRS 5286 Université Claude Bernard Lyon 1, Centre Léon Bérard, Lyon, France
| | - Aygun Imanci
- INSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-Saclay, 94805, Villejuif, France
| | - Margot Morabito
- INSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-Saclay, 94805, Villejuif, France
| | - Aline Renneville
- INSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-Saclay, 94805, Villejuif, France
- INSERM US23, CNRS UMS 3655, Gustave Roussy Cancer Center, Villejuif, France
| | - Dorothée Selimoglu-Buet
- INSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-Saclay, 94805, Villejuif, France
| | - Sylvain Thépot
- Clinical Hematology Department, University Hospital, Angers, France
| | - Raphael Itzykson
- Université Paris Cité, Génomes, Biologie Cellulaire et Thérapeutique U944, INSERM, CNRS, F-75010, Paris, France
- Département Hématologie et Immunologie, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, F-75010, Paris, France
| | - Lucie Laplane
- INSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-Saclay, 94805, Villejuif, France
- Institut d'Histoire et Philosophie des Sciences et des Techniques, Université Paris I Panthéon-Sorbonne, Paris, France
| | - Nathalie Droin
- INSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-Saclay, 94805, Villejuif, France
- INSERM US23, CNRS UMS 3655, Gustave Roussy Cancer Center, Villejuif, France
| | - Eirini Trompouki
- IRCAN Institute for Research on Cancer and Aging, INSERM U1081, CNRS UMR 7284, Université Côte d'Azur, Nice, France
| | - Emilie Elvira-Matelot
- INSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-Saclay, 94805, Villejuif, France
| | - Eric Solary
- INSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-Saclay, 94805, Villejuif, France
- Clinical Hematology Department, Gustave Roussy Cancer Center, Villejuif, France
| | - Françoise Porteu
- INSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-Saclay, 94805, Villejuif, France.
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Wang H, Tang J, Yan S, Li C, Li Z, Xiong Z, Li Z, Tu C. Liquid-liquid Phase Separation in Aging: Novel Insights in the Pathogenesis and Therapeutics. Ageing Res Rev 2024; 102:102583. [PMID: 39566743 DOI: 10.1016/j.arr.2024.102583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 10/14/2024] [Accepted: 11/12/2024] [Indexed: 11/22/2024]
Abstract
The intricate organization of distinct cellular compartments is paramount for the maintenance of normal biological functions and the orchestration of complex biochemical reactions. These compartments, whether membrane-bound organelles or membraneless structures like Cajal bodies and RNA transport granules, play crucial roles in cellular function. Liquid-liquid phase separation (LLPS) serves as a reversible process that elucidates the genesis of membranelles structures through the self-assembly of biomolecules. LLPS has been implicated in a myriad of physiological and pathological processes, encompassing immune response and tumor genesis. But the association between LLPS and aging has not been clearly clarified. A recent advancement in the realm of aging research involves the introduction of a new edition outlining the twelve hallmarks of aging, categorized into three distinct groups. By delving into the role and mechanism of LLPS in the formation of membraneless structures at a molecular level, this review encapsulates an exploration of the interaction between LLPS and these aging hallmarks, aiming to offer novel perspectives of the intricate mechanisms underlying the aging process and deeper insights into aging therapeutics.
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Affiliation(s)
- Hua Wang
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University Changsha 410011, China
| | - Jinxin Tang
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University Changsha 410011, China
| | - Shuxiang Yan
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, Institute of Nephrology, The Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Chenbei Li
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University Changsha 410011, China
| | - Zhaoqi Li
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University Changsha 410011, China
| | - Zijian Xiong
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University Changsha 410011, China
| | - Zhihong Li
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University Changsha 410011, China; Hunan Key Laboratory of Tumor Models and Individualized Medicine, Engineering Research Center of Artificial Intelligence-Driven Medical Device, The Second Xiangya Hospital of Central South University Changsha 410011, China, Changsha 410011, China; Shenzhen Research Institute of Central South University, Shenzhen 518063, China
| | - Chao Tu
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University Changsha 410011, China; Changsha Medical University, Changsha 410219, China
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Nunkoo VS, Cristian A, Jurcau A, Diaconu RG, Jurcau MC. The Quest for Eternal Youth: Hallmarks of Aging and Rejuvenating Therapeutic Strategies. Biomedicines 2024; 12:2540. [PMID: 39595108 PMCID: PMC11591597 DOI: 10.3390/biomedicines12112540] [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: 09/30/2024] [Revised: 10/26/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024] Open
Abstract
The impressive achievements made in the last century in extending the lifespan have led to a significant growth rate of elderly individuals in populations across the world and an exponential increase in the incidence of age-related conditions such as cardiovascular diseases, diabetes mellitus type 2, and neurodegenerative diseases. To date, geroscientists have identified 12 hallmarks of aging (genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, impaired macroautophagy, mitochondrial dysfunction, impaired nutrient sensing, cellular senescence, stem cell exhaustion, defective intercellular communication, chronic inflammation, and gut dysbiosis), intricately linked among each other, which can be targeted with senolytic or senomorphic drugs, as well as with more aggressive approaches such as cell-based therapies. To date, side effects seriously limit the use of these drugs. However, since rejuvenation is a dream of mankind, future research is expected to improve the tolerability of the available drugs and highlight novel strategies. In the meantime, the medical community, healthcare providers, and society should decide when to start these treatments and how to tailor them individually.
