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1
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Madreiter-Sokolowski CT, Hiden U, Krstic J, Panzitt K, Wagner M, Enzinger C, Khalil M, Abdellatif M, Malle E, Madl T, Osto E, Schosserer M, Binder CJ, Olschewski A. Targeting organ-specific mitochondrial dysfunction to improve biological aging. Pharmacol Ther 2024; 262:108710. [PMID: 39179117 DOI: 10.1016/j.pharmthera.2024.108710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 08/09/2024] [Accepted: 08/20/2024] [Indexed: 08/26/2024]
Abstract
In an aging society, unveiling new anti-aging strategies to prevent and combat aging-related diseases is of utmost importance. Mitochondria are the primary ATP production sites and key regulators of programmed cell death. Consequently, these highly dynamic organelles play a central role in maintaining tissue function, and mitochondrial dysfunction is a pivotal factor in the progressive age-related decline in cellular homeostasis and organ function. The current review examines recent advances in understanding the interplay between mitochondrial dysfunction and organ-specific aging. Thereby, we dissect molecular mechanisms underlying mitochondrial impairment associated with the deterioration of organ function, exploring the role of mitochondrial DNA, reactive oxygen species homeostasis, metabolic activity, damage-associated molecular patterns, biogenesis, turnover, and dynamics. We also highlight emerging therapeutic strategies in preclinical and clinical tests that are supposed to rejuvenate mitochondrial function, such as antioxidants, mitochondrial biogenesis stimulators, and modulators of mitochondrial turnover and dynamics. Furthermore, we discuss potential benefits and challenges associated with the use of these interventions, emphasizing the need for organ-specific approaches given the unique mitochondrial characteristics of different tissues. In conclusion, this review highlights the therapeutic potential of addressing mitochondrial dysfunction to mitigate organ-specific aging, focusing on the skin, liver, lung, brain, skeletal muscle, and lung, as well as on the reproductive, immune, and cardiovascular systems. Based on a comprehensive understanding of the multifaceted roles of mitochondria, innovative therapeutic strategies may be developed and optimized to combat biological aging and promote healthy aging across diverse organ systems.
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Affiliation(s)
| | - Ursula Hiden
- Department of Obstetrics and Gynecology, Research Unit of Early Life Determinants, Medical University of Graz, Austria
| | - Jelena Krstic
- Division of Cell Biology, Histology and Embryology, Medical University of Graz, BioTechMed-Graz, Austria
| | - Katrin Panzitt
- Diagnostic and Research Institute of Pathology, Medical University of Graz, Austria
| | - Martin Wagner
- Division of Gastroenterology and Hepatology, Medical University of Graz, Austria
| | | | - Michael Khalil
- Department of Neurology, Medical University of Graz, Austria
| | - Mahmoud Abdellatif
- Division of Cardiology, Medical University of Graz, BioTechMed-Graz, Austria
| | - Ernst Malle
- Division of Molecular Biology and Biochemistry, Medical University of Graz, BioTechMed-Graz, Austria
| | - Tobias Madl
- Division of Medicinal Chemistry, Medical University of Graz, BioTechMed-Graz, Austria
| | - Elena Osto
- Division of Physiology and Pathophysiology, Medical University of Graz
| | - Markus Schosserer
- Center for Pathobiochemistry and Genetics, Medical University of Vienna, Austria; Christian Doppler Laboratory for Skin Multimodal Imaging of Aging and Senescence, Austria
| | - Christoph J Binder
- Department of Laboratory Medicine, Medical University of Vienna, Austria
| | - Andrea Olschewski
- Department of Anesthesiology and Intensive Care Medicine, LBI for Lung Vascular Research, Medical University of Graz, Austria.
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2
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Viña J, Borrás C. Unlocking the biochemical secrets of longevity: balancing healthspan and lifespan. FEBS Lett 2024; 598:2135-2144. [PMID: 38956807 DOI: 10.1002/1873-3468.14963] [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: 04/22/2024] [Revised: 06/04/2024] [Accepted: 06/05/2024] [Indexed: 07/04/2024]
Abstract
In an era of rising global life expectancies, research focuses on enhancing the quality of extended years. This review examines the link between mitochondrial function and aging, highlighting the importance of healthspan alongside lifespan. This involves significant human and economic challenges, with longer lifespans often accompanied by reduced well-being. Addressing mitochondrial decline, exploring targeted interventions, and understanding the complexities of research models are vital for advancing our knowledge in this field. Additionally, promoting physical exercise and adopting personalized supplementation strategies based on individual needs can contribute to healthy aging. The insights from this Perspective article offer a hopeful outlook for future advances in extending both lifespan and healthspan, aiming to improve the overall quality of life in aging populations.
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Affiliation(s)
- Jose Viña
- Freshage Research Group, Department of Physiology, Faculty of Medicine, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), Institute of Health Research-INCLIVA, University of Valencia, Spain
| | - Consuelo Borrás
- Freshage Research Group, Department of Physiology, Faculty of Medicine, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), Institute of Health Research-INCLIVA, University of Valencia, Spain
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3
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Ramatchandirin B, Iijima M, Ikeda A, Pearah A, Radovick S, Wondisford FE, Sesaki H, He L. Protocol for measuring mitochondrial size in mouse and human liver tissues. STAR Protoc 2024; 5:102842. [PMID: 38244201 PMCID: PMC10831311 DOI: 10.1016/j.xpro.2024.102842] [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: 10/23/2023] [Revised: 12/10/2023] [Accepted: 01/05/2024] [Indexed: 01/22/2024] Open
Abstract
Mitochondrial dynamic process is important for cell viability, metabolic activity, and mitochondria health. Here, we present a protocol for measuring mitochondrial size through immunofluorescence staining, confocal imaging, and analysis in ImageJ. We describe the steps for tissue processing, antigen retrieval, mitochondrial staining using an integrating immunofluorescence assay, and computerized image analysis to measure each mitochondrial size in mouse and human liver tissues. This protocol reduces tissue sample volume and processing time for the preparation of primary cells. For complete details on the use and execution of this protocol, please refer to Pearah et al.1.
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Affiliation(s)
| | - Miho Iijima
- Departments of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Arisa Ikeda
- Departments of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Alexia Pearah
- Departments of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Sally Radovick
- Institute of Clinical Translational Sciences, University of Arizona, Tucson, AZ 85721, USA
| | - Fredric E Wondisford
- Departments of Internal Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA
| | - Hiromi Sesaki
- Departments of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
| | - Ling He
- Departments of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Departments of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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4
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Aging Biomarker Consortium, Jiang M, Zheng Z, Wang X, Chen Y, Qu J, Ding Q, Zhang W, Liu YS, Yang J, Tang W, Hou Y, He J, Wang L, Huang P, Li LC, He Z, Gao Q, Lu Q, Wei L, Wang YJ, Ju Z, Fan JG, Ruan XZ, Guan Y, Liu GH, Pei G, Li J, Wang Y. A biomarker framework for liver aging: the Aging Biomarker Consortium consensus statement. LIFE MEDICINE 2024; 3:lnae004. [PMID: 39872390 PMCID: PMC11749002 DOI: 10.1093/lifemedi/lnae004] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 01/29/2024] [Indexed: 01/11/2025]
Abstract
In human aging, liver aging per se not only increases susceptibility to liver diseases but also increases vulnerability of other organs given its central role in regulating metabolism. Total liver function tends to be well maintained in the healthy elderly, so liver aging is generally difficult to identify early. In response to this critical challenge, the Aging Biomarker Consortium of China has formulated an expert consensus on biomarkers of liver aging by synthesizing the latest scientific literature, comprising insights from both scientists and clinicians. This consensus provides a comprehensive assessment of biomarkers associated with liver aging and presents a systematic framework to characterize these into three dimensions: functional, imaging, and humoral. For the functional domain, we highlight biomarkers associated with cholesterol metabolism and liver-related coagulation function. For the imaging domain, we note that hepatic steatosis and liver blood flow can serve as measurable biomarkers for liver aging. Finally, in the humoral domain, we pinpoint hepatokines and enzymatic alterations worthy of attention. The aim of this expert consensus is to establish a foundation for assessing the extent of liver aging and identify early signs of liver aging-related diseases, thereby improving liver health and the healthy life expectancy of the elderly population.
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Affiliation(s)
| | - Mengmeng Jiang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
| | - Zhuozhao Zheng
- Department of Radiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Xuan Wang
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Yanhao Chen
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Jing Qu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Qiurong Ding
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, 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
| | - You-Shuo Liu
- Department of Geriatrics, the Second Xiangya Hospital, and the Institute of Aging and Geriatrics, Central South University, Changsha 410011, China
| | - Jichun Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
| | - Weiqing Tang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, China
| | - Yunlong Hou
- Yiling Pharmaceutical Academician Workstation, Shijiazhuang 050035, China
| | - Jinhan He
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Pengyu Huang
- State Key Laboratory of Advanced Medical Materials and Devices, Engineering Research Center of Pulmonary and Critical Care Medicine Technology and Device (Ministry of Education), Institute of Biomedical Engineering, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300192, China
| | - Lin-Chen Li
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China
| | - Zhiying He
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200092, China
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Qian Lu
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
- Key Laboratory of Digital Intelligence Hepatology (Ministry of Education), School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Lai Wei
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Yan-Jiang Wang
- Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Zhenyu Ju
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China
| | - Jian-Gao Fan
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xiong Zhong Ruan
- Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Youfei Guan
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Gang Pei
- Collaborative Innovation Center for Brain Science, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Jian Li
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, China
| | - Yunfang Wang
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China
- Key Laboratory of Digital Intelligence Hepatology (Ministry of Education), School of Clinical Medicine, Tsinghua University, Beijing 102218, China
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing 102218, China
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5
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Ouyang Y, Jeong MY, Cunningham CN, Berg JA, Toshniwal AG, Hughes CE, Seiler K, Van Vranken JG, Cluntun AA, Lam G, Winter JM, Akdogan E, Dove KK, Nowinski SM, West M, Odorizzi G, Gygi SP, Dunn CD, Winge DR, Rutter J. Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms. eLife 2024; 13:e84282. [PMID: 38251707 PMCID: PMC10846858 DOI: 10.7554/elife.84282] [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: 10/18/2022] [Accepted: 01/19/2024] [Indexed: 01/23/2024] Open
Abstract
Mitochondrial membrane potential directly powers many critical functions of mitochondria, including ATP production, mitochondrial protein import, and metabolite transport. Its loss is a cardinal feature of aging and mitochondrial diseases, and cells closely monitor membrane potential as an indicator of mitochondrial health. Given its central importance, it is logical that cells would modulate mitochondrial membrane potential in response to demand and environmental cues, but there has been little exploration of this question. We report that loss of the Sit4 protein phosphatase in yeast increases mitochondrial membrane potential, both by inducing the electron transport chain and the phosphate starvation response. Indeed, a similarly elevated mitochondrial membrane potential is also elicited simply by phosphate starvation or by abrogation of the Pho85-dependent phosphate sensing pathway. This enhanced membrane potential is primarily driven by an unexpected activity of the ADP/ATP carrier. We also demonstrate that this connection between phosphate limitation and enhancement of mitochondrial membrane potential is observed in primary and immortalized mammalian cells as well as in Drosophila. These data suggest that mitochondrial membrane potential is subject to environmental stimuli and intracellular signaling regulation and raise the possibility for therapeutic enhancement of mitochondrial function even in defective mitochondria.
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Affiliation(s)
- Yeyun Ouyang
- Department of Biochemistry, The University of UtahSalt Lake CityUnited States
| | - Mi-Young Jeong
- Department of Biochemistry, The University of UtahSalt Lake CityUnited States
| | - Corey N Cunningham
- Department of Biochemistry, The University of UtahSalt Lake CityUnited States
| | - Jordan A Berg
- Department of Biochemistry, The University of UtahSalt Lake CityUnited States
| | - Ashish G Toshniwal
- Department of Biochemistry, The University of UtahSalt Lake CityUnited States
| | - Casey E Hughes
- Department of Biochemistry, The University of UtahSalt Lake CityUnited States
| | - Kristina Seiler
- Department of Biochemistry, The University of UtahSalt Lake CityUnited States
| | | | - Ahmad A Cluntun
- Department of Biochemistry, The University of UtahSalt Lake CityUnited States
| | - Geanette Lam
- Department of Biochemistry, The University of UtahSalt Lake CityUnited States
| | - Jacob M Winter
- Department of Biochemistry, The University of UtahSalt Lake CityUnited States
| | - Emel Akdogan
- Department of Molecular Biology and Genetics, Koç UniversityİstanbulTurkey
| | - Katja K Dove
- Department of Biochemistry, The University of UtahSalt Lake CityUnited States
| | - Sara M Nowinski
- Department of Biochemistry, The University of UtahSalt Lake CityUnited States
| | - Matthew West
- Department of Molecular, Cellular, and Developmental Biology, University of Colorado, BoulderBoulderUnited States
| | - Greg Odorizzi
- Department of Molecular, Cellular, and Developmental Biology, University of Colorado, BoulderBoulderUnited States
| | - Steven P Gygi
- Department of Cell Biology, Harvard University School of MedicineBostonUnited States
| | - Cory D Dunn
- Department of Molecular Biology and Genetics, Koç UniversityİstanbulTurkey
- Institute of Biotechnology, University of HelsinkiHelsinkiFinland
| | - Dennis R Winge
- Department of Biochemistry, The University of UtahSalt Lake CityUnited States
- Department of Medicine, The University of UtahSalt Lake CityUnited States
| | - Jared Rutter
- Department of Biochemistry, The University of UtahSalt Lake CityUnited States
- Howard Hughes Medical Institute, University of UtahSalt Lake CityUnited States
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6
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Adhikary S, Esmeeta A, Dey A, Banerjee A, Saha B, Gopan P, Duttaroy AK, Pathak S. Impacts of gut microbiota alteration on age-related chronic liver diseases. Dig Liver Dis 2024; 56:112-122. [PMID: 37407321 DOI: 10.1016/j.dld.2023.06.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 06/08/2023] [Accepted: 06/20/2023] [Indexed: 07/07/2023]
Abstract
The gut microbiome and its metabolites are involved in developing and progressing liver disease. Various liver illnesses, such as non-alcoholic fatty liver disease, alcoholic liver disease, hepatitis C, and hepatocellular carcinoma, are made worse and have worse prognoses with aging. Dysbiosis, which occurs when the symbiosis between the microbiota and the host is disrupted, can significantly negatively impact health. Liver disease is linked to qualitative changes, such as an increase in hazardous bacteria and a decrease in good bacteria, as well as quantitative changes in the overall amount of bacteria (overgrowth). Intestinal gut microbiota and their metabolites may lead to chronic liver disease development through various mechanisms, such as increasing gut permeability, persistent systemic inflammation, production of SCFA, bile acids, and alteration in metabolism. Age-related gut dysbiosis can disrupt the communication between gut microbiota and the host, impacting the host's health and lifespan. With aging, a gradual loss of the ability to maintain homeostasis because of structural alteration and gut dysbiosis leads to the disease progression in end-stage liver disease. Recently chronic liver disease has been identified as a global problem. A large number of patients are receiving liver transplants yearly. Thereby gut microbiome ecology is changing in the patients of the gut due to the changes in pathophysiology during the preoperative stage. The present review summarises the age-associated dysbiosis of gut microbial composition and its contribution to chronic liver disease. This review also provides information about the impact of liver transplant on the gut microbiome and possible disadvantageous effects of alteration in gut microbiota.
