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Parolini C. Pathophysiology of bone remodelling cycle: Role of immune system and lipids. Biochem Pharmacol 2025; 235:116844. [PMID: 40044049 DOI: 10.1016/j.bcp.2025.116844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/31/2025] [Accepted: 02/28/2025] [Indexed: 03/15/2025]
Abstract
Osteoporosis is the most common skeletal disease worldwide, characterized by low bone mineral density, resulting in weaker bones, and an increased risk of fragility fractures. The maintenance of bone mass relies on the precise balance between bone synthesis and resorption. The close relationship between the immune and skeletal systems, called "osteoimmunology", was coined to identify these overlapping "scientific worlds", and its function resides in the evaluation of the mutual effects of the skeletal and immune systems at the molecular and cellular levels, in both physiological and pathological states. Lipids play an essential role in skeletal metabolism and bone health. Indeed, bone marrow and its skeletal components demand a dramatic amount of daily energy to control hematopoietic turnover, acquire and maintain bone mass, and actively being involved in whole-body metabolism. Statins, the main therapeutic agents in lowering plasma cholesterol levels, are able to promote osteoblastogenesis and inhibit osteoclastogenesis. This review is meant to provide an updated overview of the pathophysiology of bone remodelling cycle, focusing on the interplay between bone, immune system and lipids. Novel therapeutic strategies for the management of osteoporosis are also discussed.
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Affiliation(s)
- Cinzia Parolini
- Department of Pharmacological and Biomolecular Sciences, 'Rodolfo Paoletti', via Balzaretti 9 - Università degli Studi di Milano 20133 Milano, Italy.
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Bertolotti M, Pirotti T, Castellani Tarabini GI, Lancellotti G, Cuccorese M, Trenti T, Mussi C. Modifications in hemoglobin levels associated with age in an outpatient population from northern italy. Sci Rep 2025; 15:8960. [PMID: 40089520 PMCID: PMC11910594 DOI: 10.1038/s41598-025-92363-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 02/27/2025] [Indexed: 03/17/2025] Open
Abstract
A reduction in hemoglobin levels is common in older subjects. The objective of this study was to investigate the association between changes in blood counts and age in a large outpatient population of adult subjects, in order to verify to what extent such changes may be considered physiological.We examined blood count results in the province of Modena (Italy) from January 2010 to August 2022. Data were analyzed with the platform Anaconda 3, Python 3.7. Appropriate hemoglobin data were extracted from 4,676,003 samples. Hemoglobin levels in subjects over 75 years were largely below lower limits for both sexes (49.3% of 509,834 exams and 35.4% of 704,343 exams for males and females, respectively). The trend was similar in relation to single values per person per year. To exclude patients with some major systemic diseases, we limited our observation to subjects with normal values of serum glucose, creatinine, and alanine transaminase (ALT). In this set of 822,166 analyses, a clinically relevant proportion of older males (nearly 30%) still had hemoglobin values below normal. Such trend was apparent in older age strata. Our findings suggest caution in the interpretation of blood counts in older patients. We therefore advocate a tailored approach in this population.
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Affiliation(s)
- Marco Bertolotti
- Department of Biomedical, Metabolic and Neural Sciences and Center for Gerontological Evaluation and Research, University of Modena and Reggio Emilia, Via Campi 287, 41125, Modena, Italy.
- Division of Geriatric Medicine, University Hospital of Modena, Baggiovara City Hospital, Via Giardini 1355, 41126, Modena, Italy.
| | - Tommaso Pirotti
- Department of Laboratory Medicine and Pathology, Health District of Modena, Baggiovara City Hospital, Via Giardini 1355, 41126, Modena, Italy
| | - Giulia Isha Castellani Tarabini
- Department of Biomedical, Metabolic and Neural Sciences and Center for Gerontological Evaluation and Research, University of Modena and Reggio Emilia, Via Campi 287, 41125, Modena, Italy
- Division of Geriatric Medicine, University Hospital of Modena, Baggiovara City Hospital, Via Giardini 1355, 41126, Modena, Italy
| | - Giulia Lancellotti
- Department of Biomedical, Metabolic and Neural Sciences and Center for Gerontological Evaluation and Research, University of Modena and Reggio Emilia, Via Campi 287, 41125, Modena, Italy
- Division of Geriatric Medicine, University Hospital of Modena, Baggiovara City Hospital, Via Giardini 1355, 41126, Modena, Italy
| | - Michela Cuccorese
- Department of Laboratory Medicine and Pathology, Health District of Modena, Baggiovara City Hospital, Via Giardini 1355, 41126, Modena, Italy
| | - Tommaso Trenti
- Department of Laboratory Medicine and Pathology, Health District of Modena, Baggiovara City Hospital, Via Giardini 1355, 41126, Modena, Italy
| | - Chiara Mussi
- Department of Biomedical, Metabolic and Neural Sciences and Center for Gerontological Evaluation and Research, University of Modena and Reggio Emilia, Via Campi 287, 41125, Modena, Italy
- Division of Geriatric Medicine, University Hospital of Modena, Baggiovara City Hospital, Via Giardini 1355, 41126, Modena, Italy
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Evripidou K, Chainoglou A, Kotsis V, Stabouli S. Challenges in blood pressure measurement in children with obesity: focus on the cuff. Pediatr Nephrol 2025:10.1007/s00467-025-06678-5. [PMID: 39907759 DOI: 10.1007/s00467-025-06678-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 01/02/2025] [Accepted: 01/05/2025] [Indexed: 02/06/2025]
Abstract
Childhood obesity is a well-known risk factor for primary hypertension (HTN), especially during puberty. Validated automated oscillometric devices based on universal protocols using proper cuffs according to arm sizes must be selected for blood pressure (BP) measurement in clinical practice. Recent recommendations have addressed the importance of accurate BP measurement in patients with obesity. The American Heart Association (AHA) suggests using a cone-shaped cuff, while the European Society of Hypertension (ESH) emphasizes the significance of cuff characteristics based on arm size. The applicability of cone-shaped cuffs over cylindrical cuffs has been studied in adults with obesity. Most studies focused on the upper arm's shape and provided evidence that the use of cylindrical cuffs may overestimate BP in individuals with obesity, while the conical cuff was proposed as a proper alternative. However, current validation studies for BP measurement devices have not included the arm's size as a recruiting criterion, which may compromise the accuracy of devices in individuals with obesity. This review discusses the role of arm characteristics in cuff selection and the potential role of conical cuffs as an alternative to commonly used cylindrical ones in BP measurement in pediatric patients with obesity.
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Affiliation(s)
- Kleo Evripidou
- 1st Department of Pediatrics, Hippokration General Hospital, Aristotle University Thessaloniki, Thessaloniki, Greece
| | - Athanasia Chainoglou
- 1st Department of Pediatrics, Hippokration General Hospital, Aristotle University Thessaloniki, Thessaloniki, Greece
| | - Vasilios Kotsis
- 3rd Department of Internal Medicine, Papageorgiou Hospital, Aristotle University Thessaloniki, Thessaloniki, Greece
| | - Stella Stabouli
- 1st Department of Pediatrics, Hippokration General Hospital, Aristotle University Thessaloniki, Thessaloniki, Greece.