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Affiliation(s)
| | - Alexander Cristian
- Department of Psycho-Neurosciences and Rehabilitation, University of Oradea, 410087 Oradea, Romania
| | - Anamaria Jurcau
- Department of Psycho-Neurosciences and Rehabilitation, University of Oradea, 410087 Oradea, Romania
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Zaretsky A, Venzor AG, Eremenko E, Stein D, Smirnov D, Rabuah Y, Dryer R, Kriukov D, Kaluski-Kopatch S, Einav M, Khrameeva E, Toiber D. SIRT6-dependent functional switch via K494 modifications of RE-1 silencing transcription factor. Cell Death Dis 2024; 15:798. [PMID: 39511137 PMCID: PMC11543946 DOI: 10.1038/s41419-024-07160-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 10/08/2024] [Accepted: 10/15/2024] [Indexed: 11/15/2024]
Abstract
RE-1 silencing transcription factor (REST) is a key repressor of neural genes. REST is upregulated under stress signals, aging and neurodegenerative diseases, but although it is upregulated, its function is lost in Alzheimer's Disease. However, why it becomes inactive remains unclear. Here, we show that the NAD-dependent deacetylase SIRT6 regulates REST expression, location and activity. In the absence of SIRT6, REST is overexpressed but mislocalized, leading to a partial loss of its activity and causing it to become toxic. SIRT6 deficiency abrogates REST and EZH2 interaction, perturbs the location of REST to the heterochromatin Lamin B ring, and leads to REST target gene overexpression. SIRT6 reintroduction or REST methyl-mimic K494M expression rescues this phenotype, while an acetyl-mimic mutant loses its function even in WT cells. Our studies define a novel regulatory switch where, depending on SIRT6 presence, the function of REST is regulated by post-translational modifications on K494 (Ac/me), affecting neuronal gene expression. In WT cells (left), REST functions as a repressor due to its methylation, which allows proper localization and interaction with EZH2. In SIRT6 KO cells (right), REST is overexpressed, but it is mislocalized and acetylated instead of methylated, impairing its interaction with EZH2. REST localizes in the cytoplasm in autophagosomes. The overall increase in REST without SIRT6 results in non-functional and toxic REST proteins. During aging, SIRT6 declines in the brain, while REST is upregulated to protect it. In pathological aging, where SIRT6 levels are very low, the increase in REST without SIRT6 results in non-functional and toxic REST.
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Affiliation(s)
- Adam Zaretsky
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
- The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
| | - Alfredo Garcia Venzor
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
- The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
| | - Ekaterina Eremenko
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
- The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
| | - Daniel Stein
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
- The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
| | - Dmitrii Smirnov
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
- The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
- Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, Moscow, 121205, Russia
| | - Yuval Rabuah
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
- The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
| | - Rebecca Dryer
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
- The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
| | - Dmitrii Kriukov
- Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, Moscow, 121205, Russia
| | - Shai Kaluski-Kopatch
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
- The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
| | - Monica Einav
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
| | - Ekaterina Khrameeva
- Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, Moscow, 121205, Russia
| | - Debra Toiber
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.
- The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.
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Peñarroya A, Lorca R, Rodríguez Reguero JJ, Gómez J, Avanzas P, Tejedor JR, Fernandez AF, Fraga MF. Epigenetic Study of Cohort of Monozygotic Twins With Hypertrophic Cardiomyopathy Due to MYBPC3 (Cardiac Myosin-Binding Protein C). J Am Heart Assoc 2024; 13:e035777. [PMID: 39470061 PMCID: PMC11935665 DOI: 10.1161/jaha.124.035777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 08/12/2024] [Indexed: 10/30/2024]
Abstract
BACKGROUND Hypertrophic cardiomyopathy is an autosomal dominant cardiac disease. The mechanisms that determine its variable expressivity are poorly understood. Epigenetics could play a crucial role in bridging the gap between genotype and phenotype by orchestrating the interplay between the environment and the genome regulation. In this study we aimed to establish a possible correlation between the peripheral blood DNA methylation patterns and left ventricular hypertrophy severity in patients with hypertrophic cardiomyopathy, evaluating the potential impact of lifestyle variables and providing a biological context to the observed changes. METHODS AND RESULTS Methylation data were obtained from peripheral blood samples (Infinium MethylationEPIC BeadChip arrays). We employed multiple pair-matched models to extract genomic positions whose methylation correlates with the degree of left ventricular hypertrophy in 3 monozygotic twin pairs carrying the same founder pathogenic variant (MYBPC3 p.Gly263Ter). This model enables the isolation of the environmental influence, beyond age, on DNA methylation changes by removing the genetic background. Our results revealed a more anxious personality among more severely affected individuals. We identified 56 differentially methylated positions that exhibited moderate, proportional changes in methylation associated with left ventricular hypertrophy. These differentially methylated positions were enriched in regions regulated by repressor histone marks and tended to cluster at genes involved in left ventricular hypertrophy development, such as HOXA5, TRPC3, UCN3, or PLSCR2, suggesting that changes in peripheral blood may reflect myocardial alterations. CONCLUSIONS We present a unique pair-matched model, based on 3 monozygotic twin pairs carrying the same founder pathogenic variant and different phenotypes. This study provides further evidence of the pivotal role of epigenetics in hypertrophic cardiomyopathy variable expressivity.
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Affiliation(s)
- Alfonso Peñarroya
- Nanomaterials and Nanotechnology Research Center (CINN)Spanish National Research Council (CSIC)El EntregoAsturiasSpain
- Health Research Institute of the Principality of Asturias (ISPA)OviedoAsturiasSpain
| | - Rebeca Lorca
- Health Research Institute of the Principality of Asturias (ISPA)OviedoAsturiasSpain
- Unidad de Cardiopatías Familiares, Área del Corazón y Departamento de Genética MolecularHospital Universitario Central AsturiasOviedoSpain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORs)MadridSpain
- Departamento de Biología FuncionalUniversidad de OviedoOviedoSpain
| | - José Julián Rodríguez Reguero
- Health Research Institute of the Principality of Asturias (ISPA)OviedoAsturiasSpain