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Affiliation(s)
- Subhamay Adhikary
- Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education(CARE), Department of Medical Biotechnology, Faculty of Allied Health Sciences, Kelambakkam 603103, India
| | - Akanksha Esmeeta
- Amity Institute of Biotechnology, Amity University, Sector 125, Noida, Uttar Pradesh 201301, India
| | - Amit Dey
- Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education(CARE), Department of Medical Biotechnology, Faculty of Allied Health Sciences, Kelambakkam 603103, India
| | - Antara Banerjee
- Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education(CARE), Department of Medical Biotechnology, Faculty of Allied Health Sciences, Kelambakkam 603103, India
| | - Biki Saha
- Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education(CARE), Department of Medical Biotechnology, Faculty of Allied Health Sciences, Kelambakkam 603103, India
| | - Pournami Gopan
- Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education(CARE), Department of Medical Biotechnology, Faculty of Allied Health Sciences, Kelambakkam 603103, India
| | - Asim K Duttaroy
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Norway.
| | - Surajit Pathak
- Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education(CARE), Department of Medical Biotechnology, Faculty of Allied Health Sciences, Kelambakkam 603103, India.
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7
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Pearah A, Ramatchandirin B, Liu T, Wolf RM, Ikeda A, Radovick S, Sesaki H, Wondisford FE, O'Rourke B, He L. Blocking AMPKαS496 phosphorylation improves mitochondrial dynamics and hyperglycemia in aging and obesity. Cell Chem Biol 2023; 30:1585-1600.e6. [PMID: 37890479 PMCID: PMC10841824 DOI: 10.1016/j.chembiol.2023.09.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 08/23/2023] [Accepted: 09/28/2023] [Indexed: 10/29/2023]
Abstract
Impaired mitochondrial dynamics causes aging-related or metabolic diseases. Yet, the molecular mechanism responsible for the impairment of mitochondrial dynamics is still not well understood. Here, we report that elevated blood insulin and/or glucagon levels downregulate mitochondrial fission through directly phosphorylating AMPKα at S496 by AKT or PKA, resulting in the impairment of AMPK-MFF-DRP1 signaling and mitochondrial dynamics and activity. Since there are significantly increased AMPKα1 phosphorylation at S496 in the liver of elderly mice, obese mice, and obese patients, we, therefore, designed AMPK-specific targeting peptides (Pa496m and Pa496h) to block AMPKα1S496 phosphorylation and found that these targeting peptides can increase AMPK kinase activity, augment mitochondrial fission and oxidation, and reduce ROS, leading to the rejuvenation of mitochondria. Furthermore, these AMPK targeting peptides robustly suppress liver glucose production in obese mice. Our data suggest these targeting peptides are promising therapeutic agents for improving mitochondrial dynamics and activity and alleviating hyperglycemia in elderly and obese patients.
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Affiliation(s)
- Alexia Pearah
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | | | - Ting Liu
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Risa M Wolf
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Arisa Ikeda
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Sally Radovick
- Departments of Pediatrics and Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
| | - Hiromi Sesaki
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Fredric E Wondisford
- Departments of Pediatrics and Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
| | - Brian O'Rourke
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Ling He
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Departments of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
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8
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Nikopoulou C, Kleinenkuhnen N, Parekh S, Sandoval T, Ziegenhain C, Schneider F, Giavalisco P, Donahue KF, Vesting AJ, Kirchner M, Bozukova M, Vossen C, Altmüller J, Wunderlich T, Sandberg R, Kondylis V, Tresch A, Tessarz P. Spatial and single-cell profiling of the metabolome, transcriptome and epigenome of the aging mouse liver. NATURE AGING 2023; 3:1430-1445. [PMID: 37946043 PMCID: PMC10645594 DOI: 10.1038/s43587-023-00513-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 09/27/2023] [Indexed: 11/12/2023]
Abstract
Tissues within an organism and even cell types within a tissue can age with different velocities. However, it is unclear whether cells of one type experience different aging trajectories within a tissue depending on their spatial location. Here, we used spatial transcriptomics in combination with single-cell ATAC-seq and RNA-seq, lipidomics and functional assays to address how cells in the male murine liver are affected by age-related changes in the microenvironment. Integration of the datasets revealed zonation-specific and age-related changes in metabolic states, the epigenome and transcriptome. The epigenome changed in a zonation-dependent manner and functionally, periportal hepatocytes were characterized by decreased mitochondrial fitness, whereas pericentral hepatocytes accumulated large lipid droplets. Together, we provide evidence that changing microenvironments within a tissue exert strong influences on their resident cells that can shape epigenetic, metabolic and phenotypic outputs.
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Affiliation(s)
- Chrysa Nikopoulou
- Max Planck Research Group 'Chromatin and Ageing', Max Planck Institute for Biology of Ageing, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Cologne, Germany
| | - Niklas Kleinenkuhnen
- Max Planck Research Group 'Chromatin and Ageing', Max Planck Institute for Biology of Ageing, Cologne, Germany
- Institute of Medical Statistics and Computational Biology, Faculty of Medicine, University of Cologne, Cologne, Germany
| | - Swati Parekh
- Max Planck Research Group 'Chromatin and Ageing', Max Planck Institute for Biology of Ageing, Cologne, Germany
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma, Biberach, Germany
| | - Tonantzi Sandoval
- Max Planck Research Group 'Chromatin and Ageing', Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Christoph Ziegenhain
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Farina Schneider
- Institute for Pathology, University Hospital Cologne, Cologne, Germany
| | - Patrick Giavalisco
- Metabolic Core Facility, Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Kat-Folz Donahue
- FACS and Imaging Core Facility, Max Planck Institute for Biology of Ageing, Cologne, Germany
| | | | - Marcel Kirchner
- FACS and Imaging Core Facility, Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Mihaela Bozukova
- Max Planck Research Group 'Chromatin and Ageing', Max Planck Institute for Biology of Ageing, Cologne, Germany
| | | | - Janine Altmüller
- Cologne Center for Genomics, University of Cologne, Cologne, Germany; Berlin Institute of Health at Charité, Core Facility Genomics, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Thomas Wunderlich
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Cologne, Germany
- Max Planck Institute for Metabolism Research, Cologne, Germany
| | - Rickard Sandberg
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Vangelis Kondylis
- Institute for Pathology, University Hospital Cologne, Cologne, Germany
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany
| | - Achim Tresch
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Cologne, Germany.
- Institute of Medical Statistics and Computational Biology, Faculty of Medicine, University of Cologne, Cologne, Germany.
| | - Peter Tessarz
- Max Planck Research Group 'Chromatin and Ageing', Max Planck Institute for Biology of Ageing, Cologne, Germany.
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Cologne, Germany.
- Department of Human Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
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9
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Ge T, Shao Y, Bao X, Xu W, Lu C. Cellular senescence in liver diseases: From mechanisms to therapies. Int Immunopharmacol 2023; 121:110522. [PMID: 37385123 DOI: 10.1016/j.intimp.2023.110522] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 06/05/2023] [Accepted: 06/14/2023] [Indexed: 07/01/2023]
Abstract
Cellular senescence is an irreversible state of cell cycle arrest, characterized by a gradual decline in cell proliferation, differentiation, and biological functions. Cellular senescence is double-edged for that it can provoke organ repair and regeneration in physiological conditions but contribute to organ and tissue dysfunction and prime multiple chronic diseases in pathological conditions. The liver has a strong regenerative capacity, where cellular senescence and regeneration are closely involved. Herein, this review firstly introduces the morphological manifestations of senescent cells, the major regulators (p53, p21, and p16), and the core pathophysiologic mechanisms underlying senescence process, and then specifically generalizes the role and interventions of cellular senescence in multiple liver diseases, including alcoholic liver disease, nonalcoholic fatty liver disease, liver fibrosis, and hepatocellular carcinoma. In conclusion, this review focuses on interpreting the importance of cellular senescence in liver diseases and summarizes potential senescence-related regulatory targets, aiming to provide new insights for further researches on cellular senescence regulation and therapeutic developments for liver diseases.
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Affiliation(s)
- Ting Ge
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Yunyun Shao
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Xiaofeng Bao
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Wenxuan Xu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China.
| | - Chunfeng Lu
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China.
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10
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Bao H, Cao J, Chen M, Chen M, Chen W, Chen X, Chen Y, Chen Y, Chen Y, Chen Z, Chhetri JK, Ding Y, Feng J, Guo J, Guo M, He C, Jia Y, Jiang H, Jing Y, Li D, Li J, Li J, Liang Q, Liang R, Liu F, Liu X, Liu Z, Luo OJ, Lv J, Ma J, Mao K, Nie J, Qiao X, Sun X, Tang X, Wang J, Wang Q, Wang S, Wang X, Wang Y, Wang Y, Wu R, Xia K, Xiao FH, Xu L, Xu Y, Yan H, Yang L, Yang R, Yang Y, Ying Y, Zhang L, Zhang W, Zhang W, Zhang X, Zhang Z, Zhou M, Zhou R, Zhu Q, Zhu Z, Cao F, Cao Z, Chan P, Chen C, Chen G, Chen HZ, Chen J, Ci W, Ding BS, Ding Q, Gao F, Han JDJ, Huang K, Ju Z, Kong QP, Li J, Li J, Li X, Liu B, Liu F, Liu L, Liu Q, Liu Q, Liu X, Liu Y, Luo X, Ma S, Ma X, Mao Z, Nie J, Peng Y, Qu J, Ren J, Ren R, Song M, Songyang Z, Sun YE, Sun Y, Tian M, Wang S, et alBao H, Cao J, Chen M, Chen M, Chen W, Chen X, Chen Y, Chen Y, Chen Y, Chen Z, Chhetri JK, Ding Y, Feng J, Guo J, Guo M, He C, Jia Y, Jiang H, Jing Y, Li D, Li J, Li J, Liang Q, Liang R, Liu F, Liu X, Liu Z, Luo OJ, Lv J, Ma J, Mao K, Nie J, Qiao X, Sun X, Tang X, Wang J, Wang Q, Wang S, Wang X, Wang Y, Wang Y, Wu R, Xia K, Xiao FH, Xu L, Xu Y, Yan H, Yang L, Yang R, Yang Y, Ying Y, Zhang L, Zhang W, Zhang W, Zhang X, Zhang Z, Zhou M, Zhou R, Zhu Q, Zhu Z, Cao F, Cao Z, Chan P, Chen C, Chen G, Chen HZ, Chen J, Ci W, Ding BS, Ding Q, Gao F, Han JDJ, Huang K, Ju Z, Kong QP, Li J, Li J, Li X, Liu B, Liu F, Liu L, Liu Q, Liu Q, Liu X, Liu Y, Luo X, Ma S, Ma X, Mao Z, Nie J, Peng Y, Qu J, Ren J, Ren R, Song M, Songyang Z, Sun YE, Sun Y, Tian M, Wang S, Wang S, Wang X, Wang X, Wang YJ, Wang Y, Wong CCL, Xiang AP, Xiao Y, Xie Z, Xu D, Ye J, Yue R, Zhang C, Zhang H, Zhang L, Zhang W, Zhang Y, Zhang YW, Zhang Z, Zhao T, Zhao Y, Zhu D, Zou W, Pei G, Liu GH. Biomarkers of aging. SCIENCE CHINA. LIFE SCIENCES 2023; 66:893-1066. [PMID: 37076725 PMCID: PMC10115486 DOI: 10.1007/s11427-023-2305-0] [Show More Authors] [Citation(s) in RCA: 167] [Impact Index Per Article: 83.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 02/27/2023] [Indexed: 04/21/2023]
Abstract
Aging biomarkers are a combination of biological parameters to (i) assess age-related changes, (ii) track the physiological aging process, and (iii) predict the transition into a pathological status. Although a broad spectrum of aging biomarkers has been developed, their potential uses and limitations remain poorly characterized. An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research: How old are we? Why do we get old? And how can we age slower? This review aims to address this need. Here, we summarize our current knowledge of biomarkers developed for cellular, organ, and organismal levels of aging, comprising six pillars: physiological characteristics, medical imaging, histological features, cellular alterations, molecular changes, and secretory factors. To fulfill all these requisites, we propose that aging biomarkers should qualify for being specific, systemic, and clinically relevant.
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Affiliation(s)
- Hainan Bao
- 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
| | - Jiani Cao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Mengting Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Min Chen
- Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Clinical Research Center of Metabolic and Cardiovascular Disease, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Wei Chen
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Xiao Chen
- Department of Nuclear Medicine, Daping Hospital, Third Military Medical University, Chongqing, 400042, China
| | - Yanhao Chen
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yu Chen
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Yutian Chen
- The Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Zhiyang Chen
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Ageing and Regenerative Medicine, Jinan University, Guangzhou, 510632, China
| | - Jagadish K Chhetri
- National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Yingjie Ding
- 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
| | - Junlin Feng
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Jun Guo
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China
| | - Mengmeng Guo
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China
| | - Chuting He
- University of Chinese Academy of Sciences, Beijing, 100049, China
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Yujuan Jia
- Department of Neurology, First Affiliated Hospital, Shanxi Medical University, Taiyuan, 030001, China
| | - Haiping Jiang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Ying Jing
- Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
| | - Dingfeng Li
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, China
| | - Jiaming Li
- 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
| | - Jingyi Li
- University of Chinese Academy of Sciences, Beijing, 100049, China
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Qinhao Liang
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430072, China
| | - Rui Liang
- Research Institute of Transplant Medicine, Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, 300384, China
| | - Feng Liu
- MOE Key Laboratory of Gene Function and Regulation, Guangzhou Key Laboratory of Healthy Aging Research, School of Life Sciences, Institute of Healthy Aging Research, Sun Yat-sen University, Guangzhou, 510275, China
| | - Xiaoqian Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Zuojun Liu
- School of Life Sciences, Hainan University, Haikou, 570228, China
| | - Oscar Junhong Luo
- Department of Systems Biomedical Sciences, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Jianwei Lv
- School of Life Sciences, Xiamen University, Xiamen, 361102, China
| | - Jingyi Ma
- The State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Kehang Mao
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology (CQB), Peking University, Beijing, 100871, China
| | - Jiawei Nie
- Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine (Shanghai), International Center for Aging and Cancer, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xinhua Qiao
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Xinpei Sun
- Peking University International Cancer Institute, Health Science Center, Peking University, Beijing, 100101, China
| | - Xiaoqiang Tang
- 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
| | - Jianfang Wang
- Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Qiaoran Wang
- 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
| | - Siyuan Wang
- Clinical Research Institute, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China
| | - Xuan Wang
- Hepatobiliary and Pancreatic Center, Medical Research Center, Beijing Tsinghua Changgung Hospital, Beijing, 102218, China
| | - Yaning Wang
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Yuhan Wang
- University of Chinese Academy of Sciences, Beijing, 100049, China
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Rimo Wu
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, 510005, China
| | - Kai Xia
- Center for Stem Cell Biologyand Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, 510080, China
- National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Fu-Hui Xiao
- CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China
- State Key Laboratory of Genetic Resources and Evolution, Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Key Laboratory of Healthy Aging Study, KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
| | - Lingyan Xu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Yingying Xu
- 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
| | - Haoteng Yan
- Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
| | - Liang Yang
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, 510530, China
| | - Ruici Yang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yuanxin Yang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China
| | - Yilin Ying
- Department of Geriatrics, Medical Center on Aging of Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- International Laboratory in Hematology and Cancer, Shanghai Jiao Tong University School of Medicine/Ruijin Hospital, Shanghai, 200025, China
| | - Le Zhang
- Gerontology Center of Hubei Province, Wuhan, 430000, China
- Institute of Gerontology, Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Weiwei Zhang
- Department of Cardiology, The Second Medical Centre, Chinese PLA General Hospital, National Clinical Research Center for Geriatric Diseases, Beijing, 100853, China
| | - Wenwan Zhang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Xing Zhang
- Key Laboratory of Ministry of Education, School of Aerospace Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Zhuo Zhang
- Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
- Research Unit of New Techniques for Live-cell Metabolic Imaging, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Min Zhou
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, 410008, China
| | - Rui Zhou
- Department of Nuclear Medicine and PET Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - Qingchen Zhu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Zhengmao Zhu
- Department of Genetics and Cell Biology, College of Life Science, Nankai University, Tianjin, 300071, China
- Haihe Laboratory of Cell Ecosystem, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Feng Cao
- Department of Cardiology, The Second Medical Centre, Chinese PLA General Hospital, National Clinical Research Center for Geriatric Diseases, Beijing, 100853, China.
| | - Zhongwei Cao
- State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
| | - Piu Chan
- National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
| | - Chang Chen
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Guobing Chen
- Department of Microbiology and Immunology, School of Medicine, Jinan University, Guangzhou, 510632, China.