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Alves I, Araújo EMQ, Dalgaard LT, Singh S, Børsheim E, Carvalho E. Protective Effects of Sulforaphane Preventing Inflammation and Oxidative Stress to Enhance Metabolic Health: A Narrative Review. Nutrients 2025; 17:428. [PMID: 39940284 PMCID: PMC11821257 DOI: 10.3390/nu17030428] [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: 12/06/2024] [Revised: 01/13/2025] [Accepted: 01/16/2025] [Indexed: 02/14/2025] Open
Abstract
The worldwide obesity epidemic has led to a drastic increase in diabetes and cardiovascular disease in younger generations. Further, maintaining metabolic health during aging is frequently a challenge due to poor diets and decreased mobility. In this setting, bioactive nutrients that are naturally occurring antioxidants, such as sulforaphane (SFN), are of high nutritional interest. SFN, a bioactive compound that is present in cruciferous vegetables, is a molecule that protects cells from cytotoxic damage and mitigates oxidative stress, protecting against disease. It exerts its action through the activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). Many studies have been performed in animals and humans to evaluate its effects on cancer, brain health, and neurodegenerative disorders. However, fewer clinical studies have been performed to evaluate its effects on insulin resistance and the development of type 2 diabetes mellitus (T2DM) across the lifespan. Given that, in some parts of the world, particularly in Europe, the population is growing older at a significant rate, it is crucial to promote healthy habits (healthy foods, dietary pattern, precision nutrition, and physical activity) from an early stage in life and across the lifespan to avoid debilitating health conditions occurring during adulthood and aging. Thus, in this narrative review, we discuss the protective effects of SFN supplementation on inflammatory and oxidative stress pathways and relate them to metabolic disease.
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Affiliation(s)
- Inês Alves
- Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal;
- Arkansas Children’s Research Institute, Little Rock, AR 72202, USA;
| | - Edilene Maria Queiroz Araújo
- Nutritional Genomics and Metabolic Dysfunctions Research and Extension Center, Department of Life Sciences, State University of Bahia, Salvador 41195001, BA, Brazil;
| | - Louise T. Dalgaard
- Department of Science and Environment, Roskilde University, Universitetsvej 1, DK-4000 Roskilde, Denmark;
| | - Sharda Singh
- Division of Hematology & Oncology, Department of Internal Medicine, Texas Tech University Medical Sciences Center, Lubbock, TX 79430, USA;
| | - Elisabet Børsheim
- Arkansas Children’s Research Institute, Little Rock, AR 72202, USA;
- Department of Pediatrics & Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
- Arkansas Children’s Nutrition Center, Little Rock, AR 72202, USA
| | - Eugenia Carvalho
- CNC-UC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
- CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- Institute for Interdisciplinar Research, University of Coimbra, 3030-789 Coimbra, Portugal
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Evripidou K, Alvarez-Pitti J, De Blas-Zapata A, Chainoglou A, Goulas I, Herberigs K, Hamdani G, Stabouli S. Office BP measurement using conical cuffs in children and adolescents with obesity. Blood Press 2024; 33:2411294. [PMID: 39391937 DOI: 10.1080/08037051.2024.2411294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Accepted: 09/21/2024] [Indexed: 10/12/2024]
Abstract
OBJECTIVE Findings from adult studies suggest that tronco-conical cuffs provide more accurate blood pressure (BP) measurements in individuals with obesity. The aim of the present study was to examine differences in office blood pressure (BP) levels using conical cuffs compared to standard-shaped cylindrical cuffs in children and adolescents with obesity. DESIGN AND METHOD We performed an observational study, including 37 children and adolescents with obesity, who were consequently recruited from the outpatient clinics of the Obesity and Cardiovascular Risk Unit at General University Hospital Consortium of Valencia. Arm circumference AC was measured in all participants, and the appropriate cuff size was selected for both conical and cylindrical cuffs. RESULTS Mean participants' age was 11.8± 2.5 years, mean BMI was 28.8± 3.4 kg/m2, mean BMI z-score was 2.12± 0.32, and mean AC was 30.0± 3.6 cm. There was no statistical significance in BP levels measured by cylindrical compared to conical cuffs (mean difference cylindrical-conical cuff was -0.22± 6.55 mmHg for SBP, -0.02± 0.81 for SBP z-score, -0.70± 4.95 mmHg for DBP, and -0.06± 0.44 for DBP z-score). A significant positive association was found between the measurements obtained by cylindrical and conical cuffs in both mean and z-score SBP and DBP values (p < 0.001). Bland-Altman analysis showed good agreement, with 94.6% of the values for all BP parameters lying between the limits of agreement. CONCLUSIONS Although the use of conical cuffs in the study showed no advantage in enhancing the performance of BP measurements, they may be considered an alternative for office BP measurements in children and adolescents with obesity. Their reliability should be confirmed in larger populations and different settings.
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Affiliation(s)
- Kleo Evripidou
- 1st Department of Pediatrics, Hippocratio General Hospital, Aristotle University Thessaloniki, Thessaloniki, Greece
| | - Julio Alvarez-Pitti
- Pediatric Department, Consorcio Hospital General, University of Valencia, Valencia, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, Madrid, Spain
| | - Ana De Blas-Zapata
- Pediatric Department, Consorcio Hospital General, University of Valencia, Valencia, Spain
| | - Athanasia Chainoglou
- 1st Department of Pediatrics, Hippocratio General Hospital, Aristotle University Thessaloniki, Thessaloniki, Greece
| | - Ioannis Goulas
- 1st Department of Pediatrics, Hippocratio General Hospital, Aristotle University Thessaloniki, Thessaloniki, Greece
| | | | - Gilad Hamdani
- Nephrology and Hypertension Institute, Schneider Children's Medical Center, Petah Tikva, Israel
| | - Stella Stabouli
- 1st Department of Pediatrics, Hippocratio General Hospital, Aristotle University Thessaloniki, Thessaloniki, Greece
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Byun KA, Seo SB, Oh S, Jang JW, Son KH, Byun K. Poly-D,L-Lactic Acid Fillers Increase Subcutaneous Adipose Tissue Volume by Promoting Adipogenesis in Aged Animal Skin. Int J Mol Sci 2024; 25:12739. [PMID: 39684448 DOI: 10.3390/ijms252312739] [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: 11/10/2024] [Revised: 11/23/2024] [Accepted: 11/25/2024] [Indexed: 12/18/2024] Open
Abstract
During aging, subcutaneous white adipose tissue (sWAT) thickness and the adipogenic potential of adipose-derived stem cells (ASCs) decline. Poly-D,L-lactic acid (PDLLA) fillers are commonly used to restore diminished facial volume. Piezo1 increases polarizing macrophages towards the M2 phenotype, which promotes the secretion of fibroblast growth factor 2 (FGF2), thereby increasing ASC survival. This study evaluated whether PDLLA enhances adipogenesis in ASCs by modulating M2 polarization in an in vitro senescence model and in aged animals. Lipopolysaccharide (LPS)-induced senescent macrophages showed decreased Piezo1, which was upregulated by PDLLA. CD163 (an M2 marker) and FGF2 were downregulated in senescent macrophages but were upregulated by PDLLA. We evaluated whether reduced FGF2 secretion from senescent macrophages affects ASCs by applying conditioned media (CM) from macrophage cultures to ASCs. CM from senescent macrophages decreased ERK1/2 and proliferation in ASCs, both of which were restored by CM from PDLLA-stimulated senescent macrophages. Adipogenesis inducers (PPAR-γ and C/EBP-α) were downregulated by CM from senescent macrophages but upregulated by CM from PDLLA-stimulated senescent macrophages in ASCs. Similar patterns were observed in aged animal adipose tissue. PDLLA increased Piezo1 activity, M2 polarization, and FGF2 levels. PDLLA also enhanced ERK1/2, cell proliferation, PPAR-γ, and C/EBP-α expression, leading to increased adipose tissue thickness. In conclusion, our study showed that PDLLA increased adipose tissue thickness by modulating adipogenesis.