- Unidad de Cardiopatías Familiares, Área del Corazón y Departamento de Genética MolecularHospital Universitario Central AsturiasOviedoSpain
| | - Juan Gómez
- Health Research Institute of the Principality of Asturias (ISPA)OviedoAsturiasSpain
- Unidad de Cardiopatías Familiares, Área del Corazón y Departamento de Genética MolecularHospital Universitario Central AsturiasOviedoSpain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORs)MadridSpain
| | - Pablo Avanzas
- Health Research Institute of the Principality of Asturias (ISPA)OviedoAsturiasSpain
- Unidad de Cardiopatías Familiares, Área del Corazón y Departamento de Genética MolecularHospital Universitario Central AsturiasOviedoSpain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORs)MadridSpain
- Departamento de MedicinaUniversidad de OviedoOviedoSpain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV)OviedoSpain
| | - Juan Ramon Tejedor
- Nanomaterials and Nanotechnology Research Center (CINN)Spanish National Research Council (CSIC)El EntregoAsturiasSpain
- Health Research Institute of the Principality of Asturias (ISPA)OviedoAsturiasSpain
- Spanish Biomedical Research Network in Rare Diseases (CIBERER)MadridSpain
- Institute of Oncology of Asturias (IUOPA), University of OviedoOviedoAsturiasSpain
| | - Agustín F. Fernandez
- Nanomaterials and Nanotechnology Research Center (CINN)Spanish National Research Council (CSIC)El EntregoAsturiasSpain
- Health Research Institute of the Principality of Asturias (ISPA)OviedoAsturiasSpain
- Spanish Biomedical Research Network in Rare Diseases (CIBERER)MadridSpain
- Institute of Oncology of Asturias (IUOPA), University of OviedoOviedoAsturiasSpain
| | - Mario F. Fraga
- Nanomaterials and Nanotechnology Research Center (CINN)Spanish National Research Council (CSIC)El EntregoAsturiasSpain
- Health Research Institute of the Principality of Asturias (ISPA)OviedoAsturiasSpain
- Spanish Biomedical Research Network in Rare Diseases (CIBERER)MadridSpain
- Institute of Oncology of Asturias (IUOPA), University of OviedoOviedoAsturiasSpain
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Bordoni L, Agostinho de Sousa J, Zhuo J, von Meyenn F. Evaluating the connection between diet quality, EpiNutrient intake and epigenetic age: an observational study. Am J Clin Nutr 2024; 120:1143-1155. [PMID: 39510725 DOI: 10.1016/j.ajcnut.2024.08.033] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 08/25/2024] [Accepted: 08/30/2024] [Indexed: 11/15/2024] Open
Abstract
BACKGROUND DNA methylation (DNAm) has unique properties which makes it a potential biomarker for lifestyle-related exposures. Epigenetic clocks, particularly DNAm-based biological age predictors [epigenetic age (EA)], represent an exciting new area of clinical research and deviations of EA from chronological age [epigenetic age acceleration (EAA)] have been linked to overall health, age-related diseases, and environmental exposures. OBJECTIVES This observational study investigates the relationships between biological aging and various dietary factors within the LifeLines-DEEP Cohort. These factors include diet quality, processed food consumption, dietary glycemic load, and intake of vitamins involved in maintaining the epigenetic homeostasis (vitamins B-9, B-12, B-6, B-2, and C). METHODS Dietary records collected using food-frequency questionnaires were used to estimate diet quality [LifeLines Diet Score (LLDS)], measure the intake of unprocessed/ultraprocessed food according to the NOVA food classification system, and the adequacy of the dietary intake of vitamins B-9, B-12, B-2, B-6, and C. EA using Horvath, Hannum, Levine, and Horvath2 epigenetic clock models and DNAm-predicted telomere length (DNAm-TL) were calculated from DNAm data in 760 subjects. Associations between dietary factors and EAA were tested, adjusting for sex, energy intake, and body composition. RESULTS LLDS was associated with EAA (EAA_Horvath: β: -0.148; P = 1 × 10-4; EAA_Hannum: β: -0.148; P = 9 × 10-5; EAA_Levine: β: -0.174; P = 1 × 10-5; and EAA_Horvath2: β: -0.176; P = 4 × 10-6) and DNAm-TL (β: 0.116; P = 0.003). Particularly, EAA was associated with dietary glycemic load (EAA_Horvath: β: 0.476; P = 9 × 10-10; EAA_Hannum: β: 0.565; P = 1 × 10-13; EAA_Levine: β: 0.469; P = 5 × 10-9; EAA_Horvath2: β: 0.569; P = 1 × 10-13; and DNAmTL adjusted for age: β: -0.340; P = 2 × 10-5) and different measures of food processing (NOVA classes 1 and 4). Positive EAA was also associated with inadequate intake of vitamin B-12 (EAA_Horvath: β: -0.167; P = 0.002; EAA_Hannum: β: -0.144; P = 0.007; and EAA_Horvath2: β: -0.126; P = 0.019) and C (EAA_Hannum: β: -0.136; P = 0.010 and EAA_Horvath2: β: -0.151; P = 0.005). CONCLUSIONS Our findings corroborate the hypothesis that nutrition plays a pivotal role in influencing epigenetic homeostasis, especially DNAm, thereby contributing to individual health trajectories and the pace of aging.
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Affiliation(s)
- Laura Bordoni
- Unit of Molecular Biology and Nutrigenomics, School of Pharmacy, University of Camerino, Camerino, Italy.
| | - João Agostinho de Sousa
- Laboratory of Nutrition and Metabolic Epigenetics, Department of Health Sciences and Technology, ETH Zurich, Switzerland
| | - Jingran Zhuo
- Laboratory of Nutrition and Metabolic Epigenetics, Department of Health Sciences and Technology, ETH Zurich, Switzerland
| | - Ferdinand von Meyenn
- Laboratory of Nutrition and Metabolic Epigenetics, Department of Health Sciences and Technology, ETH Zurich, Switzerland.
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Ji X, Luo H, Li X, Wang S, Xia L, Ni M, Wang J, Peng C, Wu X, Tan R, Zhang X, Jiang H. Structural characterization, anti-aging activity and mechanisms investigation in vivo of a polysaccharide from Anthriscus sylvestris. Int J Biol Macromol 2024; 279:135256. [PMID: 39233161 DOI: 10.1016/j.ijbiomac.2024.135256] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 07/22/2024] [Accepted: 08/31/2024] [Indexed: 09/06/2024]
Abstract
Anthriscus sylvestris (L.) Hoffm has a long history of use for anti-aging, although the anti-aging properties of its decoction ingredients have been seldom explored. This study marks the first detailed examination of the in vivo anti-aging activity of A. sylvestris roots polysaccharide (AP). Structural analyses revealed that AP is a neutral heteropolysaccharide with an average molecular weight (Mw) of 34.17 kDa, comprising glucose, xylose, galactose, mannose, and arabinose, with a backbone primarily of 1,4-α-D-Glc and minor branching at 1,4,6-α-D-Man. Its advanced structure is characterized by stable triple-helical chains and nanoscale agglomerated spherical particles. Using a D-gal-induced aging mouse model, further investigation showed that AP boosts the activity of various antioxidant enzymes via the Nrf2/HO-1/NQO1 signaling pathway. Aging-related immune decline was also mitigated by an increase in lymphocyte production in thymus. Moreover, AP reduced inflammation and downregulated aging genes p53 and p21 in hippocampus and liver tissues, enhanced the cholinergic system, and improved liver functions and lipid metabolism. The collective impact of these mechanisms underscores the robust anti-aging properties of AP. These findings highlight the anti-aging and immunomodulatory potential of A. sylvestris polysaccharide, broadening the understanding of its active components.