- Guangdong-Hong Kong-Macau Great Bay Area Geroscience Joint Laboratory, Guangzhou, 510000, China.
| | - Hou-Zao Chen
- Department of Biochemistryand Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China.
| | - Jun Chen
- Peking University Research Center on Aging, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Department of Integration of Chinese and Western Medicine, School of Basic Medical Science, Peking University, Beijing, 100191, China.
| | - Weimin Ci
- 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.
| | - Bi-Sen Ding
- State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
| | - Qiurong Ding
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Feng Gao
- Key Laboratory of Ministry of Education, School of Aerospace Medicine, Fourth Military Medical University, Xi'an, 710032, China.
| | - Jing-Dong J Han
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology (CQB), Peking University, Beijing, 100871, China.
| | - Kai Huang
- Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Clinical Research Center of Metabolic and Cardiovascular Disease, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Zhenyu Ju
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Ageing and Regenerative Medicine, Jinan University, Guangzhou, 510632, China.
| | - Qing-Peng Kong
- CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China.
- State Key Laboratory of Genetic Resources and Evolution, Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Key Laboratory of Healthy Aging Study, KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
| | - Ji Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Jian Li
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China.
| | - Xin Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Baohua Liu
- School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen, 518060, China.
| | - Feng Liu
- Metabolic Syndrome Research Center, The Second Xiangya Hospital, Central South Unversity, Changsha, 410011, China.
| | - Lin Liu
- Department of Genetics and Cell Biology, College of Life Science, Nankai University, Tianjin, 300071, China.
- Haihe Laboratory of Cell Ecosystem, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
- Institute of Translational Medicine, Tianjin Union Medical Center, Nankai University, Tianjin, 300000, China.
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300350, China.
| | - Qiang Liu
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, China.
| | - Qiang Liu
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.
- Tianjin Institute of Immunology, Tianjin Medical University, Tianjin, 300070, China.
| | - Xingguo Liu
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, 510530, China.
| | - Yong Liu
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430072, China.
| | - Xianghang Luo
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, 410008, China.
| | - Shuai Ma
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Xinran Ma
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
| | - Zhiyong Mao
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
| | - Jing Nie
- The State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Yaojin Peng
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Jing Qu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Jie Ren
- 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.
| | - Ruibao Ren
- Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine (Shanghai), International Center for Aging and Cancer, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- International Center for Aging and Cancer, Hainan Medical University, Haikou, 571199, China.
| | - Moshi Song
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Zhou Songyang
- MOE Key Laboratory of Gene Function and Regulation, Guangzhou Key Laboratory of Healthy Aging Research, School of Life Sciences, Institute of Healthy Aging Research, Sun Yat-sen University, Guangzhou, 510275, China.
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
| | - Yi Eve Sun
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
| | - Yu Sun
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.
- Department of Medicine and VAPSHCS, University of Washington, Seattle, WA, 98195, USA.
| | - Mei Tian
- Human Phenome Institute, Fudan University, Shanghai, 201203, China.
| | - Shusen Wang
- Research Institute of Transplant Medicine, Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, 300384, China.
| | - Si Wang
- Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
| | - Xia Wang
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.
| | - Xiaoning Wang
- Institute of Geriatrics, The second Medical Center, Beijing Key Laboratory of Aging and Geriatrics, National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100853, China.
| | - Yan-Jiang Wang
- Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, 400042, China.
| | - Yunfang Wang
- Hepatobiliary and Pancreatic Center, Medical Research Center, Beijing Tsinghua Changgung Hospital, Beijing, 102218, China.
| | - Catherine C L Wong
- Clinical Research Institute, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China.
| | - Andy Peng Xiang
- Center for Stem Cell Biologyand Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, 510080, China.
- National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
| | - Yichuan Xiao
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Zhengwei Xie
- Peking University International Cancer Institute, Health Science Center, Peking University, Beijing, 100101, China.
- Beijing & Qingdao Langu Pharmaceutical R&D Platform, Beijing Gigaceuticals Tech. Co. Ltd., Beijing, 100101, China.
| | - Daichao Xu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China.
| | - Jing Ye
- Department of Geriatrics, Medical Center on Aging of Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- International Laboratory in Hematology and Cancer, Shanghai Jiao Tong University School of Medicine/Ruijin Hospital, Shanghai, 200025, China.
| | - Rui Yue
- Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
| | - Cuntai Zhang
- Gerontology Center of Hubei Province, Wuhan, 430000, China.
- Institute of Gerontology, Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Hongbo Zhang
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
| | - Liang Zhang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, 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.
| | - Yong Zhang
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, 510005, China.
- The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China.
| | - Yun-Wu Zhang
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, 361102, China.
| | - Zhuohua Zhang
- Key Laboratory of Molecular Precision Medicine of Hunan Province and Center for Medical Genetics, Institute of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, 410078, China.
- Department of Neurosciences, Hengyang Medical School, University of South China, Hengyang, 421001, China.
| | - Tongbiao Zhao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Yuzheng Zhao
- Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
- Research Unit of New Techniques for Live-cell Metabolic Imaging, Chinese Academy of Medical Sciences, Beijing, 100730, China.
| | - Dahai Zhu
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, 510005, China.
- The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China.
| | - Weiguo Zou
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Gang Pei
- Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-Based Biomedicine, The Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, Shanghai, 200070, China.
| | - Guang-Hui Liu
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
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11
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Witte S, Boshnakovska A, Özdemir M, Chowdhury A, Rehling P, Aich A. Defective COX1 expression in aging mice liver. Biol Open 2023; 12:292575. [PMID: 36861685 PMCID: PMC10003073 DOI: 10.1242/bio.059844] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 01/26/2023] [Indexed: 03/03/2023] Open
Abstract
Mitochondrial defects are associated with aging processes and age-related diseases, including cardiovascular diseases, neurodegenerative diseases and cancer. In addition, some recent studies suggest mild mitochondrial dysfunctions appear to be associated with longer lifespans. In this context, liver tissue is considered to be largely resilient to aging and mitochondrial dysfunction. Yet, in recent years studies report dysregulation of mitochondrial function and nutrient sensing pathways in ageing livers. Therefore, we analyzed the effects of the aging process on mitochondrial gene expression in liver using wildtype C57BL/6N mice. In our analyses, we observed alteration in mitochondrial energy metabolism with age. To assess if defects in mitochondrial gene expression are linked to this decline, we applied a Nanopore sequencing based approach for mitochondrial transcriptomics. Our analyses show that a decrease of the Cox1 transcript correlates with reduced respiratory complex IV activity in older mice livers.
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Affiliation(s)
- Steffen Witte
- Department of Cellular Biochemistry, University Medical Center, Göttingen, 37073, Germany
| | - Angela Boshnakovska
- Department of Cellular Biochemistry, University Medical Center, Göttingen, 37073, Germany
| | - Metin Özdemir
- Department of Cellular Biochemistry, University Medical Center, Göttingen, 37073, Germany
| | - Arpita Chowdhury
- Department of Cellular Biochemistry, University Medical Center, Göttingen, 37073, Germany
| | - Peter Rehling
- Department of Cellular Biochemistry, University Medical Center, Göttingen, 37073, Germany.,Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, 37075, Germany.,Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Translational Neuroinflammation and Automated Microscopy, Göttingen, 37075, Germany.,Max Planck Institute for Multidisciplinary Sciences, Göttingen, 37077, Germany
| | - Abhishek Aich
- Department of Cellular Biochemistry, University Medical Center, Göttingen, 37073, Germany.,Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, 37075, Germany
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12
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He Y, Su Y, Duan C, Wang S, He W, Zhang Y, An X, He M. Emerging role of aging in the progression of NAFLD to HCC. Ageing Res Rev 2023; 84:101833. [PMID: 36565959 DOI: 10.1016/j.arr.2022.101833] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 12/10/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022]
Abstract
With the aging of global population, the incidence of nonalcoholic fatty liver disease (NAFLD) has surged in recent decades. NAFLD is a multifactorial disease that follows a progressive course, ranging from simple fatty liver, nonalcoholic steatohepatitis (NASH) to liver cirrhosis and hepatocellular carcinoma (HCC). It is well established that aging induces pathological changes in liver and potentiates the occurrence and progression of NAFLD, HCC and other age-related liver diseases. Studies of senescent cells also indicate a pivotal engagement in the development of NAFLD via diverse mechanisms. Moreover, nicotinamide adenine dinucleotide (NAD+), silence information regulator protein family (sirtuins), and mechanistic target of rapamycin (mTOR) are three vital and broadly studied targets involved in aging process and NAFLD. Nevertheless, the crucial role of these aging-associated factors in aging-related NAFLD remains underestimated. Here, we reviewed the current research on the roles of aging, cellular senescence and three aging-related factors in the evolution of NAFLD to HCC, aiming at inspiring promising therapeutic targets for aging-related NAFLD and its progression.
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Affiliation(s)
- Yongyuan He
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yinghong Su
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chengcheng Duan
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Siyuan Wang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei He
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China; School of Basic Medicine, Kunming Medical University, China
| | - Yingting Zhang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaofei An
- Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
| | - Ming He
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.
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13
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Kim JS, Chapman WC, Lin Y. Mitochondrial Autophagy in Ischemic Aged Livers. Cells 2022; 11:cells11244083. [PMID: 36552847 PMCID: PMC9816943 DOI: 10.3390/cells11244083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 12/09/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Mitochondrial autophagy (mitophagy) is a central catabolic event for mitochondrial quality control. Defective or insufficient mitophagy, thus, can result in mitochondrial dysfunction, and ultimately cell death. There is a strong causal relationship between ischemia/reperfusion (I/R) injury and mitochondrial dysfunction following liver resection and transplantation. Compared to young patients, elderly patients poorly tolerate I/R injury. Accumulation of abnormal mitochondria after I/R is more prominent in aged livers than in young counterparts. This review highlights how altered autophagy is mechanistically involved in age-dependent hypersensitivity to reperfusion injury.
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Affiliation(s)
- Jae-Sung Kim
- Department of Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA; (W.C.C.); (Y.L.)
- Department of Cell Biology & Physiology, Washington University in St. Louis, St. Louis, MO 63110, USA
- Correspondence:
| | - William C. Chapman
- Department of Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA; (W.C.C.); (Y.L.)
| | - Yiing Lin
- Department of Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA; (W.C.C.); (Y.L.)
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14
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Effects of GH on the Aging Process in Several Organs: Mechanisms of Action. Int J Mol Sci 2022; 23:ijms23147848. [PMID: 35887196 PMCID: PMC9318627 DOI: 10.3390/ijms23147848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 06/26/2022] [Accepted: 07/11/2022] [Indexed: 11/17/2022] Open
Abstract
In order to investigate the possible beneficial effects of GH administration on the aging process, 24-month-old rats of both sexes and 10-month-old SAMP8 mice were used. Male rats showed increased fat content and decreased lean body mass together with enhanced vasoconstriction and reduced vasodilation of their aortic rings compared to young adult animals. Chronic GH treatment for 10 weeks increased lean body mass and reduced fat weight together with inducing an enhancement of the vasodilatory response by increasing eNOS and a reduction of the constrictory responses. Old SAMP8 male mice also showed insulin resistance together with a decrease in insulin production by the endocrine pancreas and a reduced expression of differentiation parameters. GH treatment decreased plasma levels and increased pancreatic production of insulin and restored differentiation parameters in these animals. Ovariectomy plus low calcium diet in rabbits induced osteoporosis Titanium implants inserted into these rabbit tibiae showed after one month lesser bone to implant (BIC) surface and bone mineral density (BMD). Local application of GH in the surgical opening was able to increase BIC in the osteoporotic group. The hippocampus of old rats showed a reduction in the number of neurons and also in neurogenesis compared to young ones, together with an increase of caspases and a reduction of Bcl-2. GH treatment was able to enhance significantly only the total number of neurons. In conclusion, GH treatment was able to show beneficial effects in old animals on all the different organs and metabolic functions studied.