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Affiliation(s)
- Kyung-A Byun
- Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Republic of Korea
- LIBON Inc., Incheon 22006, Republic of Korea
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
| | - Suk Bae Seo
- SeoAh Song Dermatologic Clinic, Seoul 05557, Republic of Korea
| | - Seyeon Oh
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
| | - Jong-Won Jang
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
- Department of Health Sciences and Technology, Gachon Advanced Institute for Health & Sciences and Technology (GAIHST), Gachon University, Incheon 21999, Republic of Korea
| | - Kuk Hui Son
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon 21565, Republic of Korea
| | - Kyunghee Byun
- Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Republic of Korea
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
- Department of Health Sciences and Technology, Gachon Advanced Institute for Health & Sciences and Technology (GAIHST), Gachon University, Incheon 21999, Republic of Korea
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Daniel E, Smith IC, Sampaio ML, Melkus G, Hamilton LE, Bourque PR, Warman-Chardon J. Current biomarkers in inclusion body myositis. J Neuromuscul Dis 2024; 11:1165-1179. [PMID: 39967427 DOI: 10.1177/22143602241286712] [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] [Indexed: 02/20/2025]
Abstract
Inclusion body myositis (IBM) is an idiopathic muscle disorder primarily affecting adults above the age of 50. IBM is characterized by weakness in the knee extensor and deep finger flexor muscles due to muscle atrophy and fibroadipose replacement. Dynamometry and manual muscle testing are commonly used to assess patient muscle strength, while magnetic resonance imaging and electromyography studies identify the patterns of muscle atrophy and motor unit potentials. Although the underlying pathophysiological mechanisms of IBM are still unknown, common histopathological markers include rimmed vacuoles and inclusions. The immune system is also largely implicated in pathogenesis, as skeletal muscle in IBM overexpresses major histocompatibility complex I (MHC-I), and cluster of differentiation (CD) 8+ T-cells, and features endomysial inflammation. Antibodies to the cytosolic 5'-nucleotidase 1A (cN1A) protein have been associated with IBM but have low sensitivity and specificity. As many classic features of IBM present only in advanced stages of disease, there are substantial challenges to the diagnosis and monitoring of IBM progression in its early stages. Identifying early diagnostic biomarkers and new biomarker signatures associated with IBM disease progression is necessary for clinical trial readiness.
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Affiliation(s)
- Eden Daniel
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Ian C Smith
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Marcos L Sampaio
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Department of Medicine, Radiology, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Gerd Melkus
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Medicine, Radiology, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Leslie E Hamilton
- Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Department of Pathology & Laboratory Medicine, The Ottawa Hospital, Ottawa, Ontario Canada
- Department of Pathology & Laboratory Medicine, Children's Hospital of Eastern Ontario, Ontario, Canada
| | - Pierre R Bourque
- Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Department of Medicine, Neurology, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Jodi Warman-Chardon
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Department of Medicine, Neurology, The Ottawa Hospital, Ottawa, Ontario, Canada
- Department of Genetics, Children's Hospital of Eastern Ontario and Research Institute, Ottawa, Ontario, Canada
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Wang T, Zhou D, Hong Z. Adipose tissue in older individuals: a contributing factor to sarcopenia. Metabolism 2024; 160:155998. [PMID: 39128607 DOI: 10.1016/j.metabol.2024.155998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 08/05/2024] [Accepted: 08/06/2024] [Indexed: 08/13/2024]
Abstract
Sarcopenia is a geriatric syndrome characterized by a functional decline in muscle. The prevalence of sarcopenia increases with natural aging, becoming a serious health problem among elderly individuals. Therefore, understanding the pathology of sarcopenia is critical for inhibiting age-related alterations and promoting health and longevity in elderly individuals. The development of sarcopenia may be influenced by interactions between visceral and subcutaneous adipose tissue and skeletal muscle, particularly under conditions of chronic low-grade inflammation and metabolic dysfunction. This hypothesis is supported by the following observations: (i) accumulation of senescent cells in both adipose tissue and skeletal muscle with age; (ii) gut dysbiosis, characterized by an imbalance in gut microbial communities as the main trigger for inflammation, sarcopenia, and aged adipose tissue; and (iii) microbial dysbiosis, which could impact the onset or progression of a senescent state. Moreover, adipose tissue acts as an endocrine organ, releasing molecules that participate in intricate communication networks between organs. Our discussion focuses on novel adipokines and their role in regulating adipose tissue and muscle, particularly those influenced by aging and obesity, emphasizing their contributions to disease development. On the basis of these findings, we propose that age-related adipose tissue and sarcopenia are disorders characterized by chronic inflammation and metabolic dysregulation. Finally, we explore new potential therapeutic strategies involving specialized proresolving mediator (SPM) G protein-coupled receptor (GPCR) agonists, non-SPM GPCR agonists, transient receptor potential (TRP) channels, antidiabetic drugs in conjunction with probiotics and prebiotics, and compounds designed to target senescent cells and mitigate their pro-inflammatory activity.
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Affiliation(s)
- Tiantian Wang
- Department of Neurology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan, China; Institute of Brain Science and Brain-inspired Technology of West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Neurology, Chengdu Shangjin Nanfu Hospital, Chengdu, Sichuan, China.
| | - Dong Zhou
- Department of Neurology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan, China; Institute of Brain Science and Brain-inspired Technology of West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Neurology, Chengdu Shangjin Nanfu Hospital, Chengdu, Sichuan, China
| | - Zhen Hong
- Department of Neurology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan, China; Institute of Brain Science and Brain-inspired Technology of West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Neurology, Chengdu Shangjin Nanfu Hospital, Chengdu, Sichuan, China.
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Suda M, Paul KH, Tripathi U, Minamino T, Tchkonia T, Kirkland JL. Targeting Cell Senescence and Senolytics: Novel Interventions for Age-Related Endocrine Dysfunction. Endocr Rev 2024; 45:655-675. [PMID: 38500373 PMCID: PMC11405506 DOI: 10.1210/endrev/bnae010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 01/11/2024] [Accepted: 03/12/2024] [Indexed: 03/20/2024]
Abstract
Multiple changes occur in hormonal regulation with aging and across various endocrine organs. These changes are associated with multiple age-related disorders and diseases. A better understanding of responsible underling biological mechanisms could help in the management of multiple endocrine disorders over and above hormone replacement therapy (HRT). Cellular senescence is involved in multiple biological aging processes and pathologies common in elderly individuals. Cellular senescence, which occurs in many older individuals but also across the lifespan in association with tissue damage, acute and chronic diseases, certain drugs, and genetic syndromes, may contribute to such endocrine disorders as osteoporosis, metabolic syndrome, and type 2 diabetes mellitus. Drugs that selectively induce senescent cell removal, "senolytics,", and drugs that attenuate the tissue-destructive secretory state of certain senescent cells, "senomorphics," appear to delay the onset of or alleviate multiple diseases, including but not limited to endocrine disorders such as diabetes, complications of obesity, age-related osteoporosis, and cancers as well as atherosclerosis, chronic kidney disease, neurodegenerative disorders, and many others. More than 30 clinical trials of senolytic and senomorphic agents have already been completed, are underway, or are planned for a variety of indications. Targeting senescent cells is a novel strategy that is distinct from conventional therapies such as HRT, and thus might address unmet medical needs and can potentially amplify effects of established endocrine drug regimens, perhaps allowing for dose decreases and reducing side effects.