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Affiliation(s)
- Xiaoyun Ji
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China
| | - Haimeng Luo
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China
| | - Xianyan Li
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China
| | - Siwei Wang
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China
| | - Lijun Xia
- Irradiation Preservation Key Laboratory of Sichuan Province, Sichuan Institute of Atomic Energy, Chengdu 610100, PR China
| | - Maojun Ni
- Irradiation Preservation Key Laboratory of Sichuan Province, Sichuan Institute of Atomic Energy, Chengdu 610100, PR China
| | - Jingxia Wang
- Irradiation Preservation Key Laboratory of Sichuan Province, Sichuan Institute of Atomic Energy, Chengdu 610100, PR China
| | - Chaorong Peng
- Irradiation Preservation Key Laboratory of Sichuan Province, Sichuan Institute of Atomic Energy, Chengdu 610100, PR China
| | - Xiaoqing Wu
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China
| | - Rui Tan
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China
| | - Xiaobin Zhang
- Irradiation Preservation Key Laboratory of Sichuan Province, Sichuan Institute of Atomic Energy, Chengdu 610100, PR China.
| | - Hezhong Jiang
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China.
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Usmani SS, Jung HG, Zhang Q, Kim MW, Choi Y, Caglayan AB, Cai D. Targeting the hypothalamus for modeling age-related DNA methylation and developing OXT-GnRH combinational therapy against Alzheimer's disease-like pathologies in male mouse model. Nat Commun 2024; 15:9419. [PMID: 39482312 PMCID: PMC11528003 DOI: 10.1038/s41467-024-53507-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 10/09/2024] [Indexed: 11/03/2024] Open
Abstract
The hypothalamus plays an important role in aging, but it remains unclear regarding the underlying epigenetics and whether this hypothalamic basis can help address aging-related diseases. Here, by comparing mouse hypothalamus with two other limbic system components, we show that the hypothalamus is characterized by distinctively high-level DNA methylation during young age and by the distinct dynamics of DNA methylation and demethylation when approaching middle age. On the other hand, age-related DNA methylation in these limbic system components commonly and sensitively applies to genes in hypothalamic regulatory pathways, notably oxytocin (OXT) and gonadotropin-releasing hormone (GnRH) pathways. Middle age is associated with transcriptional declines of genes which encode OXT, GnRH and signaling components, which similarly occur in an Alzheimer's disease (AD)-like model. Therapeutically, OXT-GnRH combination is substantially more effective than individual peptides in treating AD-like disorders in male 5×FAD model. In conclusion, the hypothalamus is important for modeling age-related DNA methylation and developing hypothalamic strategies to combat AD.
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Affiliation(s)
- Salman Sadullah Usmani
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Hyun-Gug Jung
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Qichao Zhang
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Min Woo Kim
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Yuna Choi
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Ahmet Burak Caglayan
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Dongsheng Cai
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
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Liu Y, Huang L, Hu F, Zhang X. Investigating Frailty, Polypharmacy, Malnutrition, Chronic Conditions, and Quality of Life in Older Adults: Large Population-Based Study. JMIR Public Health Surveill 2024; 10:e50617. [PMID: 39145920 PMCID: PMC11512125 DOI: 10.2196/50617] [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: 07/06/2023] [Revised: 05/31/2024] [Accepted: 08/08/2024] [Indexed: 08/16/2024] Open
Abstract
BACKGROUND Aging, a significant public health issue, is associated with multiple concurrent chronic diseases and aging-related conditions (geriatric syndromes). OBJECTIVE This study aims to investigate the impact of age and chronic conditions on geriatric syndromes and the intercorrelations between multiple geriatric syndromes and quality of life (QoL) in older adults (aged ≥65 years) at the population level. METHODS A large representative sample was randomly selected from a county in China, Feidong, with 17 towns and 811,867 residents. Multiple chronic conditions, geriatric syndromes (frailty, polypharmacy, and malnutrition), and QoL were assessed and compared. Associations of demographic information and chronic conditions with geriatric conditions and QoL in older adults were assessed using multivariable-adjusted logistic regression. Intercorrelations between age, multiple geriatric syndromes, and QoL were investigated using both correlation analysis and restricted cubic splines-based multivariable-adjusted dose-response analysis. RESULTS Older adults comprised 43.42% (3668/8447) of the entire study population. The prevalence of frailty, premalnutrition or malnutrition, polypharmacy, and impaired QoL (median age 73, IQR 69-78 years; 1871/3668, 51% men) was 8.26% (303/3668), 15.59% (572/3668), 3.22% (118/3668), and 10.8% (396/3668), respectively. Different age and sex subgroups mostly had similar prevalence of geriatric syndromes (except that frailty occurred more often with older age). Premalnutrition or malnutrition were associated with a lower frequency of obesity and a higher frequency of constipation, polypharmacy with a higher frequency of diabetes and constipation, frailty with a higher frequency of constipation and hernia, and impaired QoL with a higher frequency of hypertension, diabetes, physical disability, and constipation. Mini Nutritional Assessment-Short Form, Groningen Frailty Indicator, and EQ-5D-5L scores, as well as the number of medications used, mostly predicted each other and QoL. Impaired QoL was associated with a higher frequency of frailty, premalnutrition or malnutrition, and polypharmacy, and frailty with a higher frequency of premalnutrition or malnutrition and polypharmacy. At a 1.5-year follow-up, impaired QoL was linked to polypharmacy and frailty at baseline, premalnutrition or malnutrition and polypharmacy were associated with frailty at baseline, and frailty was linked to both premalnutrition or malnutrition and polypharmacy at baseline. Causal mediation analyses showed that frailty mediated the link between polypharmacy and worse QoL and that polypharmacy mediated the link between frailty and worse QoL. CONCLUSIONS In this large population-based study of older adults, multiple chronic conditions were associated with ≥1 of the investigated geriatric syndromes. Geriatric syndromes were mostly intercorrelated with, and well predictive of, each other and QoL; and causal relationships existed between geriatric syndromes and QoL, with other geriatric syndromes being mediators. The findings might be biased by residual confounding factors. It is important to perform personalized geriatric syndrome assessments stratified by chronic condition; active prevention of, or intervention for, any syndrome might help to reduce the others and improve QoL.