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15
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Chen W, Liu L, Li Y, Li S, Li Z, Zhang W, Zhang X, Wu R, Hu D, Sun H, Zhou Y, Fan W, Zhao Y, Zhang Y, Hu Y. Evaluation of pediatric malignancies using total-body PET/CT with half-dose [ 18F]-FDG. Eur J Nucl Med Mol Imaging 2022; 49:4145-4155. [PMID: 35788704 DOI: 10.1007/s00259-022-05893-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 06/25/2022] [Indexed: 11/25/2022]
Abstract
PURPOSE To explore the impact of a true half dose of [18F]-FDG on image quality in pediatric oncological patients undergoing total-body PET/CT and investigate short acquisition times with half-dose injected activity. METHODS One hundred pediatric oncological patients who underwent total-body PET/CT using the uEXPLORER scanner after receiving a true half dose of [18F]-FDG (1.85 MBq/kg) were retrospectively enrolled. The PET images were first reconstructed using complete 600-s data and then split into 300-s, 180-s, 60-s, 40-s, and 20-s duration groups (G600 to G20). The subjective analysis was performed using 5-point Likert scales. Objective quantitative metrics included the maximum standard uptake value (SUVmax), SUVmean, standard deviation (SD), signal-to-noise ratio (SNR), and SNRnorm of the background. The variabilities in lesion SUVmean, SUVmax, and tumor-to-background ratio (TBR) were also calculated. RESULTS The overall image quality scores in the G600, G300, G180, and G60 groups were 4.9 ± 0.2, 4.9 ± 0.3, 4.4 ± 0.5, and 3.5 ± 0.5 points, respectively. All the lesions identified in the half-dose images were localized in the G60 images, while 56% of the lesions could be clearly identified in the G20 images. With reduced acquisition time, the SUVmax and SD of the backgrounds were gradually increased, while the TBR values showed no statistically significant differences among the groups (all p > 0.1). Using the half-dose images as a reference, the variability in the lesion SUVmax gradually increased from the G180 to G20 images, while the lesion SUVmean remained stable across all age groups. SNRnorm was highly negatively correlated with age. CONCLUSION Total-body PET/CT with a half dose of [18F]-FDG (1.85 MBq/kg, estimated whole-body effective dose: 1.76-2.57 mSv) achieved good performance in pediatric patients, with sufficient image quality and good lesion conspicuity. Sufficient image quality and lesion conspicuity could be maintained at a fast scanning time of 60 s with half-dose activity.
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Affiliation(s)
- Wanqi Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfengdong Road, Guangzhou, 510060, Guangdong, China
- Department of Nuclear Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Lei Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfengdong Road, Guangzhou, 510060, Guangdong, China
- Department of Nuclear Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Yinghe Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfengdong Road, Guangzhou, 510060, Guangdong, China
- Department of Nuclear Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Shatong Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfengdong Road, Guangzhou, 510060, Guangdong, China
- Department of Nuclear Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Zhijian Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfengdong Road, Guangzhou, 510060, Guangdong, China
- Department of Nuclear Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Weiguang Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfengdong Road, Guangzhou, 510060, Guangdong, China
- Department of Nuclear Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Xu Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfengdong Road, Guangzhou, 510060, Guangdong, China
- Department of Nuclear Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Runze Wu
- Central Research Institute, United Imaging Healthcare Group Co., Ltd, Shanghai, China
| | - Debin Hu
- Central Research Institute, United Imaging Healthcare Group Co., Ltd, Shanghai, China
| | - Hongyan Sun
- Central Research Institute, United Imaging Healthcare Group Co., Ltd, Shanghai, China
| | - Yun Zhou
- Central Research Institute, United Imaging Healthcare Group Co., Ltd, Shanghai, China
| | - Wei Fan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfengdong Road, Guangzhou, 510060, Guangdong, China
- Department of Nuclear Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Yumo Zhao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfengdong Road, Guangzhou, 510060, Guangdong, China.
- Department of Nuclear Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
| | - Yizhuo Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfengdong Road, Guangzhou, 510060, Guangdong, China.
- Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
| | - Yingying Hu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfengdong Road, Guangzhou, 510060, Guangdong, China.
- Department of Nuclear Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
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16
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Gancheva S, Kahl S, Pesta D, Mastrototaro L, Dewidar B, Strassburger K, Sabah E, Esposito I, Weiß J, Sarabhai T, Wolkersdorfer M, Fleming T, Nawroth P, Zimmermann M, Reichert AS, Schlensak M, Roden M. Impaired Hepatic Mitochondrial Capacity in Nonalcoholic Steatohepatitis Associated With Type 2 Diabetes. Diabetes Care 2022; 45:928-937. [PMID: 35113139 DOI: 10.2337/dc21-1758] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 01/13/2022] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Individuals with type 2 diabetes are at higher risk of progression of nonalcoholic fatty liver (steatosis) to steatohepatitis (NASH), fibrosis, and cirrhosis. The hepatic metabolism of obese individuals adapts by upregulation of mitochondrial capacity, which may be lost during the progression of steatosis. However, the role of type 2 diabetes with regard to hepatic mitochondrial function in NASH remains unclear. RESEARCH DESIGN AND METHODS We therefore examined obese individuals with histologically proven NASH without (OBE) (n = 30; BMI 52 ± 9 kg/m2) or with type 2 diabetes (T2D) (n = 15; 51 ± 7 kg/m2) as well as healthy individuals without liver disease (CON) (n = 14; 25 ± 2 kg/m2). Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamps with d-[6,6-2H2]glucose. Liver biopsies were used for assessing mitochondrial capacity by high-resolution respirometry and protein expression. RESULTS T2D and OBE had comparable hepatic fat content, lobular inflammation, and fibrosis. Oxidative capacity in liver tissue normalized for citrate synthase activity was 59% greater in OBE than in CON, whereas T2D presented with 33% lower complex II-linked oxidative capacity than OBE and higher H2O2 production than CON. Interestingly, those with NASH and hepatic fibrosis score ≥1 had lower oxidative capacity and antioxidant defense than those without fibrosis. CONCLUSIONS Loss of hepatic mitochondrial adaptation characterizes NASH and type 2 diabetes or hepatic fibrosis and may thereby favor accelerated disease progression.
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Affiliation(s)
- Sofiya Gancheva
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich Heine University, Düsseldorf, Germany.,Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany.,German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
| | - Sabine Kahl
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich Heine University, Düsseldorf, Germany.,Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany.,German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
| | - Dominik Pesta
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany.,German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
| | - Lucia Mastrototaro
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany.,German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
| | - Bedair Dewidar
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany.,German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Klaus Strassburger
- German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany.,Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany
| | - Ehsan Sabah
- Obesity and Reflux Center, Neuwerk Hospital, Mönchengladbach, Germany
| | - Irene Esposito
- Institute of Pathology, Heinrich Heine University, Düsseldorf, Germany
| | - Jürgen Weiß
- German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany.,Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany
| | - Theresia Sarabhai
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich Heine University, Düsseldorf, Germany.,Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany.,German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
| | | | - Thomas Fleming
- Department of Internal Medicine I, University Hospital Heidelberg, Heidelberg, Germany
| | - Peter Nawroth
- Department of Internal Medicine I, University Hospital Heidelberg, Heidelberg, Germany
| | - Marcel Zimmermann
- Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Andreas S Reichert
- Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | | | - Michael Roden
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich Heine University, Düsseldorf, Germany.,Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany.,German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
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17
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Hyun DH, Lee J. A New Insight into an Alternative Therapeutic Approach to Restore Redox Homeostasis and Functional Mitochondria in Neurodegenerative Diseases. Antioxidants (Basel) 2021; 11:antiox11010007. [PMID: 35052511 PMCID: PMC8772965 DOI: 10.3390/antiox11010007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 12/16/2021] [Accepted: 12/17/2021] [Indexed: 11/16/2022] Open
Abstract
Neurodegenerative diseases are accompanied by oxidative stress and mitochondrial dysfunction, leading to a progressive loss of neuronal cells, formation of protein aggregates, and a decrease in cognitive or motor functions. Mitochondrial dysfunction occurs at the early stage of neurodegenerative diseases. Protein aggregates containing oxidatively damaged biomolecules and other misfolded proteins and neuroinflammation have been identified in animal models and patients with neurodegenerative diseases. A variety of neurodegenerative diseases commonly exhibits decreased activity of antioxidant enzymes, lower amounts of antioxidants, and altered cellular signalling. Although several molecules have been approved clinically, there is no known cure for neurodegenerative diseases, though some drugs are focused on improving mitochondrial function. Mitochondrial dysfunction is caused by oxidative damage and impaired cellular signalling, including that of peroxisome proliferator-activated receptor gamma coactivator 1α. Mitochondrial function can also be modulated by mitochondrial biogenesis and the mitochondrial fusion/fission cycle. Mitochondrial biogenesis is regulated mainly by sirtuin 1, NAD+, AMP-activated protein kinase, mammalian target of rapamycin, and peroxisome proliferator-activated receptor γ. Altered mitochondrial dynamics, such as increased fission proteins and decreased fusion products, are shown in neurodegenerative diseases. Due to the restrictions of a target-based approach, a phenotype-based approach has been performed to find novel proteins or pathways. Alternatively, plasma membrane redox enzymes improve mitochondrial function without the further production of reactive oxygen species. In addition, inducers of antioxidant response elements can be useful to induce a series of detoxifying enzymes. Thus, redox homeostasis and metabolic regulation can be important therapeutic targets for delaying the progression of neurodegenerative diseases.
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18
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Gallo P, De Vincentis A, Bandinelli S, Ferrucci L, Picardi A, Antonelli Incalzi R, Vespasiani-Gentilucci U. Combined evaluation of aminotransferases improves risk stratification for overall and cause-specific mortality in older patients. Aging Clin Exp Res 2021; 33:3321-3331. [PMID: 34506007 DOI: 10.1007/s40520-021-01979-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 09/01/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Recent studies identified low levels of alanine aminotransferase (ALT) as strong predictors of mortality in older people. AIMS Here we verified if the combined evaluation of aminotransferases may improve risk stratification for adverse outcomes in older patients. METHODS Data are from 761 participants aged more than 65 years from a prospective population-based database (InCHIANTI study), without known baseline chronic liver disease or malignancies. Associations between aminotransferase levels and the risk of all-cause, cardiovascular- and cancer-death were assessed by Cox-models with time-dependent covariates. RESULTS The association of ALT and aspartate aminotransferase (AST) with mortality was non-linear, mirroring a J- and a U-shaped curve, respectively. Based on quintiles of transaminase activities and on their association with overall mortality, low, intermediate (reference group) and high levels were defined. Having at least one transaminase in the low range [aHR 1.76 (1.31-2.36), p < 0.001], mainly if both [(aHR 2.39 (1.81-3.15), p < 0.001], increased the risk of overall mortality, as well as having both enzymes in the high range [aHR 2.14 (1.46-3.15), p < 0.001]. While similar trends were confirmed with respect to cardiovascular mortality, subjects with the highest risk of cancer mortality were those with both enzymes in the high range [aHR 3.48 (1.43-8.44), p = 0.006]. Low levels of transaminases were associated with frailty, sarcopenia and disability, while high levels did not capture any known proxy of adverse outcome. Conclusions and discussion The prognostic information is maximized by the combination of the 2 liver enzymes. While both aminotransferases in low range are characteristically found in the most fragile phenotype, both enzymes in high range are more likely to identify new-onset vascular/infiltrative diseases with adverse outcome.
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Affiliation(s)
- Paolo Gallo
- Clinical Medicine and Hepatology Unit, Campus Bio-Medico University, Rome, Italy
| | - Antonio De Vincentis
- Internal Medicine Unit, Campus Bio-Medico University, Via Alvaro del Portillo 200 , Rome, Italy.
| | | | - Luigi Ferrucci
- National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Antonio Picardi
- Clinical Medicine and Hepatology Unit, Campus Bio-Medico University, Rome, Italy
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Yi W, Sylvester E, Lian J, Deng C. Kidney plays an important role in ketogenesis induced by risperidone and voluntary exercise in juvenile female rats. Psychiatry Res 2021; 305:114196. [PMID: 34488011 DOI: 10.1016/j.psychres.2021.114196] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/16/2021] [Accepted: 08/28/2021] [Indexed: 11/27/2022]
Abstract
The positive role of ketone bodies in the treatment for mental disorders has been demonstrated. Ketogenesis can be triggered by not only exercise and diet but also metabolic disorders. This study aimed to explore the role of risperidone and exercise in ketogenesis. Thirty-two juvenile female Sprague Dawley rats were randomly assigned into four groups: Vehicle-Sedentary, Risperidone (0.9 mg/kg; b.i.d)-Sedentary, Vehicle-Exercise (three hours daily access to running wheels) and Risperidone-Exercise groups for four weeks. Exercise-intervention significantly ameliorated the risperidone-induced increase in white adipose mass, fasting plasma triglyceride and insulin levels. Compared to the vehicle-exercise group, the risperidone-exercise group had significantly higher plasma β-hydroxybutyrate (β-HB) level, which had a positive correlation with plasma non-esterified fatty acid levels. Risperidone-treatment upregulated expression of ketogenic key enzyme, mitochondrial 3-hydroxy-3-methyl-glutaryl-CoA synthase 2 (HMGCS2) in the kidney rather than liver. Exercise-intervention significantly enhanced renal carnitine palmitoyltransferase1A (CPT1A) expression. These results suggested that the kidney plays an important role in ketogenesis associated with risperidone and exercise. Therefore, it is important to monitor the levels of plasma ketone bodies while exercise intervention is utilized to prevent risperidone-induced metabolic disorders in young people.
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Affiliation(s)
- Weijie Yi
- Department of Nutrition and Food Hygiene, School of Public Health and Management, Binzhou Medical University, Yantai, Shandong 264003, China; Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia; School of Medicine and Molecular Horizons, University of Wollongong, Wollongong, NSW, Australia
| | - Emma Sylvester
- Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia; School of Medicine and Molecular Horizons, University of Wollongong, Wollongong, NSW, Australia
| | - Jiamei Lian
- Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia; School of Medicine and Molecular Horizons, University of Wollongong, Wollongong, NSW, Australia
| | - Chao Deng
- Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia; School of Medicine and Molecular Horizons, University of Wollongong, Wollongong, NSW, Australia.
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20
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Abstract
Significance: During aging, excessive production of reactive species in the liver leads to redox imbalance with consequent oxidative damage and impaired organ homeostasis. Nevertheless, slight amounts of reactive species may modulate several transcription factors, acting as second messengers and regulating specific signaling pathways. These redox-dependent alterations may impact the age-associated decline in liver regeneration. Recent Advances: In the last few decades, relevant findings related to redox alterations in the aging liver were investigated. Consistently, recent research broadened understanding of redox modifications and signaling related to liver regeneration. Other than reporting the effect of oxidative stress, epigenetic and post-translational modifications, as well as modulation of specific redox-sensitive cellular signaling, were described. Among them, the present review focuses on Wnt/β-catenin, the nuclear factor (erythroid-derived 2)-like 2 (NRF2), members of the Forkhead box O (FoxO) family, and the p53 tumor suppressor. Critical Issues: Even though alteration in redox homeostasis occurs both in aging and in impaired liver regeneration, the associative mechanisms are not clearly defined. Of note, antioxidants are not effective in slowing hepatic senescence, and do not clearly improve liver repopulation after hepatectomy or transplant in humans. Future Directions: Further investigations are needed to define mutual redox-dependent molecular pathways involved both in aging and in the decline of liver regeneration. Preclinical studies aimed at the characterization of these pathways would define possible therapeutic targets for human trials. Antioxid. Redox Signal. 35, 832-847.
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Affiliation(s)
- Francesco Bellanti
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Gianluigi Vendemiale
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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21
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Alqahtani SA, Schattenberg JM. NAFLD in the Elderly. Clin Interv Aging 2021; 16:1633-1649. [PMID: 34548787 PMCID: PMC8448161 DOI: 10.2147/cia.s295524] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 08/12/2021] [Indexed: 12/25/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent disease globally. Current estimates are that 24% of the adult population, thus, one billion individuals worldwide, are affected. Interestingly, the prevalence of fatty liver seems to peak between 40─50 years of age in males and 60─69 years in females, often slightly decreasing in older (>70 years) cohorts. Furthermore, several risk factors for NAFLD development, such as hypertension, diabetes, hyperlipidemia, and obesity are higher in older adults. The diagnosis and management strategies in older adults are sometimes challenging, and certain age-specific factors have to be taken into account by healthcare professionals. In this review, we provide an overview of considerations relevant to the management and diagnosis of NAFLD in older adults (age >65 years) and discuss the types of pharmacological interventions available for the management of non-alcoholic steatohepatitis (NASH) in the aging population.