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Affiliation(s)
- Masayoshi Suda
- Departments of Medicine and Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Karl H Paul
- Departments of Medicine and Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
- Department of Physiology and Pharmacology, Karolinska Institutet, Solnavägen 9, 171 65 Solna, Sweden
| | - Utkarsh Tripathi
- Departments of Medicine and Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
| | - Tohru Minamino
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
- Japan Agency for Medical Research and Development-Core Research for Evolutionary Medical Science and Technology (AMED-CREST), Japan Agency for Medical Research and Development, Tokyo, 100-0004, Japan
| | - Tamara Tchkonia
- Departments of Medicine and Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
| | - James L Kirkland
- Departments of Medicine and Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
- Division of General Internal Medicine, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
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10
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Liao Y, Peng Z, Zhou X, Zhou H, Meng Z, Xu S, Sun T, Nüssler AK, Yang W. Competing endogenous RNA networks were associated with fat accumulation in skeletal muscle of aged male mice. Mech Ageing Dev 2024; 220:111953. [PMID: 38834155 DOI: 10.1016/j.mad.2024.111953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 05/24/2024] [Accepted: 05/26/2024] [Indexed: 06/06/2024]
Abstract
Muscle aging contributed to morbidity and mortality in the elderly adults by leading to severe outcomes such as frailty, falls and fractures. Post-transcriptional regulation especially competing endogenous RNA (ceRNA) mechanism may modulate the process of skeletal muscle aging. RNA-seq was performed in quadriceps of 6-month-old (adult) and 22-month-old (aged) male mice to identify differentially expressed ncRNAs and mRNAs and further construct ceRNA networks. Decreased quadriceps-body weight ratio and muscle fiber cross-sectional area as well as histological characteristics of aging were observed in the aged mice. Besides, there were higher expressions of atrogin-1 and MuRF-1 and lower expression of Myog, Myf4 and Myod1 in the quadriceps of aged mice relative to that of adult mice. The expression of 85 lncRNAs, 52 circRNAs, 10 miRNAs and 277 mRNAs were significantly dysregulated in quadriceps between the two groups, among which two ceRNA networks lncRNA 2700081O15Rik/circRNA_0000820-miR-673-3p-Tmem120b were constructed. Level of triglycerides and expression of PPARγ, C/EBPα, FASN and leptin were elevated and the expression of adiponectin was reduced in quadriceps of aged mice compared with that of adult mice. LncRNA 2700081O15Rik/circRNA_0000820-miR-673-3p-Tmem120b were possibly associated with the adipogenesis and fat accumulation in skeletal muscle of age male mice.
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Affiliation(s)
- Yuxiao Liao
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, China
| | - Zhao Peng
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, China
| | - Xiaolei Zhou
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, China
| | - Huanhuan Zhou
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, China
| | - Zitong Meng
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, China
| | - Shiyin Xu
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, China
| | - Taoping Sun
- Zhuhai Precision Medicine Center, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai 519000, China
| | - Andreas K Nüssler
- Department of Traumatology, BG Trauma Center, University of Tübingen, Schnarrenbergstr. 95, Tübingen 72076, Germany
| | - Wei Yang
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, China.
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11
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Hemagirri M, Chen Y, Gopinath SCB, Sahreen S, Adnan M, Sasidharan S. Crosstalk between protein misfolding and endoplasmic reticulum stress during ageing and their role in age-related disorders. Biochimie 2024; 221:159-181. [PMID: 37918463 DOI: 10.1016/j.biochi.2023.10.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/25/2023] [Accepted: 10/30/2023] [Indexed: 11/04/2023]
Abstract
Maintaining the proteome is crucial to retaining cell functionality and response to multiple intrinsic and extrinsic stressors. Protein misfolding increased the endoplasmic reticulum (ER) stress and activated the adaptive unfolded protein response (UPR) to restore cell homeostasis. Apoptosis occurs when ER stress is prolonged or the adaptive response fails. In healthy young cells, the ratio of protein folding machinery to quantities of misfolded proteins is balanced under normal circumstances. However, the age-related deterioration of the complex systems for handling protein misfolding is accompanied by ageing-related disruption of protein homeostasis, which results in the build-up of misfolded and aggregated proteins. This ultimately results in decreased cell viability and forms the basis of common age-related diseases called protein misfolding diseases. Proteins or protein fragments convert from their ordinarily soluble forms to insoluble fibrils or plaques in many of these disorders, which build up in various organs such as the liver, brain, or spleen. Alzheimer's, Parkinson's, type II diabetes, and cancer are diseases in this group commonly manifest in later life. Thus, protein misfolding and its prevention by chaperones and different degradation paths are becoming understood from molecular perspectives. Proteodynamics information will likely affect future interventional techniques to combat cellular stress and support healthy ageing by avoiding and treating protein conformational disorders. This review provides an overview of the diverse proteostasis machinery, protein misfolding, and ER stress involvement, which activates the UPR sensors. Here, we will discuss the crosstalk between protein misfolding and ER stress and their role in developing age-related diseases.
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Affiliation(s)
- Manisekaran Hemagirri
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia
| | - Yeng Chen
- Department of Oral & Craniofacial Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, 50603, Malaysia
| | - Subash C B Gopinath
- Faculty of Chemical Engineering and Technology, Universiti Malaysia Perlis, Arau, 02600, Malaysia
| | - Sumaira Sahreen
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia
| | - Mohd Adnan
- Department of Biology, College of Science, University of Ha'il, Ha'il, P. O. Box 2440, Saudi Arabia.
| | - Sreenivasan Sasidharan
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia.
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12
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Zhao Y, Yue R. Aging adipose tissue, insulin resistance, and type 2 diabetes. Biogerontology 2024; 25:53-69. [PMID: 37725294 DOI: 10.1007/s10522-023-10067-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Accepted: 08/28/2023] [Indexed: 09/21/2023]
Abstract
With the increase of population aging, the prevalence of type 2 diabetes (T2D) is also rising. Aging affects the tissues and organs of the whole body, which is the result of various physiological and pathological processes. Adipose tissue has a high degree of plasticity and changes with aging. Aging changes the distribution of adipose tissue, affects adipogenesis, browning characteristics, inflammatory status and adipokine secretion, and increases lipotoxicity. These age-dependent changes in adipose tissue are an important cause of insulin resistance and T2D. Understanding adipose tissue changes can help promote healthy aging process. This review summarizes changes in adipose tissue ascribable to aging, with a focus on the role of aging adipose tissue in insulin resistance and T2D.
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Affiliation(s)
- Yixuan Zhao
- Hospital of Chengdu University of Traditional Chinese Medicine, NO. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Rensong Yue
- Hospital of Chengdu University of Traditional Chinese Medicine, NO. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China.