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Affiliation(s)
- Yunmei Liu
- School of Cultural Heritage and Information Management, Shanghai University, Shanghai, China
| | - Lei Huang
- Department of Gastroenterology, National Clinical Research Center for Digestive Diseases, Shanghai Institute of Pancreatic Diseases, The First Affiliated Hospital of Naval Medical University/Changhai Hospital, Naval Medical University, Shanghai, China
- National Key Laboratory of Immunity and Inflammation, Changhai Clinical Research Unit, The First Affiliated Hospital of Naval Medical University/Changhai Hospital, Naval Medical University, Shanghai, China
| | - Fei Hu
- Department of General Surgery, Feidong People's Hospital, East District of the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiuwen Zhang
- Department of General Surgery, Feidong People's Hospital, East District of the First Affiliated Hospital of Anhui Medical University, Hefei, China
- School of Clinical Medicine, Anhui Medical University, Hefei, China
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Song Y, Spurlock B, Liu J, Qian L. Cardiac Aging in the Multi-Omics Era: High-Throughput Sequencing Insights. Cells 2024; 13:1683. [PMID: 39451201 PMCID: PMC11506570 DOI: 10.3390/cells13201683] [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: 09/11/2024] [Revised: 10/08/2024] [Accepted: 10/08/2024] [Indexed: 10/26/2024] Open
Abstract
Cardiovascular diseases are a leading cause of mortality worldwide, and the risks of both developing a disease and receiving a poor prognosis increase with age. With increasing life expectancy, understanding the mechanisms underlying heart aging has become critical. Traditional techniques have supported research into finding the physiological changes and hallmarks of cardiovascular aging, including oxidative stress, disabled macroautophagy, loss of proteostasis, and epigenetic alterations, among others. The advent of high-throughput multi-omics techniques offers new perspectives on the molecular mechanisms and cellular processes in the heart, guiding the development of therapeutic targets. This review explores the contributions and characteristics of these high-throughput techniques to unraveling heart aging. We discuss how different high-throughput omics approaches, both alone and in combination, produce robust and exciting new findings and outline future directions and prospects in studying heart aging in this new era.
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Affiliation(s)
- Yiran Song
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA; (Y.S.); (B.S.); (J.L.)
- McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA
- Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Brian Spurlock
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA; (Y.S.); (B.S.); (J.L.)
- McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Jiandong Liu
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA; (Y.S.); (B.S.); (J.L.)
- McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Li Qian
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA; (Y.S.); (B.S.); (J.L.)
- McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA
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Postberg J, Schubert MT, Nin V, Wagner L, Piefke M. A perspective on epigenomic aging processes in the human brain and their plasticity in patients with mental disorders - a systematic review. Neurogenetics 2024; 25:351-366. [PMID: 38967831 PMCID: PMC11534990 DOI: 10.1007/s10048-024-00771-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 06/28/2024] [Indexed: 07/06/2024]
Abstract
The debate surrounding nature versus nurture remains a central question in neuroscience, psychology, and in psychiatry, holding implications for both aging processes and the etiology of mental illness. Epigenetics can serve as a bridge between genetic predisposition and environmental influences, thus offering a potential avenue for addressing these questions. Epigenetic clocks, in particular, offer a theoretical framework for measuring biological age based on DNA methylation signatures, enabling the identification of disparities between biological and chronological age. This structured review seeks to consolidate current knowledge regarding the relationship between mental disorders and epigenetic age within the brain. Through a comprehensive literature search encompassing databases such as EBSCO, PubMed, and ClinicalTrials.gov, relevant studies were identified and analyzed. Studies that met inclusion criteria were scrutinized, focusing on those with large sample sizes, analyses of both brain tissue and blood samples, investigation of frontal cortex markers, and a specific emphasis on schizophrenia and depressive disorders. Our review revealed a paucity of significant findings, yet notable insights emerged from studies meeting specific criteria. Studies characterized by extensive sample sizes, analysis of brain tissue and blood samples, assessment of frontal cortex markers, and a focus on schizophrenia and depressive disorders yielded particularly noteworthy results. Despite the limited number of significant findings, these studies shed light on the complex interplay between epigenetic aging and mental illness. While the current body of literature on epigenetic aging in mental disorders presents limited significant findings, it underscores the importance of further research in this area. Future studies should prioritize large sample sizes, comprehensive analyses of brain tissue and blood samples, exploration of specific brain regions such as the frontal cortex, and a focus on key mental disorders. Such endeavors will contribute to a deeper understanding of the relationship between epigenetic aging and mental illness, potentially informing novel diagnostic and therapeutic approaches.
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Affiliation(s)
- Jan Postberg
- Clinical Molecular Genetics and Epigenetics, Faculty of Health, Witten/Herdecke University, Alfred-Herrhausen-Str. 50, 58448, Witten, Germany.
- Centre for Biomedical Education & Research (ZBAF), Witten/Herdecke University, Alfred-Herrhausen-Str. 50, 58448, Witten, Germany.