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Affiliation(s)
- Saleh A Alqahtani
- Liver Transplantation Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.,Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD, USA
| | - Jörn M Schattenberg
- Metabolic Liver Research Program, I. Department of Medicine, University Medical Center, Mainz, Germany
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22
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Cox CPW, van Assema DME, Verburg FA, Brabander T, Konijnenberg M, Segbers M. A dedicated paediatric [ 18F]FDG PET/CT dosage regimen. EJNMMI Res 2021; 11:65. [PMID: 34279735 PMCID: PMC8289942 DOI: 10.1186/s13550-021-00812-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 07/09/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The role of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) in children is still expanding. Dedicated paediatric dosage regimens are needed to keep the radiation dose as low as reasonably achievable and reduce the risk of radiation-induced carcinogenesis. The aim of this study is to investigate the relation between patient-dependent parameters and [18F]FDG PET image quality in order to propose a dedicated paediatric dose regimen. METHODS In this retrospective analysis, 102 children and 85 adults were included that underwent a diagnostic [18F]FDG PET/CT scan. The image quality of the PET scans was measured by the signal-to-noise ratio (SNR) in the liver. The SNR liver was normalized (SNRnorm) for administered activity and acquisition time to apply curve fitting with body weight, body length, body mass index, body weight/body length and body surface area. Curve fitting was performed with two power fits, a nonlinear two-parameter model α p-d and a linear single-parameter model α p-0.5. The fit parameters of the preferred model were combined with a user preferred SNR to obtain at least moderate or good image quality for the dosage regimen proposal. RESULTS Body weight demonstrated the highest coefficient of determination for the nonlinear (R2 = 0.81) and linear (R2 = 0.80) models. The nonlinear model was preferred by the Akaike's corrected information criterion. We decided to use a SNR of 6.5, based on the expert opinion of three nuclear medicine physicians. Comparison with the quadratic adult protocol confirmed the need for different dosage regimens for both patient groups. In this study, the amount of administered activity can be considerably reduced in comparison with the current paediatric guidelines. CONCLUSION Body weight has the strongest relation with [18F]FDG PET image quality in children. The proposed nonlinear dosage regimen based on body mass will provide a constant and clinical sufficient image quality with a significant reduction of the effective dose compared to the current guidelines. A dedicated paediatric dosage regimen is necessary, as a universal dosing regimen for paediatric and adult is not feasible.
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Affiliation(s)
- Christina P W Cox
- Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Postbus, 2040 3000 CA, Rotterdam, The Netherlands.
| | - Daniëlle M E van Assema
- Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Postbus, 2040 3000 CA, Rotterdam, The Netherlands
| | - Frederik A Verburg
- Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Postbus, 2040 3000 CA, Rotterdam, The Netherlands
| | - Tessa Brabander
- Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Postbus, 2040 3000 CA, Rotterdam, The Netherlands
| | - Mark Konijnenberg
- Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Postbus, 2040 3000 CA, Rotterdam, The Netherlands
| | - Marcel Segbers
- Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Postbus, 2040 3000 CA, Rotterdam, The Netherlands
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23
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Andrianova NV, Buyan MI, Bolikhova AK, Zorov DB, Plotnikov EY. Dietary Restriction for Kidney Protection: Decline in Nephroprotective Mechanisms During Aging. Front Physiol 2021; 12:699490. [PMID: 34295266 PMCID: PMC8291992 DOI: 10.3389/fphys.2021.699490] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 06/10/2021] [Indexed: 01/07/2023] Open
Abstract
Dietary restriction (DR) is believed to be one of the most promising approaches to extend life span of different animal species and to delay deleterious age-related physiological alterations and diseases. Among others, DR was shown to ameliorate acute kidney injury (AKI) and chronic kidney disease (CKD). However, to date, a comprehensive analysis of the mechanisms of the protective effect of DR specifically in kidney pathologies has not been carried out. The protective properties of DR are mediated by a range of signaling pathways associated with adaptation to reduced nutrient intake. The adaptation is accompanied by a number of metabolic changes, such as autophagy activation, metabolic shifts toward lipid utilization and ketone bodies production, improvement of mitochondria functioning, and decreased oxidative stress. However, some studies indicated that with age, the gain of DR-mediated positive remodeling gradually decreases. This may be an obstacle if we seek to translate the DR approach into a clinic for the treatment of kidney diseases as most patients with AKI and CKD are elderly. It is well known that aging is accompanied by impairments in a huge variety of organs and systems, such as hormonal regulation, stress sensing, autophagy and proteasomal activity, gene expression, and epigenome profile, increased damage to macromolecules and organelles including mitochondria. All these age-associated changes might be the reasons for the reduced protective potential of the DR during aging. We summarized the available mechanisms of DR-mediated nephroprotection and described ways to improve the effectiveness of this approach for an aged kidney.
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Affiliation(s)
- Nadezda V Andrianova
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.,Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia
| | - Marina I Buyan
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia
| | - Anastasia K Bolikhova
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia
| | - Dmitry B Zorov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.,V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow, Russia
| | - Egor Y Plotnikov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.,V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow, Russia
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24
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Arslan E, Çermik TF. PET/CT Variants and Pitfalls in Liver, Biliary Tract, Gallbladder and Pancreas. Semin Nucl Med 2021; 51:502-518. [PMID: 34049687 DOI: 10.1053/j.semnuclmed.2021.04.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
A wide variety of pathological anomalies may occur in the liver, biliary system, and pancreas. It is a necessity to use many different imaging techniques in order to distinguish such varied pathologies, especially those from malignant processes. Positron Emission Tomography/Computed Tomography (PET/CT) is an imaging method that has proven its diagnostic value in oncology and can be used for different clinical purposes. Fluoro-18 fluoro-2-deoxy-D-glucose has a wide range of uses as a dominant radiopharmaceutical in routine molecular imaging, however, molecular imaging has started to play a more important role in personalized cancer treatment in recent years with new Fluoro-18 and Gallium-68 labeled tracers. Although molecular imaging has a strong diagnostic effect, the surprises and pitfalls of molecular imaging can lead us to unexpected and misleading results. Prior to PET/CT analysis and reporting, information about possible technical and physiological pitfalls, normal histological features of tissues, inflammatory pathologies, specific clinical features of the case, treatment-related complications and past treatments should be evaluated in advance to avoid misinterpretation. In this review, the physiological and pathophysiological variants as well as pitfalls encountered in PET/CT imaging of the liver, biliary tract, gallbladder, and pancreas will be examined. Other benign and malignant pathologies that have been reported to date and that have led to incorrect evaluation will be listed. It is expected that the devices, software, and artificial intelligence applications that will be developed in the near future will enable much more effective and faster imaging that will reduce the potential causes of error. However, as a result of the dynamic and evolving structure of the information obtained by molecular imaging, the inclusion of the newly developed radiopharmaceuticals in routine practice will continue to carry new potentials as well as new troubles. Although molecular imaging will be the flagship of diagnostic oncology in the 21st century, the correct analysis and interpretation by the physician will continue to form the basis of achieving optimal performance.
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Affiliation(s)
- Esra Arslan
- Istanbul Training and Research Hospital, Clinic of Nuclear Medicine, University of Health and Sciences Turkey, Istanbul, Turkey.
| | - Tevfik Fikret Çermik
- Istanbul Training and Research Hospital, Clinic of Nuclear Medicine, University of Health and Sciences Turkey, Istanbul, Turkey
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25
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Chung KW. Advances in Understanding of the Role of Lipid Metabolism in Aging. Cells 2021; 10:cells10040880. [PMID: 33924316 PMCID: PMC8068994 DOI: 10.3390/cells10040880] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 04/09/2021] [Accepted: 04/12/2021] [Indexed: 02/06/2023] Open
Abstract
During aging, body adiposity increases with changes in the metabolism of lipids and their metabolite levels. Considering lipid metabolism, excess adiposity with increased lipotoxicity leads to various age-related diseases, including cardiovascular disease, cancer, arthritis, type 2 diabetes, and Alzheimer's disease. However, the multifaceted nature and complexities of lipid metabolism make it difficult to delineate its exact mechanism and role during aging. With advances in genetic engineering techniques, recent studies have demonstrated that changes in lipid metabolism are associated with aging and age-related diseases. Lipid accumulation and impaired fatty acid utilization in organs are associated with pathophysiological phenotypes of aging. Changes in adipokine levels contribute to aging by modulating changes in systemic metabolism and inflammation. Advances in lipidomic techniques have identified changes in lipid profiles that are associated with aging. Although it remains unclear how lipid metabolism is regulated during aging, or how lipid metabolites impact aging, evidence suggests a dynamic role for lipid metabolism and its metabolites as active participants of signaling pathways and regulators of gene expression. This review describes recent advances in our understanding of lipid metabolism in aging, including established findings and recent approaches.
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Affiliation(s)
- Ki Wung Chung
- College of Pharmacy, Pusan National University, Busan 46214, Korea
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26
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Nagai N, Kudo Y, Aki D, Nakagawa H, Taniguchi K. Immunomodulation by Inflammation during Liver and Gastrointestinal Tumorigenesis and Aging. Int J Mol Sci 2021; 22:ijms22052238. [PMID: 33668122 PMCID: PMC7956754 DOI: 10.3390/ijms22052238] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 02/19/2021] [Indexed: 12/19/2022] Open
Abstract
Chronic inflammation is thought to promote tumorigenesis and metastasis by several mechanisms, such as affecting tumor cells directly, establishing a tumor-supporting microenvironment, enhancing tumor angiogenesis, and suppressing antitumor immunity. In this review, we discuss the recent advances in our understanding of how inflammation induces the immunosuppressive tumor microenvironment, such as increasing the level of pro-inflammatory cytokines, chemokines, and immunosuppressive molecules, inducing immune checkpoint molecules and cytotoxic T-cell exhaustion, and accumulating regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs). The suppression of antitumor immunity by inflammation is especially examined in the liver and colorectal cancer. In addition, chronic inflammation is induced during aging and causes age-related diseases, including cancer, by affecting immunity. Therefore, we also discuss the age-related diseases regulated by inflammation, especially in the liver and colon.
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Affiliation(s)
- Nao Nagai
- Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; (N.N.); (D.A.)
| | - Yotaro Kudo
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; (Y.K.); (H.N.)
| | - Daisuke Aki
- Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; (N.N.); (D.A.)
| | - Hayato Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; (Y.K.); (H.N.)
| | - Koji Taniguchi
- Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; (N.N.); (D.A.)
- Department of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan
- Correspondence: ; Tel.: +81-3-5363-3483
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27
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Xu F, Tautenhahn HM, Dirsch O, Dahmen U. Modulation of Autophagy: A Novel "Rejuvenation" Strategy for the Aging Liver. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6611126. [PMID: 33628363 PMCID: PMC7889356 DOI: 10.1155/2021/6611126] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 12/08/2020] [Accepted: 01/23/2021] [Indexed: 12/11/2022]
Abstract
Aging is a natural life process which leads to a gradual decline of essential physiological processes. For the liver, it leads to alterations in histomorphology (steatosis and fibrosis) and function (protein synthesis and energy generation) and affects central hepatocellular processes (autophagy, mitochondrial respiration, and hepatocyte proliferation). These alterations do not only impair the metabolic capacity of the liver but also represent important factors in the pathogenesis of malignant liver disease. Autophagy is a recycling process for eukaryotic cells to degrade dysfunctional intracellular components and to reuse the basic substances. It plays a crucial role in maintaining cell homeostasis and in resisting environmental stress. Emerging evidence shows that modulating autophagy seems to be effective in improving the age-related alterations of the liver. However, autophagy is a double-edged sword for the aged liver. Upregulating autophagy alleviates hepatic steatosis and ROS-induced cellular stress and promotes hepatocyte proliferation but may aggravate hepatic fibrosis. Therefore, a well-balanced autophagy modulation strategy might be suitable to alleviate age-related liver dysfunction. Conclusion. Modulation of autophagy is a promising strategy for "rejuvenation" of the aged liver. Detailed knowledge regarding the most devastating processes in the individual patient is needed to effectively counteract aging of the liver without causing obvious harm.
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Affiliation(s)
- Fengming Xu
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena 07747, Germany
| | - Hans-Michael Tautenhahn
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena 07747, Germany
| | - Olaf Dirsch
- Institute of Pathology, Klinikum Chemnitz gGmbH, Chemnitz 09111, Germany
| | - Uta Dahmen
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena 07747, Germany
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28
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Zhang F, Kerbl-Knapp J, Akhmetshina A, Korbelius M, Kuentzel KB, Vujić N, Hörl G, Paar M, Kratky D, Steyrer E, Madl T. Tissue-Specific Landscape of Metabolic Dysregulation during Ageing. Biomolecules 2021; 11:235. [PMID: 33562384 PMCID: PMC7914945 DOI: 10.3390/biom11020235] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 01/22/2021] [Accepted: 02/02/2021] [Indexed: 12/14/2022] Open
Abstract
The dysregulation of cellular metabolism is a hallmark of ageing. To understand the metabolic changes that occur as a consequence of the ageing process and to find biomarkers for age-related diseases, we conducted metabolomic analyses of the brain, heart, kidney, liver, lung and spleen in young (9-10 weeks) and old (96-104 weeks) wild-type mice [mixed genetic background of 129/J and C57BL/6] using NMR spectroscopy. We found differences in the metabolic fingerprints of all tissues and distinguished several metabolites to be altered in most tissues, suggesting that they may be universal biomarkers of ageing. In addition, we found distinct tissue-clustered sets of metabolites throughout the organism. The associated metabolic changes may reveal novel therapeutic targets for the treatment of ageing and age-related diseases. Moreover, the identified metabolite biomarkers could provide a sensitive molecular read-out to determine the age of biologic tissues and organs and to validate the effectiveness and potential off-target effects of senolytic drug candidates on both a systemic and tissue-specific level.