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13
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Maestri A, Garagnani P, Pedrelli M, Hagberg CE, Parini P, Ehrenborg E. Lipid droplets, autophagy, and ageing: A cell-specific tale. Ageing Res Rev 2024; 94:102194. [PMID: 38218464 DOI: 10.1016/j.arr.2024.102194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 12/22/2023] [Accepted: 01/08/2024] [Indexed: 01/15/2024]
Abstract
Lipid droplets are the essential organelle for storing lipids in a cell. Within the variety of the human body, different cells store, utilize and release lipids in different ways, depending on their intrinsic function. However, these differences are not well characterized and, especially in the context of ageing, represent a key factor for cardiometabolic diseases. Whole body lipid homeostasis is a central interest in the field of cardiometabolic diseases. In this review we characterize lipid droplets and their utilization via autophagy and describe their diverse fate in three cells types central in cardiometabolic dysfunctions: adipocytes, hepatocytes, and macrophages.
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Affiliation(s)
- Alice Maestri
- Division of Cardiovascular Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Paolo Garagnani
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Matteo Pedrelli
- Cardio Metabolic Unit, Department of Laboratory Medicine, and Department of Medicine (Huddinge), Karolinska Institutet, Stockholm, Sweden; Medicine Unit of Endocrinology, Theme Inflammation and Ageing, Karolinska University Hospital, Stockholm, Sweden
| | - Carolina E Hagberg
- Division of Cardiovascular Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Paolo Parini
- Cardio Metabolic Unit, Department of Laboratory Medicine, and Department of Medicine (Huddinge), Karolinska Institutet, Stockholm, Sweden; Medicine Unit of Endocrinology, Theme Inflammation and Ageing, Karolinska University Hospital, Stockholm, Sweden
| | - Ewa Ehrenborg
- Division of Cardiovascular Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
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14
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Zhang L, Guan Q, Wang Z, Feng J, Zou J, Gao B. Consequences of Aging on Bone. Aging Dis 2023; 15:2417-2452. [PMID: 38029404 PMCID: PMC11567267 DOI: 10.14336/ad.2023.1115] [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: 09/21/2023] [Accepted: 11/16/2023] [Indexed: 12/01/2023] Open
Abstract
With the aging of the global population, the incidence of musculoskeletal diseases has been increasing, seriously affecting people's health. As people age, the microenvironment within skeleton favors bone resorption and inhibits bone formation, accompanied by bone marrow fat accumulation and multiple cellular senescence. Specifically, skeletal stem/stromal cells (SSCs) during aging tend to undergo adipogenesis rather than osteogenesis. Meanwhile, osteoblasts, as well as osteocytes, showed increased apoptosis, decreased quantity, and multiple functional limitations including impaired mechanical sensing, intercellular modulation, and exosome secretion. Also, the bone resorption function of macrophage-lineage cells (including osteoclasts and preosteoclasts) was significantly enhanced, as well as impaired vascularization and innervation. In this study, we systematically reviewed the effect of aging on bone and the within microenvironment (including skeletal cells as well as their intracellular structure variations, vascular structures, innervation, marrow fat distribution, and lymphatic system) caused by aging, and mechanisms of osteoimmune regulation of the bone environment in the aging state, and the causal relationship with multiple musculoskeletal diseases in addition with their potential therapeutic strategy.
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Affiliation(s)
- Lingli Zhang
- College of Athletic Performance, Shanghai University of Sport, Shanghai, China
| | - Qiao Guan
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Zhikun Wang
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Jie Feng
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Jun Zou
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Bo Gao
- Department of Orthopedic Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
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15
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Clemente-Olivo MP, Hernández-Quiles M, Sparrius R, van der Stoel MM, Janssen V, Habibe JJ, van den Burg J, Jongejan A, Alcaraz-Sobrevals P, van Es R, Vos H, Kalkhoven E, de Vries CJM. Early adipogenesis is repressed through the newly identified FHL2-NFAT5 signaling complex. Cell Signal 2023; 104:110587. [PMID: 36610523 DOI: 10.1016/j.cellsig.2023.110587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/25/2022] [Accepted: 01/03/2023] [Indexed: 01/06/2023]
Abstract
The LIM-domain-only protein FHL2 is a modulator of signal transduction and has been shown to direct the differentiation of mesenchymal stem cells towards osteoblast and myocyte phenotypes. We hypothesized that FHL2 may simultaneously interfere with the induction of the adipocyte lineage. Therefore, we investigated the role of FHL2 in adipocyte differentiation. For these studies pre-adipocytes isolated from mouse adipose tissue and the 3T3-L1 (pre)adipocyte cell line were applied. We performed FHL2 gain of function and knockdown experiments followed by extensive RNAseq analyses and phenotypic characterization of the cells by oil-red O (ORO) lipid staining. Through affinity-purification mass spectrometry (AP-MS) novel FHL2 interacting proteins were identified. Here we report that FHL2 is expressed in pre-adipocytes and for accurate adipocyte differentiation, this protein needs to be downregulated during the early stages of adipogenesis. More specifically, constitutive overexpression of FHL2 drastically inhibits adipocyte differentiation in 3T3-L1 cells, which was demonstrated by suppressed activation of the adipogenic gene expression program as shown by RNAseq analyses, and diminished lipid accumulation. Analysis of the protein-protein interactions mediating this repressive activity of FHL2 on adipogenesis revealed the interaction of FHL2 with the Nuclear factor of activated T-cells 5 (NFAT5). NFAT5 is an established inhibitor of adipocyte differentiation and its knockdown rescued the inhibitory effect of FHL2 overexpression on 3T3-L1 differentiation, indicating that these proteins act cooperatively. We present a new regulatory function of FHL2 in early adipocyte differentiation and revealed that FHL2-mediated inhibition of pre-adipocyte differentiation is dependent on its interaction with NFAT5. FHL2 expression increases with aging, which may affect mesenchymal stem cell differentiation, more specifically inhibit adipocyte differentiation.
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Affiliation(s)
- Maria P Clemente-Olivo
- Amsterdam UMC location University of Amsterdam, Department of Medical Biochemistry, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, and Amsterdam Gastroenterology, Endocrinology and Metabolism, University of Amsterdam, Amsterdam, the Netherlands
| | - Miguel Hernández-Quiles
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Rinske Sparrius
- Amsterdam UMC location University of Amsterdam, Department of Medical Biochemistry, Amsterdam, the Netherlands
| | - Miesje M van der Stoel
- Amsterdam UMC location University of Amsterdam, Department of Medical Biochemistry, Amsterdam, the Netherlands
| | - Vera Janssen
- Amsterdam UMC location University of Amsterdam, Department of Medical Biochemistry, Amsterdam, the Netherlands
| | - Jayron J Habibe
- Amsterdam UMC location University of Amsterdam, Department of Medical Biochemistry, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, and Amsterdam Gastroenterology, Endocrinology and Metabolism, University of Amsterdam, Amsterdam, the Netherlands
| | - Janny van den Burg
- Amsterdam UMC location University of Amsterdam, Department of Medical Biochemistry, Amsterdam, the Netherlands
| | - Aldo Jongejan
- Amsterdam UMC location University of Amsterdam, Department of Bioinformatics, Amsterdam, the Netherlands
| | - Paula Alcaraz-Sobrevals
- Oncode Institute and Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Robert van Es
- Oncode Institute and Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Harmjan Vos
- Oncode Institute and Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Eric Kalkhoven
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Carlie J M de Vries
- Amsterdam UMC location University of Amsterdam, Department of Medical Biochemistry, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, and Amsterdam Gastroenterology, Endocrinology and Metabolism, University of Amsterdam, Amsterdam, the Netherlands.