| | - Michèle Tina Schubert
- Neurobiology and Genetics of Behavior, Department of Psychology and Psychotherapy, Faculty of Health, Witten/Herdecke University, Alfred-Herrhausen-Str. 50, 58448, Witten, Germany
| | - Vincent Nin
- Neurobiology and Genetics of Behavior, Department of Psychology and Psychotherapy, Faculty of Health, Witten/Herdecke University, Alfred-Herrhausen-Str. 50, 58448, Witten, Germany
| | - Lukas Wagner
- Neurobiology and Genetics of Behavior, Department of Psychology and Psychotherapy, Faculty of Health, Witten/Herdecke University, Alfred-Herrhausen-Str. 50, 58448, Witten, Germany
| | - Martina Piefke
- Centre for Biomedical Education & Research (ZBAF), Witten/Herdecke University, Alfred-Herrhausen-Str. 50, 58448, Witten, Germany
- Neurobiology and Genetics of Behavior, Department of Psychology and Psychotherapy, Faculty of Health, Witten/Herdecke University, Alfred-Herrhausen-Str. 50, 58448, Witten, Germany
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Xie J, Lu ZN, Bai SH, Cui XF, Lian HY, Xie CY, Wang N, Wang L, Han ZG. Heterochromatin formation and remodeling by IRTKS condensates counteract cellular senescence. EMBO J 2024; 43:4542-4577. [PMID: 39192031 PMCID: PMC11480336 DOI: 10.1038/s44318-024-00212-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 06/30/2024] [Accepted: 07/16/2024] [Indexed: 08/29/2024] Open
Abstract
Heterochromatin, a key component of the eukaryotic nucleus, is fundamental to the regulation of genome stability, gene expression and cellular functions. However, the factors and mechanisms involved in heterochromatin formation and maintenance still remain largely unknown. Here, we show that insulin receptor tyrosine kinase substrate (IRTKS), an I-BAR domain protein, is indispensable for constitutive heterochromatin formation via liquid‒liquid phase separation (LLPS). In particular, IRTKS droplets can infiltrate heterochromatin condensates composed of HP1α and diverse DNA-bound nucleosomes. IRTKS can stabilize HP1α by recruiting the E2 ligase Ubc9 to SUMOylate HP1α, which enables it to form larger phase-separated droplets than unmodified HP1α. Furthermore, IRTKS deficiency leads to loss of heterochromatin, resulting in genome-wide changes in chromatin accessibility and aberrant transcription of repetitive DNA elements. This leads to activation of cGAS-STING pathway and type-I interferon (IFN-I) signaling, as well as to the induction of cellular senescence and senescence-associated secretory phenotype (SASP) responses. Collectively, our findings establish a mechanism by which IRTKS condensates consolidate constitutive heterochromatin, revealing an unexpected role of IRTKS as an epigenetic mediator of cellular senescence.
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Affiliation(s)
- Jia Xie
- Key Laboratory of Systems Biomedicine (Ministry of Education) and State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Zhao-Ning Lu
- Key Laboratory of Systems Biomedicine (Ministry of Education) and State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Shi-Hao Bai
- Key Laboratory of Systems Biomedicine (Ministry of Education) and State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Xiao-Fang Cui
- Key Laboratory of Systems Biomedicine (Ministry of Education) and State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - He-Yuan Lian
- Key Laboratory of Systems Biomedicine (Ministry of Education) and State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Chen-Yi Xie
- Key Laboratory of Systems Biomedicine (Ministry of Education) and State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Na Wang
- Key Laboratory of Systems Biomedicine (Ministry of Education) and State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Lan Wang
- Key Laboratory of Systems Biomedicine (Ministry of Education) and State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Ze-Guang Han
- Key Laboratory of Systems Biomedicine (Ministry of Education) and State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
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Liu Y, Fang M, Tu X, Mo X, Zhang L, Yang B, Wang F, Kim YB, Huang C, Chen L, Fan S. Dietary Polyphenols as Anti-Aging Agents: Targeting the Hallmarks of Aging. Nutrients 2024; 16:3305. [PMID: 39408272 PMCID: PMC11478989 DOI: 10.3390/nu16193305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 09/20/2024] [Accepted: 09/27/2024] [Indexed: 10/20/2024] Open
Abstract
Background: Aging is a natural biological process influenced by multiple factors and is a significant contributor to various chronic diseases. Slowing down the aging process and extending health span have been pursuits of the scientific field. Methods: Examination of the effects of dietary polyphenols on hallmarks of aging such as genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. Results: Polyphenols, abundant in nature, exhibit numerous biological activities, including antioxidant effects, free radical scavenging, neuroprotection, and anti-aging properties. These compounds are generally safe and effective in potentially slowing aging and preventing age-related disorders. Conclusions: The review encourages the development of novel therapeutic strategies using dietary polyphenols to create holistic anti-aging therapies and nutritional supplements.
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Affiliation(s)
- Ying Liu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (Y.L.); (C.H.)
| | - Minglv Fang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (Y.L.); (C.H.)
| | - Xiaohui Tu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (Y.L.); (C.H.)
| | - Xueying Mo
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (Y.L.); (C.H.)
| | - Lu Zhang
- Nutrilite Health Institute, Amway (Shanghai) Innovation and Science Co., Ltd., Shanghai 201203, China
| | - Binrui Yang
- Nutrilite Health Institute, Amway (Shanghai) Innovation and Science Co., Ltd., Shanghai 201203, China
| | - Feijie Wang
- Nutrilite Health Institute, Amway (Shanghai) Innovation and Science Co., Ltd., Shanghai 201203, China
| | - Young-Bum Kim
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
| | - Cheng Huang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (Y.L.); (C.H.)
| | - Liang Chen
- Nutrilite Health Institute, Amway (Shanghai) Innovation and Science Co., Ltd., Shanghai 201203, China
| | - Shengjie Fan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (Y.L.); (C.H.)
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Li X, Yu H, Li D, Liu N. LINE-1 transposable element renaissance in aging and age-related diseases. Ageing Res Rev 2024; 100:102440. [PMID: 39059477 DOI: 10.1016/j.arr.2024.102440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/16/2024] [Accepted: 07/24/2024] [Indexed: 07/28/2024]
Abstract
Transposable elements (TEs) are essential components of eukaryotic genomes and subject to stringent regulatory mechanisms to avoid their potentially deleterious effects. However, numerous studies have verified the resurrection of TEs, particularly long interspersed nuclear element-1 (LINE-1), during preimplantation development, aging, cancer, and other age-related diseases. The LINE-1 family has also been implicated in several aging-related processes, including genomic instability, loss of heterochromatin, DNA methylation, and the senescence-associated secretory phenotype (SASP). Additionally, the role of the LINE-1 family in cancer development has also been substantiated. Research in this field has offered valuable insights into the functional mechanisms underlying LINE-1 activity, enhancing our understanding of aging regulation. This review provides a comprehensive summary of current findings on LINE-1 and their roles in aging and age-related diseases.
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Affiliation(s)
- Xiang Li
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Huaxin Yu
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Dong Li
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Na Liu
- School of Medicine, Nankai University, Tianjin 300071, China.