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Affiliation(s)
- Fangrong Zhang
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Ageing, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (F.Z.); (J.K.-K.); (A.A.); (M.K.); (K.B.K.); (N.V.); (D.K.); (E.S.)
| | - Jakob Kerbl-Knapp
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Ageing, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (F.Z.); (J.K.-K.); (A.A.); (M.K.); (K.B.K.); (N.V.); (D.K.); (E.S.)
| | - Alena Akhmetshina
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Ageing, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (F.Z.); (J.K.-K.); (A.A.); (M.K.); (K.B.K.); (N.V.); (D.K.); (E.S.)
| | - Melanie Korbelius
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Ageing, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (F.Z.); (J.K.-K.); (A.A.); (M.K.); (K.B.K.); (N.V.); (D.K.); (E.S.)
| | - Katharina Barbara Kuentzel
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Ageing, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (F.Z.); (J.K.-K.); (A.A.); (M.K.); (K.B.K.); (N.V.); (D.K.); (E.S.)
| | - Nemanja Vujić
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Ageing, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (F.Z.); (J.K.-K.); (A.A.); (M.K.); (K.B.K.); (N.V.); (D.K.); (E.S.)
| | - Gerd Hörl
- Otto-Loewi Research Center, Physiological Chemistry, Medical University of Graz, 8010 Graz, Austria; (G.H.); (M.P.)
| | - Margret Paar
- Otto-Loewi Research Center, Physiological Chemistry, Medical University of Graz, 8010 Graz, Austria; (G.H.); (M.P.)
| | - Dagmar Kratky
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Ageing, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (F.Z.); (J.K.-K.); (A.A.); (M.K.); (K.B.K.); (N.V.); (D.K.); (E.S.)
- BioTechMed-Graz, 8010 Graz, Austria
| | - Ernst Steyrer
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Ageing, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (F.Z.); (J.K.-K.); (A.A.); (M.K.); (K.B.K.); (N.V.); (D.K.); (E.S.)
| | - Tobias Madl
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Ageing, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; (F.Z.); (J.K.-K.); (A.A.); (M.K.); (K.B.K.); (N.V.); (D.K.); (E.S.)
- BioTechMed-Graz, 8010 Graz, Austria
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Peroxisome Proliferator-Activated Receptors as Molecular Links between Caloric Restriction and Circadian Rhythm. Nutrients 2020; 12:nu12113476. [PMID: 33198317 PMCID: PMC7696073 DOI: 10.3390/nu12113476] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 11/04/2020] [Accepted: 11/09/2020] [Indexed: 02/06/2023] Open
Abstract
The circadian rhythm plays a chief role in the adaptation of all bodily processes to internal and environmental changes on the daily basis. Next to light/dark phases, feeding patterns constitute the most essential element entraining daily oscillations, and therefore, timely and appropriate restrictive diets have a great capacity to restore the circadian rhythm. One of the restrictive nutritional approaches, caloric restriction (CR) achieves stunning results in extending health span and life span via coordinated changes in multiple biological functions from the molecular, cellular, to the whole-body levels. The main molecular pathways affected by CR include mTOR, insulin signaling, AMPK, and sirtuins. Members of the family of nuclear receptors, the three peroxisome proliferator-activated receptors (PPARs), PPARα, PPARβ/δ, and PPARγ take part in the modulation of these pathways. In this non-systematic review, we describe the molecular interconnection between circadian rhythm, CR-associated pathways, and PPARs. Further, we identify a link between circadian rhythm and the outcomes of CR on the whole-body level including oxidative stress, inflammation, and aging. Since PPARs contribute to many changes triggered by CR, we discuss the potential involvement of PPARs in bridging CR and circadian rhythm.
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Abstract
Aging increases the incidence of chronic liver disease (CLD), worsens its prognosis, and represents the predominant risk factor for its development at all different stages. The hepatic sinusoid, which is fundamental for maintaining liver homeostasis, is composed by hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells, and hepatic macrophages. During CLD progression, hepatic cells suffer deregulations in their phenotype, which ultimately lead to disease development. The effects of aging on the hepatic sinusoid phenotype and function are not well understood, nevertheless, studies performed in experimental models of liver diseases and aging demonstrate alterations in all hepatic sinusoidal cells. This review provides an updated description of age-related changes in the hepatic sinusoid and discusses the implications for CLD development and treatment. Lastly, we propose aging as a novel therapeutic target to treat liver diseases and summarize the most promising therapies to prevent or improve CLD and extend healthspan.
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Affiliation(s)
- Raquel Maeso-Díaz
- Division of Gastroenterology, Department of Medicine, Duke University Health System, Durham, North Carolina
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Barcelona, Spain.,Division of Hepatology, Department of Biomedical Research, Inselspital, University of Bern, Bern, Switzerland
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Andrianova NV, Zorova LD, Pevzner IB, Popkov VA, Chernikov VP, Silachev DN, Plotnikov EY, Zorov DB. Resemblance and differences in dietary restriction nephroprotective mechanisms in young and old rats. Aging (Albany NY) 2020; 12:18693-18715. [PMID: 32970613 PMCID: PMC7585108 DOI: 10.18632/aging.103960] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 07/21/2020] [Indexed: 01/24/2023]
Abstract
Dietary restriction (DR) is the strategy ameliorating the morbidity of various pathologies, including age-associated diseases. Acute kidney injury (AKI) remains a problem for the elderly with DR being a promising approach for diminishing its consequences. We evaluated the possible nephroprotective potential of short-term DR in young and old rats. DR in young rats resulted in pronounced beneficial effects normalizing lipid metabolism (triglycerides concentration, adiponectin level) activating autophagic-lysosomal system evaluated by LC3II/LC3I ratio, LAMP1, p62/SQSTM1 levels, and LysoTracker Green staining. DR had a remarkable recovering effect on mitochondrial structure and functions including regaining of mitochondrial membrane potential, the elevation of SIRT-3, PGC-1α, Bcl-XL levels and partial restoration of ultrastructure. The beneficial effects of DR resulted in the mitigation of oxidative stress including a decrease in levels of protein carbonylation and lipid peroxidation. Aging led to decreased activity of autophagy, elevated oxidative stress and impaired kidney regenerative capacity. Eventually, in old rats, even 8-week DR was not able to ameliorate AKI, but it caused some rejuvenating effects including elevation of mitochondrial membrane potential and Bcl-XL levels, as well as lowered severity of the oxidative stress. Thus, the age-associated decline of protective signaling demands extended DR to achieve nephroprotective potential in old animals.
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Affiliation(s)
- Nadezda V. Andrianova
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia,Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow 119992, Russia
| | - Ljubava D. Zorova
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia,V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia
| | - Irina B. Pevzner
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia,V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia
| | - Vasily A. Popkov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia,V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia
| | | | - Denis N. Silachev
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia,V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia
| | - Egor Y. Plotnikov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia,V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia,Sechenov First Moscow State Medical University, Institute of Molecular Medicine, Moscow 119991, Russia
| | - Dmitry B. Zorov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia,V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia
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Viña J, Olaso-Gonzalez G, Arc-Chagnaud C, De la Rosa A, Gomez-Cabrera MC. Modulating Oxidant Levels to Promote Healthy Aging. Antioxid Redox Signal 2020; 33:570-579. [PMID: 32008355 DOI: 10.1089/ars.2020.8036] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Significance: Free radicals although originally thought of as damaging molecules, inevitable side effects of the utilization of oxygen by cells, are now considered as signals that by modifying, among others, the thiol-disulfide balance regulate many cell processes from metabolism to cell cycle. Recent Advances: This review discusses the importance of the modulation of the oxidant levels through physiological strategies such as physical exercise or genetic manipulations such as the overexpression of antioxidant enzymes, in the promotion of healthy aging. Critical Issues: We have divided the review into five different sections. In the first two sections of the article "Oxidants are signals" and "Exercise training is an antioxidant," we discuss the main sources of free radicals during muscle contraction and their role, as hormetic substances, in the regulation of two main muscle adaptations to exercise in skeletal muscle; that is, mitochondrial biogenesis and the endogenous antioxidant defense. In the third section of the review, we deal with "the energy collapse in aging." The increased rate of reactive oxygen species (ROS) production and the low rate of mitochondria biosynthesis in the old cells are examined. Finally, in the fourth and fifth sections entitled "Overexpression of antioxidants enzymes in healthy aging" and "Exercise, longevity, and frailty," we consider the importance of the potentiation of the cellular defenses in health span and in life span. Future Directions: A correct manipulation of the ROS generation, directing these species to their physiological signaling role and preventing their deleterious effects, would allow the promotion of healthy aging. Antioxid. Redox Signal. 33, 570-579.
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Affiliation(s)
- Jose Viña
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia and CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain
| | - Gloria Olaso-Gonzalez
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia and CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain
| | - Coralie Arc-Chagnaud
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia and CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain.,Université de Montpellier, INRA, UMR866 Dynamique Musculaire et Métabolisme, Montpellier, France
| | - Adrián De la Rosa
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia and CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain
| | - Mari Carmen Gomez-Cabrera
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia and CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain
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Peroxisome Proliferator-Activated Receptors and Caloric Restriction-Common Pathways Affecting Metabolism, Health, and Longevity. Cells 2020; 9:cells9071708. [PMID: 32708786 PMCID: PMC7407644 DOI: 10.3390/cells9071708] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/14/2020] [Accepted: 07/14/2020] [Indexed: 02/06/2023] Open
Abstract
Caloric restriction (CR) is a traditional but scientifically verified approach to promoting health and increasing lifespan. CR exerts its effects through multiple molecular pathways that trigger major metabolic adaptations. It influences key nutrient and energy-sensing pathways including mammalian target of rapamycin, Sirtuin 1, AMP-activated protein kinase, and insulin signaling, ultimately resulting in reductions in basic metabolic rate, inflammation, and oxidative stress, as well as increased autophagy and mitochondrial efficiency. CR shares multiple overlapping pathways with peroxisome proliferator-activated receptors (PPARs), particularly in energy metabolism and inflammation. Consequently, several lines of evidence suggest that PPARs might be indispensable for beneficial outcomes related to CR. In this review, we present the available evidence for the interconnection between CR and PPARs, highlighting their shared pathways and analyzing their interaction. We also discuss the possible contributions of PPARs to the effects of CR on whole organism outcomes.
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Li S, Shi B, Huang K, Wang Y. Different intracellular signalling sensitivity and cell behaviour of porcine insulin with aging. Peptides 2020; 127:170278. [PMID: 32109654 DOI: 10.1016/j.peptides.2020.170278] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 02/02/2020] [Accepted: 02/15/2020] [Indexed: 01/30/2023]
Abstract
Insulin has many important biological functions. Insulin interacts with the insulin receptor (IR) to play its physiological role and execute its functions. Here, we isolated porcine hepatocytes from young and aged pigs, which endogenously express the IR, as a model to study the intracellular signalling properties and cellular behaviour of insulin with aging. Firstly, we analysed the intracellular signal transduction that is triggered by insulin in porcine hepatocytes that were isolated from young and aged pigs and found that insulin can strongly activate insulin receptor subunit (IRS), protein kinase B (AKT), and GSK in a time- and dose-dependent manner in hepatocytes from young pigs. On the contrary, the signalling response to insulin in hepatocytes from aged pigs was significantly reduced compared to that of the young pig. Secondly, the different subcellular locations of insulin/insulin receptor (IR) may result in different biological activities, although nuclear-localized insulin/IR still could exhibit important functions and roles. We found that insulin can translocate into cell nuclei in the hepatocytes of the young pigs; however, insulin/insulin receptor fails to transports into the cell nucleus in hepatocytes from aged pigs, although insulin/insulin receptor could internalize into cell cytoplasm. In summary, in the current study, we explored and compared for the first time insulin's behaviour and signalling properties in the cells of young pig hepatocytes and aged pig hepatocytes. Furthermore, we found that the insulin signalling response in hepatocytes was significantly reduced with age; more importantly, we found that the cell behaviour of insulin was changed significantly in the hepatocytes from aged pigs compared to young pigs, and it is noteworthy that insulin/IR cannot translocate into the cell nuclei in the hepatocytes from the aged pig. This may be a potential new reason contributing to insulin resistance with aging, suggesting that we need to study the reason for insulin resistance from a new point of view.
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Affiliation(s)
- Shichun Li
- The Third Operating Room Of The First Hospital of Jilin University, Jilin University, Changchun 130021, People's Republic of China
| | - Bo Shi
- Experimental Center of Biochemistry and Molecular Biology, College of Basic Medicine, Jilin University, Changchun 130021, People's Republic of China
| | - Kexin Huang
- Department of Histology and Embryology, College of Basic Medicine, Jilin University, Changchun 130021, People's Republic of China
| | - Ying Wang
- The First Operating Room of the First Hospital of Jilin University, Jilin University, Changchun 130021, People's Republic of China.
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Goldberg EL, Shchukina I, Asher JL, Sidorov S, Artyomov MN, Dixit VD. Ketogenesis activates metabolically protective γδ T cells in visceral adipose tissue. Nat Metab 2020; 2:50-61. [PMID: 32694683 PMCID: PMC10150608 DOI: 10.1038/s42255-019-0160-6] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 12/11/2019] [Indexed: 12/29/2022]
Abstract
Ketone bodies are essential alternative fuels that allow humans to survive periods of glucose scarcity induced by starvation and prolonged exercise. A widely used ketogenic diet (KD), which is extremely high in fat with very low carbohydrates, drives the host into using β-hydroxybutyrate for the production of ATP and lowers NLRP3-mediated inflammation. However, the extremely high fat composition of KD raises the question of how ketogenesis affects adipose tissue to control inflammation and energy homeostasis. Here, by using single-cell RNA sequencing of adipose-tissue-resident immune cells, we show that KD expands metabolically protective γδ T cells that restrain inflammation. Notably, long-term ad libitum KD feeding in mice causes obesity, impairs metabolic health and depletes the adipose-resident γδ T cells. In addition, mice lacking γδ T cells have impaired glucose homeostasis. Our results suggest that γδ T cells are mediators of protective immunometabolic responses that link fatty acid-driven fuel use to reduced adipose tissue inflammation.
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Affiliation(s)
- Emily L Goldberg
- Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
| | - Irina Shchukina
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA
| | - Jennifer L Asher
- Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Sviatoslav Sidorov
- Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Maxim N Artyomov
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA
| | - Vishwa Deep Dixit
- Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA.
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
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Sahara K, Paredes AZ, Tsilimigras DI, Hyer JM, Merath K, Wu L, Mehta R, Beal EW, White S, Endo I, Pawlik TM. Impact of Liver Cirrhosis on Perioperative Outcomes Among Elderly Patients Undergoing Hepatectomy: the Effect of Minimally Invasive Surgery. J Gastrointest Surg 2019; 23:2346-2353. [PMID: 30719676 DOI: 10.1007/s11605-019-04117-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 01/09/2019] [Indexed: 01/31/2023]
Abstract
BACKGROUND The impact of cirrhosis on perioperative outcomes for elderly patients undergoing hepatectomy remains not well defined. We sought to determine the influence of underlying cirrhosis and minimally invasive surgery (MIS) on postoperative outcomes among elderly patients who underwent a hepatectomy. METHODS Patients who underwent hepatectomy between 2013 and 2015 were identified using the Center for Medicare Services (CMS) 100% Limited Data Set (LDS) Standard Analytic Files (SAFs). Short-term outcomes after hepatectomy, stratified by the presence of cirrhosis and MIS, were examined. RESULTS Among 7452 patients who underwent a hepatectomy, a minority had cirrhosis (n = 481, 6.5%) whereas the vast majority did not (n = 6971, 93.5%). Overall, median patient age was 72 years (IQR 68-76) and preoperative Charlson comorbidity score was 6 (IQR 2-8). Patients with cirrhosis were more likely to be younger (median age 71 [67-76] vs 72 [IQR 68-76] years), male (64.4% vs 50%), African American (8.1% vs 6.4%) and have a malignant diagnosis (87.1% vs 78.7%) compared to non-cirrhotic patients (all p < 0.001). There was no difference among patients with and without cirrhosis regarding type of hepatectomy or surgical approach (open vs MIS) (both p > 0.05). Patients with versus without cirrhosis had similar complication rates (24.1% vs 22.3%, p = 0.36), as well as 30-day (6.2% vs 5%, p = 0.25) and 90-day (10.4% vs 8.5%, p = 0.15) mortality. MIS reduced the length-of-stay in non-cirrhotic patients (OR 0.79, 95% CI 0.62-0.99, p < 0.05), yet was not associated with morbidity or mortality (both p > 0.05). CONCLUSION The presence of cirrhosis did not generally impact outcomes in elderly patients undergoing hepatectomy for benign and malignant diseases. MIS hepatectomy in the elderly Medicare beneficiary population reduced LOS among patients without cirrhosis, yet was not associated with differences in morbidity or mortality.