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16
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Wiesenthal AA, Legroux TM, Richter C, Junker BH, Hecksteden A, Kessler SM, Hoppstädter J, Kiemer AK. Endotoxin Tolerance Acquisition and Altered Hepatic Fatty Acid Profile in Aged Mice. BIOLOGY 2023; 12:biology12040530. [PMID: 37106731 PMCID: PMC10135800 DOI: 10.3390/biology12040530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 03/13/2023] [Accepted: 03/24/2023] [Indexed: 04/03/2023]
Abstract
(1) Background: Aging is linked to an altered immune response and metabolism. Inflammatory conditions, such as sepsis, COVID-19, and steatohepatitis are more prevalent in the elderly and steatosis is linked both to severe COVID-19 and sepsis. We hypothesized that aging is linked to a loss of endotoxin tolerance, which normally protects the host from excessive inflammation, and that this is accompanied by elevated levels of hepatic lipids. (2) Methods: An in vivo lipopolysaccharide (LPS) tolerance model in young and old mice was used and the cytokine serum levels were measured by ELISA. Cytokine and toll-like receptor gene expression was determined by qPCR in the lungs and the liver; hepatic fatty acid composition was assessed by GC–MS. (3) Results: The old mice showed a distinct potential for endotoxin tolerance as suggested by the serum cytokine levels and gene expression in the lung tissue. Endotoxin tolerance was less pronounced in the livers of the aged mice. However, the fatty acid composition strongly differed in the liver tissues of the young and old mice with a distinct change in the ratio of C18 to C16 fatty acids. (4) Conclusions: Endotoxin tolerance is maintained in advanced age, but changes in the metabolic tissue homeostasis may lead to an altered immune response in old individuals.
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Affiliation(s)
- Amanda A. Wiesenthal
- Pharmaceutical Biology, Department of Pharmacy, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany
- Marine Biology, Institute of Biological Sciences, University of Rostock, D-18059 Rostock, Germany
| | - Thierry M. Legroux
- Pharmaceutical Biology, Department of Pharmacy, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany
| | - Chris Richter
- Biosynthesis of Active Substances, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, D-06120 Halle, Germany
| | - Björn H. Junker
- Biosynthesis of Active Substances, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, D-06120 Halle, Germany
| | - Anne Hecksteden
- Institute of Sports and Preventive Medicine, Saarland University, D-66123 Saarbrücken, Germany
| | - Sonja M. Kessler
- Experimental Pharmacology for Natural Sciences, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, D-06120 Halle, Germany
| | - Jessica Hoppstädter
- Pharmaceutical Biology, Department of Pharmacy, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany
| | - Alexandra K. Kiemer
- Pharmaceutical Biology, Department of Pharmacy, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany
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17
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Oyebanji OA, Mylonakis E, Canaday DH. Vaccines for the Prevention of Coronavirus Disease 2019 in Older Adults. Infect Dis Clin North Am 2023; 37:27-45. [PMID: 36805013 PMCID: PMC9633624 DOI: 10.1016/j.idc.2022.11.002] [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] [Indexed: 11/06/2022]
Abstract
Institutionalized and community-dwelling older adults have been greatly impacted by the coronavirus disease 2019 (COVID-19) pandemic with increased morbidity and mortality. The advent of vaccines and their widespread use in this population has brought about a dramatic turnaround in COVID-19 outcomes. The immunogenicity and effectiveness of the various vaccine options worldwide are discussed. Optimization of vaccine usage will still be important to maximize protection due to reduced initial immunity, development of variant strains, and fading of immunity over time. There are also lessons learned specific to older populations for future pandemics of novel pathogens.
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Affiliation(s)
- Oladayo A Oyebanji
- Case Western Reserve University, School of Medicine, 10900 Euclid Ave, BRB 1025, Cleveland, OH 44106-4984, USA
| | - Eleftherios Mylonakis
- Infectious Diseases Division, The Miriam Hospital and Rhode Island Hospital, Warren Alpert Medical School of Brown University, Rhode Island Hospital, 593 Eddy Street, POB, 3rd Floor, Suite 328/330, Providence, RI 02903, USA
| | - David H Canaday
- Case Western Reserve University, School of Medicine, 10900 Euclid Ave, BRB 1025, Cleveland, OH 44106-4984, USA; Geriatric Research, Education and Clinical Center, Cleveland Veterans Affairs Medical Center, 10900 Euclid Ave, BRB 1025, Cleveland, OH 44106-4984, USA.
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18
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Scheidl TB, Brightwell AL, Easson SH, Thompson JA. Maternal obesity and programming of metabolic syndrome in the offspring: searching for mechanisms in the adipocyte progenitor pool. BMC Med 2023; 21:50. [PMID: 36782211 PMCID: PMC9924890 DOI: 10.1186/s12916-023-02730-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 01/09/2023] [Indexed: 02/15/2023] Open
Abstract
BACKGROUND It is now understood that it is the quality rather than the absolute amount of adipose tissue that confers risk for obesity-associated disease. Adipose-derived stem cells give rise to adipocytes during the developmental establishment of adipose depots. In adult depots, a reservoir of progenitors serves to replace adipocytes that have reached their lifespan and for recruitment to increase lipid buffering capacity under conditions of positive energy balance. MAIN: The adipose tissue expandability hypothesis posits that a failure in de novo differentiation of adipocytes limits lipid storage capacity and leads to spillover of lipids into the circulation, precipitating the onset of obesity-associated disease. Since adipose progenitors are specified to their fate during late fetal life, perturbations in the intrauterine environment may influence the rapid expansion of adipose depots that occurs in childhood or progenitor function in established adult depots. Neonates born to mothers with obesity or diabetes during pregnancy tend to have excessive adiposity at birth and are at increased risk for childhood adiposity and cardiometabolic disease. CONCLUSION In this narrative review, we synthesize current knowledge in the fields of obesity and developmental biology together with literature from the field of the developmental origins of health and disease (DOHaD) to put forth the hypothesis that the intrauterine milieu of pregnancies complicated by maternal metabolic disease disturbs adipogenesis in the fetus, thereby accelerating the trajectory of adipose expansion in early postnatal life and predisposing to impaired adipose plasticity.
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Affiliation(s)
- Taylor B. Scheidl
- Cumming School of Medicine, Calgary, Canada
- Alberta Children’s Hospital Research Institute, Calgary, Canada
- Libin Cardiovascular Institute, Calgary, Canada
- University of Calgary, 3330 Hospital Dr. NW, Calgary, AB T2N 4N1 Canada
| | - Amy L. Brightwell
- University of Calgary, 3330 Hospital Dr. NW, Calgary, AB T2N 4N1 Canada
| | - Sarah H. Easson
- Cumming School of Medicine, Calgary, Canada
- University of Calgary, 3330 Hospital Dr. NW, Calgary, AB T2N 4N1 Canada
| | - Jennifer A. Thompson
- Cumming School of Medicine, Calgary, Canada
- Alberta Children’s Hospital Research Institute, Calgary, Canada
- Libin Cardiovascular Institute, Calgary, Canada
- University of Calgary, 3330 Hospital Dr. NW, Calgary, AB T2N 4N1 Canada
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19
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Wang M, Li H, Tang J, Xi Y, Chen S, Liu M. Effect of simvastatin on osteogenesis of the extremity bones in aging rats. Connect Tissue Res 2023; 64:64-74. [PMID: 35816110 DOI: 10.1080/03008207.2022.2094790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
PURPOSE Simvastatin is a prodrug of the potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. The main purpose of the current study is to assess the accurate function of simvastatin on osteoporosis of extremity bones in aging rats. MATERIALS AND METHODS Fifty 15-month-old SD rats were divided into five groups (four simvastatin groups and one control group). The rats in four simvastatin groups were fed with different doses of simvastatin (5, 10, 20, and 40 mg/kg/d, respectively) for 3 months, whereas the rats in control group were fed the equal physiological saline. Calcium (Ca), phosphorus (P), and the lipid spectrum in serum were measured. Biochemical markers of bone metabolism, osteocalcin (OC), and tartrate-resistant acid phosphatase (Trap-5b), were analyzed using ELISA. The content of adipocytes in bone marrow was analyzed by histological staining. Finally, the bone quality of the femur and tibia were evaluated using dual-energy X-ray absorptiometry (DEXA), peri-quantity CT (pQCT), and the 3-point bending biomechanical test. RESULTS Simvastatin reduced serum triglycerides (TG), and 10 mg/kg/d of simvastatin significantly reduced the content of adipocytes in bone marrow compared to the control group. However, statistically significant differences between the simvastatin groups and the control group were not found in the CA, P, OC, Trap-5b, or the evaluation indexes of bone quality from DEXA, pQCT, and biomechanical tests. CONCLUSION Simvastatin could not prevent osteoporosis of the extremity bones in aging rats.