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Zhao H, Zhao H, Ji S. A Mesenchymal stem cell Aging Framework, from Mechanisms to Strategies. Stem Cell Rev Rep 2024; 20:1420-1440. [PMID: 38727878 DOI: 10.1007/s12015-024-10732-4] [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] [Accepted: 05/02/2024] [Indexed: 08/13/2024]
Abstract
Mesenchymal stem cells (MSCs) are extensively researched for therapeutic applications in tissue engineering and show significant potential for clinical use. Intrinsic or extrinsic factors causing senescence may lead to reduced proliferation, aberrant differentiation, weakened immunoregulation, and increased inflammation, ultimately limiting the potential of MSCs. It is crucial to comprehend the molecular pathways and internal processes responsible for the decline in MSC function due to senescence in order to devise innovative approaches for rejuvenating senescent MSCs and enhancing MSC treatment. We investigate the main molecular processes involved in senescence, aiming to provide a thorough understanding of senescence-related issues in MSCs. Additionally, we analyze the most recent advancements in cutting-edge approaches to combat MSC senescence based on current research. We are curious whether the aging process of stem cells results in a permanent "memory" and if cellular reprogramming may potentially revert the aging epigenome to a more youthful state.
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Affiliation(s)
- Hongqing Zhao
- Nanbu County People's Hospital, Nanchong City, 637300, Sichuan Province, China
- Jinzhou Medical University, No.82 Songpo Road, Guta District, Jinzhou, 121001, Liaoning Province, China
| | - Houming Zhao
- Graduate School of PLA Medical College, Chinese PLA General Hospital, Beijing, 100083, China
| | - Shuaifei Ji
- Graduate School of PLA Medical College, Chinese PLA General Hospital, Beijing, 100083, China.
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47
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Zocher S. Targeting neuronal epigenomes for brain rejuvenation. EMBO J 2024; 43:3312-3326. [PMID: 39009672 PMCID: PMC11329789 DOI: 10.1038/s44318-024-00148-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 05/21/2024] [Accepted: 05/28/2024] [Indexed: 07/17/2024] Open
Abstract
Aging is associated with a progressive decline of brain function, and the underlying causes and possible interventions to prevent this cognitive decline have been the focus of intense investigation. The maintenance of neuronal function over the lifespan requires proper epigenetic regulation, and accumulating evidence suggests that the deterioration of the neuronal epigenetic landscape contributes to brain dysfunction during aging. Epigenetic aging of neurons may, however, be malleable. Recent reports have shown age-related epigenetic changes in neurons to be reversible and targetable by rejuvenation strategies that can restore brain function during aging. This review discusses the current evidence that identifies neuronal epigenetic aging as a driver of cognitive decline and a promising target of brain rejuvenation strategies, and it highlights potential approaches for the specific manipulation of the aging neuronal epigenome to restore a youthful epigenetic state in the brain.
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Affiliation(s)
- Sara Zocher
- German Center for Neurodegenerative Diseases, Tatzberg 41, 01307, Dresden, Germany.
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48
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Zhang M, Hu T, Ma T, Huang W, Wang Y. Epigenetics and environmental health. Front Med 2024; 18:571-596. [PMID: 38806988 DOI: 10.1007/s11684-023-1038-2] [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: 07/03/2023] [Accepted: 10/15/2023] [Indexed: 05/30/2024]
Abstract
Epigenetic modifications including DNA methylation, histone modifications, chromatin remodeling, and RNA modifications complicate gene regulation and heredity and profoundly impact various physiological and pathological processes. In recent years, accumulating evidence indicates that epigenetics is vulnerable to environmental changes and regulates the growth, development, and diseases of individuals by affecting chromatin activity and regulating gene expression. Environmental exposure or induced epigenetic changes can regulate the state of development and lead to developmental disorders, aging, cardiovascular disease, Alzheimer's disease, cancers, and so on. However, epigenetic modifications are reversible. The use of specific epigenetic inhibitors targeting epigenetic changes in response to environmental exposure is useful in disease therapy. Here, we provide an overview of the role of epigenetics in various diseases. Furthermore, we summarize the mechanism of epigenetic alterations induced by different environmental exposures, the influence of different environmental exposures, and the crosstalk between environmental variation epigenetics, and genes that are implicated in the body's health. However, the interaction of multiple factors and epigenetics in regulating the initiation and progression of various diseases complicates clinical treatments. We discuss some commonly used epigenetic drugs targeting epigenetic modifications and methods to prevent or relieve various diseases regulated by environmental exposure and epigenetics through diet.
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Affiliation(s)
- Min Zhang
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Ting Hu
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Tianyu Ma
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Wei Huang
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
| | - Yan Wang
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
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49
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Mei J, Ju C, Wang B, Gao R, Zhang Y, Zhou S, Liu E, Zhang L, Meng H, Liu Y, Zhao R, Zhao J, Zhang Y, Zeng W, Li J, Zhang P, Zhao J, Liu Y, Huan L, Huang Y, Zhu F, Liu H, Luo R, Yang Q, Gao S, Wang X, Fang Q, Lu Y, Dong Y, Yin X, Qiu P, Yang Q, Yang L, Xu F. The efficacy and safety of Bazi Bushen Capsule in treating premature aging: A randomized, double blind, multicenter, placebo-controlled clinical trial. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 130:155742. [PMID: 38838635 DOI: 10.1016/j.phymed.2024.155742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 04/17/2024] [Accepted: 05/14/2024] [Indexed: 06/07/2024]
Abstract
PURPOSE It is unclear whether traditional Chinese patent medicines can resist premature aging. This prospective study investigated the effects of Bazi Bushen Capsule (BZBS) which is a traditional Chinese patent medicine for tonifying the kidney essence on premature senility symptoms and quality of life, telomerase activity and telomere length. STUDY DESIGN AND METHODS It was a parallel, multicenter, double-blind, randomized, and placebo-controlled trial. Subjects (n = 530) aged 30-78 years were randomized to receive BZBS or placebo capsules 12 weeks. The primary outcome was the clinical feature of change in kidney deficiency for aging evaluation scale (CFCKD-AES) and tilburg frailty indicator (TFI). The secondary outcomes were SF-36, serum sex hormone level, five times sit-to-stand time (FTSST), 6MWT, motor function test-grip strength, balance test, walking speed, muscle mass measurement, telomerase and telomere length. RESULTS After 12 weeks of treatment, the CFCKD-AES and TFI scores in the BZBS group decreased by 13.79 and 1.50 respectively (6.42 and 0.58 in the placebo group, respectively); The SF-36 in the BZBS group increased by 98.38 (23.79 in the placebo group). The FTSST, motor function test grip strength, balance test, walking speed, and muscle mass in the elderly subgroup were all improved in the BZBS group. The telomerase content in the BZBS group increased by 150.04 ng/ml compared to the placebo group. The fever led one patient in the placebo group to discontinue the trial. One patient in the placebo group withdrew from the trial due to pregnancy. None of the serious AEs led to treatment discontinuation, and 3 AEs (1.14%) were assessed as related to BZBS by the primary investigator. CONCLUSIONS BZBS can improve premature aging symptoms, frailty scores, and quality of life, as well as improve FTSST, motor function: grip strength, balance test, walking speed, and muscle mass in elderly subgroups of patients, and enhance telomerase activity, but it is not significantly associated with increasing telomere length which is important for healthy aging. TRIAL REGISTRY https://www.chictr.org.cn/showproj.html?proj=166181.