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Affiliation(s)
- Kota Sahara
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA.,Gastroenterological Surgery Division, Yokohama City University School of Medicine, Yokohama, Japan
| | - Anghela Z Paredes
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Diamantis I Tsilimigras
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - J Madison Hyer
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Katiuscha Merath
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Lu Wu
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Rittal Mehta
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Eliza W Beal
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Susan White
- Division of Health Information Management and Systems, The Ohio State Wexner Medical Center, The Ohio State University, Columbus, OH, USA
| | - Itaru Endo
- Gastroenterological Surgery Division, Yokohama City University School of Medicine, Yokohama, Japan
| | - Timothy M Pawlik
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA. .,Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, The Ohio State University, Wexner Medical Center, 395 W. 12th Ave., Suite 670, Columbus, OH, USA.
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Oxidative Stress in Neurodegenerative Diseases: From a Mitochondrial Point of View. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:2105607. [PMID: 31210837 PMCID: PMC6532273 DOI: 10.1155/2019/2105607] [Citation(s) in RCA: 318] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 04/15/2019] [Indexed: 12/12/2022]
Abstract
Age is the main risk factor for a number of human diseases, including neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, which increasing numbers of elderly individuals suffer. These pathological conditions are characterized by progressive loss of neuron cells, compromised motor or cognitive functions, and accumulation of abnormally aggregated proteins. Mitochondrial dysfunction is one of the main features of the aging process, particularly in organs requiring a high-energy source such as the heart, muscles, brain, or liver. Neurons rely almost exclusively on the mitochondria, which produce the energy required for most of the cellular processes, including synaptic plasticity and neurotransmitter synthesis. The brain is particularly vulnerable to oxidative stress and damage, because of its high oxygen consumption, low antioxidant defenses, and high content of polyunsaturated fats very prone to be oxidized. Thus, it is not surprising the importance of protecting systems, including antioxidant defenses, to maintain neuronal integrity and survival. Here, we review the role of mitochondrial oxidative stress in the aging process, with a specific focus on neurodegenerative diseases. Understanding the molecular mechanisms involving mitochondria and oxidative stress in the aging and neurodegeneration may help to identify new strategies for improving the health and extending lifespan.
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Stahl EC, Haschak MJ, Popovic B, Brown BN. Macrophages in the Aging Liver and Age-Related Liver Disease. Front Immunol 2018; 9:2795. [PMID: 30555477 PMCID: PMC6284020 DOI: 10.3389/fimmu.2018.02795] [Citation(s) in RCA: 117] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 11/13/2018] [Indexed: 12/11/2022] Open
Abstract
The number of individuals aged 65 or older is projected to increase globally from 524 million in 2010 to nearly 1. 5 billion in 2050. Aged individuals are particularly at risk for developing chronic illness, while being less able to regenerate healthy tissue and tolerate whole organ transplantation procedures. In the liver, these age-related diseases include non-alcoholic fatty liver disease, alcoholic liver disease, hepatitis, fibrosis, and cirrhosis. Hepatic macrophages, a population comprised of both Kupffer cells and infiltrating monocyte derived macrophages, are implicated in several chronic liver diseases and also play important roles in the homeostatic functions of the liver. The effects of aging on hepatic macrophage population dynamics, polarization, and function are not well understood. Studies performed on macrophages derived from other aged sources, such as the bone marrow, peritoneal cavity, lungs, and brain, demonstrate general reductions in autophagy and phagocytosis, dysfunction in cytokine signaling, and altered morphology and distribution, likely mediated by epigenetic changes and mitochondrial defects, that may be applicable to hepatic macrophages. This review highlights recent findings in macrophage developmental biology and function, particularly in the liver, and discusses the role of macrophages in various age-related liver diseases. A better understanding of the biology of aging that influences hepatic macrophages and thus the progression of chronic liver disease will be crucial in order to develop new interventions and treatments for liver disease in aging populations.
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Affiliation(s)
- Elizabeth C Stahl
- Department of Bioengineering, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Martin J Haschak
- Department of Bioengineering, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Branimir Popovic
- Department of Bioengineering, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Bryan N Brown
- Department of Bioengineering, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
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Andrianova NV, Jankauskas SS, Zorova LD, Pevzner IB, Popkov VA, Silachev DN, Plotnikov EY, Zorov DB. Mechanisms of Age-Dependent Loss of Dietary Restriction Protective Effects in Acute Kidney Injury. Cells 2018; 7:cells7100178. [PMID: 30360430 PMCID: PMC6209903 DOI: 10.3390/cells7100178] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 10/16/2018] [Accepted: 10/19/2018] [Indexed: 11/24/2022] Open
Abstract
Dietary restriction (DR) is one of the most efficient approaches ameliorating the severity of different pathological conditions including aging. We investigated the protective potential of short-term DR in the model of acute kidney injury (AKI) in young and old rats. In kidney tissue, the levels of autophagy and mitophagy were examined, and proliferative properties of renal cells obtained from rats of different age were compared. DR afforded a significant nephroprotection to ischemic kidneys of young rats. However, in old rats, DR did not provide such beneficial effect. On the assessment of the autophagy marker, the LC3 II/LC3 I ratio, and after staining the tissue with LysoTracker Green, we concluded that in old rats activity of the autophagic-lysosomal system decreased. Mitophagy, as assessed by the levels of PINK-1, was also deteriorated in old animals. Renal cells from old rats showed impaired proliferative capacity, a worse rate of recovery after ischemic injury, increased levels of oxidative stress, accumulation of lipofuscin granules and lower mitochondria membrane potential. The results suggest that the loss of DR benefits in old animals could be due to deterioration in the autophagy/mitophagy flux.
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Affiliation(s)
- Nadezda V Andrianova
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119992 Moscow, Russia.
| | - Stanislovas S Jankauskas
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia.
| | - Ljubava D Zorova
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia.
| | - Irina B Pevzner
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia.
| | - Vasily A Popkov
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119992 Moscow, Russia.
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia.
| | - Denis N Silachev
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia.
| | - Egor Y Plotnikov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia.
| | - Dmitry B Zorov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia.
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Šilkūnienė G, Žūkienė R, Naučienė Z, Degutytė-Fomins L, Mildažienė V. Impact of Gender and Age on Hyperthermia-Induced Changes in Respiration of Liver Mitochondria. ACTA ACUST UNITED AC 2018; 54:medicina54040062. [PMID: 30344293 PMCID: PMC6174333 DOI: 10.3390/medicina54040062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 08/28/2018] [Accepted: 08/29/2018] [Indexed: 11/29/2022]
Abstract
Aim: This study aimed to compare hyperthermia-induced changes in respiration and generation of reactive oxygen species (ROS) in liver mitochondria derived from animals of different gender and age. Methods: The effects of hyperthermia (40–47 °C) on oxidation of different substrates and ROS production were estimated in mitochondria isolated from the liver of male and female rats of the 1–1.5, 3–4, or 6–7 months age. Results: Gender-dependent differences in response of respiration to hyperthermia were the highest at 3–4 months of age, less so at 6–7 months of age, and only minor at juvenile age. Mild hyperthermia (40–42 °C) stimulated pyruvate + malate oxidation in mitochondria of females, but inhibited in mitochondria of males in the 3–4 month age group. The resistance of mitochondrial membrane to hyperthermia was the highest at 3–4 month males, and the lowest in the 6–7 month age group. Inhibition of glutamate + malate oxidation by hyperthermia was caused by thermal inactivation of glutamate dehydrogenase. ROS generation at 37 °C was higher at 1–1.5 month of age, but the increase in ROS generation with rise in temperature in this age group was the smallest, and the strongest in 6–7 month old animals of both genders. Conclusions: The response to hyperthermia varies during the first 6–7 months of life of experimental animals: stronger gender dependence is characteristic at 3–4 months of age, while mitochondria from 6–7 months animals are less resistant to hyperthermia.
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Affiliation(s)
- Giedrė Šilkūnienė
- Department of Biochemistry, Faculty of Natural Sciences, Vytautas Magnus University, LT-44404 Kaunas, Lithuania.
| | - Rasa Žūkienė
- Department of Biochemistry, Faculty of Natural Sciences, Vytautas Magnus University, LT-44404 Kaunas, Lithuania.
| | - Zita Naučienė
- Department of Biochemistry, Faculty of Natural Sciences, Vytautas Magnus University, LT-44404 Kaunas, Lithuania.
| | - Laima Degutytė-Fomins
- Department of Biochemistry, Faculty of Natural Sciences, Vytautas Magnus University, LT-44404 Kaunas, Lithuania.
| | - Vida Mildažienė
- Department of Biochemistry, Faculty of Natural Sciences, Vytautas Magnus University, LT-44404 Kaunas, Lithuania.
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Panel M, Ghaleh B, Morin D. Mitochondria and aging: A role for the mitochondrial transition pore? Aging Cell 2018; 17:e12793. [PMID: 29888494 PMCID: PMC6052406 DOI: 10.1111/acel.12793] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/15/2018] [Indexed: 12/15/2022] Open
Abstract
The cellular mechanisms responsible for aging are poorly understood. Aging is considered as a degenerative process induced by the accumulation of cellular lesions leading progressively to organ dysfunction and death. The free radical theory of aging has long been considered the most relevant to explain the mechanisms of aging. As the mitochondrion is an important source of reactive oxygen species (ROS), this organelle is regarded as a key intracellular player in this process and a large amount of data supports the role of mitochondrial ROS production during aging. Thus, mitochondrial ROS, oxidative damage, aging, and aging-dependent diseases are strongly connected. However, other features of mitochondrial physiology and dysfunction have been recently implicated in the development of the aging process. Here, we examine the potential role of the mitochondrial permeability transition pore (mPTP) in normal aging and in aging-associated diseases.
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Affiliation(s)
- Mathieu Panel
- INSERM U955, équipe 3; Créteil France
- Université Paris-Est, UMR_S955, DHU A-TVB, UPEC; Créteil France
| | - Bijan Ghaleh
- INSERM U955, équipe 3; Créteil France
- Université Paris-Est, UMR_S955, DHU A-TVB, UPEC; Créteil France
| | - Didier Morin
- INSERM U955, équipe 3; Créteil France
- Université Paris-Est, UMR_S955, DHU A-TVB, UPEC; Créteil France
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Giorgi C, Marchi S, Simoes IC, Ren Z, Morciano G, Perrone M, Patalas-Krawczyk P, Borchard S, Jȩdrak P, Pierzynowska K, Szymański J, Wang DQ, Portincasa P, Wȩgrzyn G, Zischka H, Dobrzyn P, Bonora M, Duszynski J, Rimessi A, Karkucinska-Wieckowska A, Dobrzyn A, Szabadkai G, Zavan B, Oliveira PJ, Sardao VA, Pinton P, Wieckowski MR. Mitochondria and Reactive Oxygen Species in Aging and Age-Related Diseases. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2018; 340:209-344. [PMID: 30072092 PMCID: PMC8127332 DOI: 10.1016/bs.ircmb.2018.05.006] [Citation(s) in RCA: 256] [Impact Index Per Article: 36.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Aging has been linked to several degenerative processes that, through the accumulation of molecular and cellular damage, can progressively lead to cell dysfunction and organ failure. Human aging is linked with a higher risk for individuals to develop cancer, neurodegenerative, cardiovascular, and metabolic disorders. The understanding of the molecular basis of aging and associated diseases has been one major challenge of scientific research over the last decades. Mitochondria, the center of oxidative metabolism and principal site of reactive oxygen species (ROS) production, are crucial both in health and in pathogenesis of many diseases. Redox signaling is important for the modulation of cell functions and several studies indicate a dual role for ROS in cell physiology. In fact, high concentrations of ROS are pathogenic and can cause severe damage to cell and organelle membranes, DNA, and proteins. On the other hand, moderate amounts of ROS are essential for the maintenance of several biological processes, including gene expression. In this review, we provide an update regarding the key roles of ROS-mitochondria cross talk in different fundamental physiological or pathological situations accompanying aging and highlighting that mitochondrial ROS may be a decisive target in clinical practice.