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Affiliation(s)
- Mengran Wang
- Department of Orthopedics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Haowei Li
- Department of Orthopedics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jiaxin Tang
- Department of Orthopedics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yue Xi
- Department of Orthopedics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shiyi Chen
- Department of Orthopedics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Ming Liu
- Department of Orthopedics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
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20
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Kaushik S, Juste YR, Lindenau K, Dong S, Macho-González A, Santiago-Fernández O, McCabe M, Singh R, Gavathiotis E, Cuervo AM. Chaperone-mediated autophagy regulates adipocyte differentiation. SCIENCE ADVANCES 2022; 8:eabq2733. [PMID: 36383673 PMCID: PMC9668314 DOI: 10.1126/sciadv.abq2733] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 09/28/2022] [Indexed: 06/16/2023]
Abstract
Adipogenesis is a tightly orchestrated multistep process wherein preadipocytes differentiate into adipocytes. The most studied aspect of adipogenesis is its transcriptional regulation through timely expression and silencing of a vast number of genes. However, whether turnover of key regulatory proteins per se controls adipogenesis remains largely understudied. Chaperone-mediated autophagy (CMA) is a selective form of lysosomal protein degradation that, in response to diverse cues, remodels the proteome for regulatory purposes. We report here the activation of CMA during adipocyte differentiation and show that CMA regulates adipogenesis at different steps through timely degradation of key regulatory signaling proteins and transcription factors that dictate proliferation, energetic adaptation, and signaling changes required for adipogenesis.
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Affiliation(s)
- Susmita Kaushik
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA
- Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Yves R. Juste
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA
- Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Kristen Lindenau
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA
- Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Shuxian Dong
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA
- Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Adrián Macho-González
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA
- Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Olaya Santiago-Fernández
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA
- Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Mericka McCabe
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA
- Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Rajat Singh
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA
- Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Evripidis Gavathiotis
- Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Ana Maria Cuervo
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA
- Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
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Mezzetto L, D'Oria M, Mani K, Scali S, Bastos Gonçalves F, Trimarchi S, Budtz-Lilly J, DeMartino R, Veraldi G, Mastrorilli D, Calvagna C, Grando B, Bissacco D, Lepidi S. Scoping review of radiologic assessment and prognostic impact of skeletal muscle sarcopenia in patients undergoing endovascular repair for aortic disease. J Vasc Surg 2022; 76:1407-1416. [PMID: 35667604 PMCID: PMC9613481 DOI: 10.1016/j.jvs.2022.05.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 05/10/2022] [Accepted: 05/19/2022] [Indexed: 12/25/2022]
Abstract
OBJECTIVE The primary objectives of our scoping review were to evaluate the methods used by research groups to assess the incidence of sarcopenia in patients with aortic disease and the extent of the evidence base that links sarcopenia to the survival of patients undergoing elective endovascular aortic repair and to identify the recurring themes or gaps in the literature to guide future research. METHODS A scoping review in accordance with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) protocols extension for scoping reviews was performed. The available studies included those fully reported in English (last query, April 30, 2022). The following PICO question was used to build the search equation: "in patients with aortic disease [population] undergoing endovascular repair [intervention], what was the prevalence and prognosis of radiologically defined sarcopenia [comparison] on the short- and long-term outcomes?" RESULTS A total of 31 studies were considered relevant, and 18 were included in the present scoping review. In brief, 12 studies had focused on standard endovascular aneurysm repair (EVAR), 2 on thoracic EVAR, and 4 on complex EVAR. All but two studies were retrospective in design, and only one study had included patients from a multicenter database. Sarcopenia had generally been defined using the computed tomography angiography (CTA) findings of the cross-sectional area of the psoas muscle at L3 or L4, sometimes with normalization against the height. Overall, despite the heterogeneity in the methods used for its definition, sarcopenia was highly prevalent (range, 12.5%-67.6%). The patients with sarcopenia had had higher rates of mortality (ratio ranged from 2.28 [95% confidence interval, 1.35-3.84] to 6.34 [95% confidence interval, 3.37-10.0]) and adverse events (41% vs 16%; P = .020). CONCLUSIONS Sarcopenia, as identified using computed tomography angiography-based measurements of the skeletal muscle mass, was prevalent among patients undergoing elective EVAR, thoracic EVAR, or complex EVAR. The presence of sarcopenia has been shown to have a negative prognostic impact, increasing the operative risk and has been linked to poorer long-term survival.
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Affiliation(s)
- Luca Mezzetto
- Unit of Vascular Surgery, Integrated University Hospital of Verona, Verona, Italy
| | - Mario D'Oria
- Division of Vascular and Endovascular Surgery, Cardiovascular Department, University Hospital of Trieste ASUGI, Trieste, Italy.
| | - Kevin Mani
- Section of Vascular Surgery, Department of Surgical Sciences, University of Uppsala, Uppsala, Sweden
| | - Salvatore Scali
- Division of Vascular Surgery and Endovascular Therapy, University of Florida, Gainesville, FL
| | - Frederico Bastos Gonçalves
- Department of Vascular Surgery, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Angiology and Vascular Surgery, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal
| | - Santi Trimarchi
- Division of Vascular Surgery, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Jacob Budtz-Lilly
- Division of Vascular Surgery, Department of Cardiovascular Surgery, Aarhus University Hospital, Aarhus, Denmark
| | - Randall DeMartino
- Division of Vascular and Endovascular Surgery, Gonda Vascular Center, Mayo Clinic Rochester Campus, Rochester, MN
| | - Gianfranco Veraldi
- Unit of Vascular Surgery, Integrated University Hospital of Verona, Verona, Italy
| | - Davide Mastrorilli
- Unit of Vascular Surgery, Integrated University Hospital of Verona, Verona, Italy
| | - Cristiano Calvagna
- Division of Vascular and Endovascular Surgery, Cardiovascular Department, University Hospital of Trieste ASUGI, Trieste, Italy
| | - Beatrice Grando
- Division of Vascular and Endovascular Surgery, Cardiovascular Department, University Hospital of Trieste ASUGI, Trieste, Italy
| | - Daniele Bissacco
- Division of Vascular Surgery, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Sandro Lepidi
- Division of Vascular and Endovascular Surgery, Cardiovascular Department, University Hospital of Trieste ASUGI, Trieste, Italy
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22
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Zamboni M, Mazzali G, Brunelli A, Saatchi T, Urbani S, Giani A, Rossi AP, Zoico E, Fantin F. The Role of Crosstalk between Adipose Cells and Myocytes in the Pathogenesis of Sarcopenic Obesity in the Elderly. Cells 2022; 11:3361. [PMID: 36359757 PMCID: PMC9655977 DOI: 10.3390/cells11213361] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 10/08/2022] [Accepted: 10/14/2022] [Indexed: 11/15/2023] Open
Abstract
As a result of aging, body composition changes, with a decline in muscle mass and an increase in adipose tissue (AT), which reallocates from subcutaneous to visceral depots and stores ectopically in the liver, heart and muscles. Furthermore, with aging, muscle and AT, both of which have recognized endocrine activity, become dysfunctional and contribute, in the case of positive energy balance, to the development of sarcopenic obesity (SO). SO is defined as the co-existence of excess adiposity and low muscle mass and function, and its prevalence increases with age. SO is strongly associated with greater morbidity and mortality. The pathogenesis of SO is complex and multifactorial. This review focuses mainly on the role of crosstalk between age-related dysfunctional adipose and muscle cells as one of the mechanisms leading to SO. A better understanding of this mechanisms may be useful for development of prevention strategies and treatments aimed at reducing the occurrence of SO.