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Affiliation(s)
- Jun Mei
- Institute of geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - Chunxiao Ju
- Institute of geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - Biqing Wang
- Institute of geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China; Graduate School, Beijing University of Chinese Medicine, Beijing, PR China
| | - Rui Gao
- Clinical Pharmacology Research Institute, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - Yanhong Zhang
- Institute of geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - Shunlin Zhou
- Department of Rehabilitation, Hebei Yiling Hospital, Shijiazhuang, 050000, PR China
| | - Erjun Liu
- Department of Traditional Chinese Medicine, The First Hospital of Hebei Medical University, Shijiazhuang, 050000, PR China
| | - Lirui Zhang
- Department of Traditional Chinese Medicine, Tangshan Central Hospital, Tangshan, 063000, PR China
| | - Hong Meng
- International school of cosmetics, Beijing Technology and Business University, Beijing, 100048, PR China
| | - Yafeng Liu
- Department of Traditional Chinese Medicine, Shenzhen Third People's Hospital, Shenzhen, 518112, PR China
| | - Ruihua Zhao
- Department of gynaecology, Guang'anmen Hospital China Academy of Chinese Medical Sciences, Beijing, 100053, PR China
| | - Jiajun Zhao
- Department of Traditional Chinese Medicine, Shandong Provincial Hospital, Jinan, 250021, PR China
| | - Ying Zhang
- Institute of geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - Wenying Zeng
- Institute of geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - Jing Li
- Institute of geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - Ping Zhang
- Institute of geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - Junnan Zhao
- Institute of geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - Yanfei Liu
- Institute of geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - Luyao Huan
- Institute of geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - Yuxiao Huang
- Department of gynaecology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - Fuli Zhu
- Department of gynaecology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - Huiyan Liu
- Department of gynaecology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - Ran Luo
- Department of gynaecology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - Qi Yang
- Department of gynaecology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - Shanfeng Gao
- Department of gynaecology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - Xiaoyuan Wang
- Department of gynaecology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - Qingxia Fang
- Department of gynaecology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - YuHong Lu
- LNKMED Tech Co., Ltd, Beijing, 100000, PR China
| | - Yan Dong
- LNKMED Tech Co., Ltd, Beijing, 100000, PR China
| | - Xueying Yin
- Clinical Pharmacology Research Institute, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - Panbo Qiu
- Clinical Pharmacology Research Institute, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - Qiaoning Yang
- Clinical Pharmacology Research Institute, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China
| | - Limin Yang
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Shijiazhuang, 050035, PR China
| | - Fengqin Xu
- Institute of geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, PR China.
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50
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Hu Q, Zhang B, Jing Y, Ma S, Hu L, Li J, Zheng Y, Xin Z, Peng J, Wang S, Cheng B, Qu J, Zhang W, Liu GH, Wang S. Single-nucleus transcriptomics uncovers a geroprotective role of YAP in primate gingival aging. Protein Cell 2024; 15:612-632. [PMID: 38577810 PMCID: PMC11259548 DOI: 10.1093/procel/pwae017] [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: 12/09/2023] [Accepted: 02/01/2024] [Indexed: 04/06/2024] Open
Abstract
Aging has a profound impact on the gingiva and significantly increases its susceptibility to periodontitis, a worldwide prevalent inflammatory disease. However, a systematic characterization and comprehensive understanding of the regulatory mechanism underlying gingival aging is still lacking. Here, we systematically dissected the phenotypic characteristics of gingiva during aging in primates and constructed the first single-nucleus transcriptomic landscape of gingival aging, by which a panel of cell type-specific signatures were elucidated. Epithelial cells were identified as the most affected cell types by aging in the gingiva. Further analyses pinpointed the crucial role of YAP in epithelial self-renew and homeostasis, which declined during aging in epithelial cells, especially in basal cells. The decline of YAP activity during aging was confirmed in the human gingival tissues, and downregulation of YAP in human primary gingival keratinocytes recapitulated the major phenotypic defects observed in the aged primate gingiva while overexpression of YAP showed rejuvenation effects. Our work provides an in-depth understanding of gingival aging and serves as a rich resource for developing novel strategies to combat aging-associated gingival diseases, with the ultimate goal of advancing periodontal health and promoting healthy aging.
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Affiliation(s)
- Qinchao Hu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510060, China
| | - Bin Zhang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yaobin Jing
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- International Center for Aging and Cancer, Hainan Medical University, Haikou 571199, China
| | - Shuai Ma
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- Aging Biomarker Consortium, Beijing 100101, China
| | - Lei Hu
- Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health and Beijing Stomatological Hospital, Capital Medical University, Beijing 100050, China
| | - Jingyi Li
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- Aging Biomarker Consortium, Beijing 100101, China
| | - Yandong Zheng
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zijuan Xin
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Jianmin Peng
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510060, China
| | - Si Wang
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuan Wu Hospital, Capital Medical University, Beijing 100053, China
- Aging Biomarker Consortium, Beijing 100101, China
| | - Bin Cheng
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510060, China
| | - Jing Qu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- Aging Biomarker Consortium, Beijing 100101, China
| | - Weiqi Zhang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Aging Biomarker Consortium, Beijing 100101, China
| | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuan Wu Hospital, Capital Medical University, Beijing 100053, China
- Aging Biomarker Consortium, Beijing 100101, China
| | - Songlin Wang
- Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health and Beijing Stomatological Hospital, Capital Medical University, Beijing 100050, China
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
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