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Affiliation(s)
- Carlotta Giorgi
- Department of Morphology Surgery and Experimental Medicine, Section of Pathology Oncology and Experimental Biology, Interdisciplinary Center for the Study of Inflammation (ICSI), Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
| | - Saverio Marchi
- Department of Morphology Surgery and Experimental Medicine, Section of Pathology Oncology and Experimental Biology, Interdisciplinary Center for the Study of Inflammation (ICSI), Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
| | - Ines C.M. Simoes
- Department of Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
| | - Ziyu Ren
- Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, United Kingdom
| | - Giampaolo Morciano
- Department of Morphology Surgery and Experimental Medicine, Section of Pathology Oncology and Experimental Biology, Interdisciplinary Center for the Study of Inflammation (ICSI), Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
- Cecilia Hospital, GVM Care & Research, 48033 Cotignola, Ravenna, Italy
- Maria Pia Hospital, GVM Care & Research, Torino, Italy
| | - Mariasole Perrone
- Department of Morphology Surgery and Experimental Medicine, Section of Pathology Oncology and Experimental Biology, Interdisciplinary Center for the Study of Inflammation (ICSI), Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
| | - Paulina Patalas-Krawczyk
- Department of Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
| | - Sabine Borchard
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Paulina Jȩdrak
- Department of Molecular Biology, University of Gdańsk, Gdańsk, Poland
| | | | - Jȩdrzej Szymański
- Department of Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
| | - David Q. Wang
- Department of Medicine, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Dept. of Biomedical Sciences & Human Oncology, University of Bari "Aldo Moro" Medical School, Bari, Italy
| | - Grzegorz Wȩgrzyn
- Department of Molecular Biology, University of Gdańsk, Gdańsk, Poland
| | - Hans Zischka
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
- Institute of Toxicology and Environmental Hygiene, Technical University Munich, Munich, Germany
| | - Pawel Dobrzyn
- Department of Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
| | - Massimo Bonora
- Departments of Cell Biology and Gottesman Institute for Stem Cell & Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Jerzy Duszynski
- Department of Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
| | - Alessandro Rimessi
- Department of Morphology Surgery and Experimental Medicine, Section of Pathology Oncology and Experimental Biology, Interdisciplinary Center for the Study of Inflammation (ICSI), Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
| | | | | | - Gyorgy Szabadkai
- Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, United Kingdom
- The Francis Crick Institute, London, United Kingdom
- Department of Biomedical Sciences, University of Padua, Padua, Italy
| | - Barbara Zavan
- Cecilia Hospital, GVM Care & Research, 48033 Cotignola, Ravenna, Italy
- Department of Biomedical Sciences, University of Padua, Padua, Italy
| | - Paulo J. Oliveira
- CNC - Center for Neuroscience and Cell Biology, UC-Biotech, Biocant Park, University of Coimbra, Cantanhede, Portugal
| | - Vilma A. Sardao
- CNC - Center for Neuroscience and Cell Biology, UC-Biotech, Biocant Park, University of Coimbra, Cantanhede, Portugal
| | - Paolo Pinton
- Department of Morphology Surgery and Experimental Medicine, Section of Pathology Oncology and Experimental Biology, Interdisciplinary Center for the Study of Inflammation (ICSI), Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
- Cecilia Hospital, GVM Care & Research, 48033 Cotignola, Ravenna, Italy
| | - Mariusz R. Wieckowski
- Department of Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
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Theurey P, Pizzo P. The Aging Mitochondria. Genes (Basel) 2018; 9:genes9010022. [PMID: 29315229 PMCID: PMC5793175 DOI: 10.3390/genes9010022] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 12/15/2017] [Accepted: 01/04/2018] [Indexed: 12/14/2022] Open
Abstract
Mitochondrial dysfunction is a central event in many pathologies and contributes as well to age-related processes. However, distinguishing between primary mitochondrial dysfunction driving aging and a secondary mitochondrial impairment resulting from other cell alterations remains challenging. Indeed, even though mitochondria undeniably play a crucial role in aging pathways at the cellular and organismal level, the original hypothesis in which mitochondrial dysfunction and production of free radicals represent the main driving force of cell degeneration has been strongly challenged. In this review, we will first describe mitochondrial dysfunctions observed in aged tissue, and how these features have been linked to mitochondrial reactive oxygen species (ROS)–mediated cell damage and mitochondrial DNA (mtDNA) mutations. We will also discuss the clues that led to consider mitochondria as the starting point in the aging process, and how recent research has showed that the mitochondria aging axis represents instead a more complex and multifactorial signaling pathway. New working hypothesis will be also presented in which mitochondria are considered at the center of a complex web of cell dysfunctions that eventually leads to cell senescence and death.
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Affiliation(s)
- Pierre Theurey
- Department of Biomedical Sciences, University of Padova, Padova 35121, Italy.
| | - Paola Pizzo
- Department of Biomedical Sciences, University of Padova, Padova 35121, Italy.
- Neuroscience Institute, National Research Council (CNR), Padova 35121, Italy.
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Antikainen H, Driscoll M, Haspel G, Dobrowolski R. TOR-mediated regulation of metabolism in aging. Aging Cell 2017; 16:1219-1233. [PMID: 28971552 PMCID: PMC5676073 DOI: 10.1111/acel.12689] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2017] [Indexed: 01/06/2023] Open
Abstract
Cellular metabolism is regulated by the mTOR kinase, a key component of the molecular nutrient sensor pathway that plays a central role in cellular survival and aging. The mTOR pathway promotes protein and lipid synthesis and inhibits autophagy, a process known for its contribution to longevity in several model organisms. The nutrient‐sensing pathway is regulated at the lysosomal membrane by a number of proteins for which deficiency triggers widespread aging phenotypes in tested animal models. In response to environmental cues, this recently discovered lysosomal nutrient‐sensing complex regulates autophagy transcriptionally through conserved factors, such as the transcription factors TFEB and FOXO, associated with lifespan extension. This key metabolic pathway strongly depends on nucleocytoplasmic compartmentalization, a cellular phenomenon gradually lost during aging. In this review, we discuss the current progress in understanding the contribution of mTOR‐regulating factors to autophagy and longevity. Furthermore, we review research on the regulation of metabolism conducted in multiple aging models, including Caenorhabditis elegans, Drosophila and mouse, and human iPSCs. We suggest that conserved molecular pathways have the strongest potential for the development of new avenues for treatment of age‐related diseases.
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Affiliation(s)
- Henri Antikainen
- Federated Department of Biological Sciences New Jersey Institute of Technology Rutgers University Newark NJ 07102 USA
| | - Monica Driscoll
- Department of Molecular Biology and Biochemistry Rutgers University Piscataway NJ 08854 USA
| | - Gal Haspel
- Federated Department of Biological Sciences New Jersey Institute of Technology Rutgers University Newark NJ 07102 USA
| | - Radek Dobrowolski
- Federated Department of Biological Sciences New Jersey Institute of Technology Rutgers University Newark NJ 07102 USA
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The mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic TCA cycle capacity. Mol Metab 2017; 6:1468-1479. [PMID: 29107293 PMCID: PMC5681281 DOI: 10.1016/j.molmet.2017.09.002] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 09/08/2017] [Accepted: 09/12/2017] [Indexed: 01/18/2023] Open
Abstract
Objective Excessive hepatic gluconeogenesis is a defining feature of type 2 diabetes (T2D). Most gluconeogenic flux is routed through mitochondria. The mitochondrial pyruvate carrier (MPC) transports pyruvate from the cytosol into the mitochondrial matrix, thereby gating pyruvate-driven gluconeogenesis. Disruption of the hepatocyte MPC attenuates hyperglycemia in mice during high fat diet (HFD)-induced obesity but exerts minimal effects on glycemia in normal chow diet (NCD)-fed conditions. The goal of this investigation was to test whether hepatocyte MPC disruption provides sustained protection from hyperglycemia during long-term HFD and the differential effects of hepatocyte MPC disruption on TCA cycle metabolism in NCD versus HFD conditions. Method We utilized long-term high fat feeding, serial measurements of postabsorptive blood glucose and metabolomic profiling and 13C-lactate/13C-pyruvate tracing to investigate the contribution of the MPC to hyperglycemia and altered hepatic TCA cycle metabolism during HFD-induced obesity. Results Hepatocyte MPC disruption resulted in long-term attenuation of hyperglycemia induced by HFD. HFD increased hepatic mitochondrial pyruvate utilization and TCA cycle capacity in an MPC-dependent manner. Furthermore, MPC disruption decreased progression of fibrosis and levels of transcript markers of inflammation. Conclusions By contributing to chronic hyperglycemia, fibrosis, and TCA cycle expansion, the hepatocyte MPC is a key mediator of the pathophysiology induced in the HFD model of T2D.
Hepatic MPC disruption protects from hyperglycemia during long-term HFD. HFD increases TCA cycle metabolite pool capacity and flux. Hepatic MPC disruption abrogates HFD-induced TCA cycle expansion.
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Schofield Z, Reed MAC, Newsome PN, Adams DH, Günther UL, Lalor PF. Changes in human hepatic metabolism in steatosis and cirrhosis. World J Gastroenterol 2017; 23:2685-2695. [PMID: 28487605 PMCID: PMC5403747 DOI: 10.3748/wjg.v23.i15.2685] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Revised: 01/11/2017] [Accepted: 03/15/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To understand the underlying metabolic changes in human liver disease we have applied nuclear magnetic resonance (NMR) metabolomics analysis to human liver tissue.
METHODS We have carried out pilot study using 1H-NMR to derive metabolomic signatures from human liver from patients with steatosis, nonalcoholic steatohepatitis (NASH) or alcohol-related liver damage (ARLD) to identify species that can predict outcome and discriminate between alcohol and metabolic-induced liver injuries.
RESULTS Changes in branched chain amino acid homeostasis, tricarboxylic acid cycle and purine biosynthesis intermediates along with betaine were associated with the development of cirrhosis in both ARLD and nonalcoholic fatty liver disease. Species such as propylene glycol and as yet unidentified moieties that allowed discrimination between NASH and ARLD samples were also detected using our approach.
CONCLUSION Our high throughput, non-destructive technique for multiple analyte quantification in human liver specimens has potential for identification of biomarkers with prognostic and diagnostic significance.
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48
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Bell R, Pandanaboyana S, Nisar S, Upasani V, Toogood G, Lodge JP, Prasad KR. The Impact of Advancing Age on Recurrence and Survival Following Major Hepatectomy for Colorectal Liver Metastases. J Gastrointest Surg 2017; 21:266-274. [PMID: 27770289 DOI: 10.1007/s11605-016-3296-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 10/03/2016] [Indexed: 01/31/2023]
Abstract
INTRODUCTION This study analysed the effect of age on survival in patients undergoing major hepatectomy (MH) for colorectal liver metastases (CRLM). The effect of adjuvant chemotherapy (AC) with age was also assessed. METHOD Patients undergoing MH for CRLM between 1996 and 2011 were reviewed. Patients aged <75 or ≥75 were compared for disease-free (DFS) and overall survival (OS) as well as impact of AC on survival. RESULTS Seven hundred twenty-seven patients underwent MH of which 105 (14 %) were aged ≥75. Morbidity was greater in the ≥75 group (25 versus 34 %, p = 0.048). No difference was noted in mortality. There was no difference in DFS between the two groups at 5 years (16.8 vs 18.9 months (p = 0.570). OS was longer in the <75 group (38.6 vs 32.0 months (p = 0.001). DFS was better in groups receiving AC than those not (<75 24.2 vs 12.2 months (p = <0.001) and ≥75 24 vs 12.1 months (p = 0.007)). OS in the ≥75 group was improved in the group receiving AC compared to the ≥75 group not (41.1 vs 16.6 months, p = 0.005). Age ≥75 was not an independent risk factor for reduced DFS on multivariate analysis. CONCLUSION Well-selected patients aged ≥75 should be considered for MH followed by adjuvant chemotherapy.
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Affiliation(s)
- Richard Bell
- Department of Hepatobiliary and Transplant Surgery, St James University Hospital, ICU Offices, Level 3 Bexley Wing, Leeds, LS9 7TF, UK.
| | - Sanjay Pandanaboyana
- Department of Hepatobiliary Surgery, Auckland City Hospital, Auckland, New Zealand.,Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Saira Nisar
- Department of Hepatobiliary and Transplant Surgery, St James University Hospital, ICU Offices, Level 3 Bexley Wing, Leeds, LS9 7TF, UK
| | - Vivek Upasani
- Department of Hepatobiliary and Transplant Surgery, St James University Hospital, ICU Offices, Level 3 Bexley Wing, Leeds, LS9 7TF, UK
| | - Giles Toogood
- Department of Hepatobiliary and Transplant Surgery, St James University Hospital, ICU Offices, Level 3 Bexley Wing, Leeds, LS9 7TF, UK
| | - J Peter Lodge
- Department of Hepatobiliary and Transplant Surgery, St James University Hospital, ICU Offices, Level 3 Bexley Wing, Leeds, LS9 7TF, UK
| | - K Raj Prasad
- Department of Hepatobiliary and Transplant Surgery, St James University Hospital, ICU Offices, Level 3 Bexley Wing, Leeds, LS9 7TF, UK
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Viña J, Salvador-Pascual A, Tarazona-Santabalbina FJ, Rodriguez-Mañas L, Gomez-Cabrera MC. Exercise training as a drug to treat age associated frailty. Free Radic Biol Med 2016; 98:159-164. [PMID: 27021963 DOI: 10.1016/j.freeradbiomed.2016.03.024] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 03/16/2016] [Accepted: 03/24/2016] [Indexed: 12/31/2022]
Abstract
Exercise causes an increase in the production of free radicals [1]. As a result of a hormetic mechanism antioxidant enzymes are synthesised and the cells are protected against further oxidative stress. Thus, exercise can be considered as an antioxidant [2]. Age-associated frailty is a major medical and social concern as it can easily lead to dependency. In this review we describe that oxidative stress is associated with frailty and the mechanism by which exercise prevents age-associated frailty. We propose that individually tailored multicomponent exercise programmes are one of the best ways to prevent and to treat age-associated frailty.
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Affiliation(s)
- Jose Viña
- Department of Physiology, University of Valencia, Investigación Hospital Clínico Universitario/INCLIVA, Spain; Hospital Universitario de la Ribera, Alzira, Valencia, Spain; School of Nursing, Catholic University of Valencia San Vicente Mártir, Spain; Servicio de Geriatría, Hospital Universitario de Getafe, Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), Instituto de Salud Carlos III, Spain
| | - Andrea Salvador-Pascual
- Department of Physiology, University of Valencia, Investigación Hospital Clínico Universitario/INCLIVA, Spain; Hospital Universitario de la Ribera, Alzira, Valencia, Spain; School of Nursing, Catholic University of Valencia San Vicente Mártir, Spain; Servicio de Geriatría, Hospital Universitario de Getafe, Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), Instituto de Salud Carlos III, Spain
| | | | - Leocadio Rodriguez-Mañas
- Servicio de Geriatría, Hospital Universitario de Getafe, Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), Instituto de Salud Carlos III, Spain
| | - Mari Carmen Gomez-Cabrera
- Department of Physiology, University of Valencia, Investigación Hospital Clínico Universitario/INCLIVA, Spain; Hospital Universitario de la Ribera, Alzira, Valencia, Spain; School of Nursing, Catholic University of Valencia San Vicente Mártir, Spain; Servicio de Geriatría, Hospital Universitario de Getafe, Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), Instituto de Salud Carlos III, Spain.
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Mahmoud YI, Hegazy HG. Ginger and alpha lipoic acid ameliorate age-related ultrastructural changes in rat liver. Biotech Histochem 2015; 91:86-95. [PMID: 26528730 DOI: 10.3109/10520295.2015.1076578] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Because of the important role that oxidative stress is thought to play in the aging process, antioxidants could be candidates for preventing its related pathologies. We investigated the ameliorative effects of two antioxidant supplements, ginger and alpha lipoic acid (ALA), on hepatic ultrastructural alterations in old rats. Livers of young (4 months) and old (24 months) Wistar rats were studied using transmission electron microscopy. Livers of old rats showed sinusoidal collapse and congestion, endothelial thickening and defenestration, and inconsistent perisinusoidal extracellular matrix deposition. Aged hepatocytes were characterized by hypertrophy, cytoplasmic vacuolization and a significant increase in the volume densities of the nuclei, mitochondria and dense bodies. Lipofuscin accumulation and decreased microvilli in bile canaliculi and space of Disse also were observed. The adverse alterations were ameliorated significantly by both ginger and ALA supplementation; ALA was more effective than ginger. Ginger and ALA appear to be promising anti-aging agents based on their amelioration of ultrastructural alterations in livers of old rats.
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Affiliation(s)
- Y I Mahmoud
- a Zoology Department, Faculty of Science , Ain Shams University , Cairo , Egypt
| | - H G Hegazy
- a Zoology Department, Faculty of Science , Ain Shams University , Cairo , Egypt
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