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Affiliation(s)
- Mauro Zamboni
- Geriatrics Division, Department of Surgery, Dentistry, Pediatric and Gynecology, Healthy Aging Center, University of Verona, 37126 Verona, Italy
| | - Gloria Mazzali
- Geriatrics Division, Department of Medicine, University of Verona, 37126 Verona, Italy
| | - Anna Brunelli
- Geriatrics Division, Department of Surgery, Dentistry, Pediatric and Gynecology, Healthy Aging Center, University of Verona, 37126 Verona, Italy
| | - Tanaz Saatchi
- Geriatrics Division, Department of Surgery, Dentistry, Pediatric and Gynecology, Healthy Aging Center, University of Verona, 37126 Verona, Italy
| | - Silvia Urbani
- Geriatrics Division, Department of Surgery, Dentistry, Pediatric and Gynecology, Healthy Aging Center, University of Verona, 37126 Verona, Italy
| | - Anna Giani
- Geriatrics Division, Department of Surgery, Dentistry, Pediatric and Gynecology, Healthy Aging Center, University of Verona, 37126 Verona, Italy
| | - Andrea P. Rossi
- Geriatrics Division, Department of Medicine, AULSS2, Ospedale Ca’Foncello, 31100 Treviso, Italy
| | - Elena Zoico
- Geriatrics Division, Department of Medicine, University of Verona, 37126 Verona, Italy
| | - Francesco Fantin
- Geriatrics Division, Department of Medicine, University of Verona, 37126 Verona, Italy
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Wang G, Song A, Bae M, Wang QA. Adipose Tissue Plasticity in Aging. Compr Physiol 2022; 12:4119-4132. [PMID: 36214190 DOI: 10.1002/cphy.c220005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
As a dynamic endocrine organ, white adipose tissue (WAT) stores lipids and plays a critical role in maintaining whole-body energy homeostasis and insulin sensitivity. A large group of the population over 65 years old suffer from increased WAT mass, especially in the visceral location. Visceral adiposity accelerates aging through promoting age-associated chronic conditions, significantly shortening life expectancy. Unlike WAT, brown adipose tissue (BAT) functions as an effective energy sink that burns and disposes of excess lipids and glucose upon activation of thermogenesis. Unfortunately, the thermogenic activity of BAT declines during aging. New appreciation of cellular and functional remodeling of WAT and BAT during aging has emerged in recent years. Efforts are underway to explore the potential underlying mechanisms behind these age-associated alterations in WAT and BAT and the impact of these alterations on whole-body metabolism. Lastly, it is intriguing to translate our knowledge obtained from animal models to the clinic to prevent and treat age-associated metabolic disorders. © 2022 American Physiological Society. Compr Physiol 12: 4119-4132, 2022.
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Affiliation(s)
- Guan Wang
- Department of Molecular & Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Medical Center, Duarte, California, USA
| | - Anying Song
- Department of Molecular & Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Medical Center, Duarte, California, USA
| | - Marie Bae
- Department of Molecular & Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Medical Center, Duarte, California, USA
| | - Qiong A Wang
- Department of Molecular & Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Medical Center, Duarte, California, USA.,Comprehensive Cancer Center, Beckman Research Institute, City of Hope Medical Center, Duarte, California, USA
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24
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Muellner M, Chiapparelli E, Moser M, Haffer H, Dodo Y, Adl Amini D, Carrino JA, Tan ET, Shue J, Zhu J, Sama AA, Cammisa FP, Girardi FP, Hughes AP. The effect of age on psoas and paraspinal muscle morphology in patients undergoing posterior lumbar fusion surgery. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2022; 31:2619-2628. [PMID: 35984509 PMCID: PMC10583000 DOI: 10.1007/s00586-022-07346-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 06/16/2022] [Accepted: 07/28/2022] [Indexed: 06/15/2023]
Abstract
PURPOSE The aim of this study was to determine the effect of age on the psoas and posterior paraspinal muscles (PPM; multifidus muscle and erector spinae) and to evaluate potential sex-related differences. METHODS MRI-based quantitative assessments of the cross-sectional area (CSA), the functional cross-sectional area (fCSA), the fat area (FAT) and the proportion of intramuscular fat (FI) were conducted on patients undergoing lumbar fusion surgery between 2014 and 2021. The regions of interest were the psoas muscle and the PPM at the superior endplate of L4. The left and right sides of the muscle groups were summarized and normalized by the patient's height (cm2/m2). The relationships between age and muscular parameters were analyzed stratified by sex. RESULTS A total of 195 patients (57.9%female) with a median age of 64.2 years and a body mass index of 28.3 kg/m2 were analyzed. The CSAPsoas was 7.7 cm2/m2 and differed significantly between females and males (p < 0.001); likewise, the fCSAPsoas differed significantly between the sexes. The CSAPPM was 18.8 cm2/m2 with no sex-specific differences. Significant differences were found in the FIPPM (males: 41.1% vs. females: 47.9%; p < 0.001), but not in the FIPsoas (males: 3.7% vs. females: 4.5%; p = 0.276). Considering the effect of age on FI, a significant positive correlation was observed for the PPMs for both sexes. Only in women, there was a negative correlation between age and CSAPsoas (ρ = - 0.248; p = 0.008), FATPsoas (ρ = - 0.421; p < 0.001) and FIPsoas (ρ = - 0.371; p < 0.001). CONCLUSION This study demonstrated sex-specific differences in spinal muscle morphology in relation to patient age. With increasing age there was a decrease in FIPsoas in women only, unlike in the PPMs in which there was increased FI that was significantly higher in women compared to men.
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Affiliation(s)
- Maximilian Muellner
- Spine Care Institute, Hospital for Special Surgery, Weill Cornell Medicine, 535 East 70th Street, New York, NY, 10021, USA
- Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Berlin, Germany
| | - Erika Chiapparelli
- Spine Care Institute, Hospital for Special Surgery, Weill Cornell Medicine, 535 East 70th Street, New York, NY, 10021, USA
| | - Manuel Moser
- Spine Care Institute, Hospital for Special Surgery, Weill Cornell Medicine, 535 East 70th Street, New York, NY, 10021, USA
- Department of Spine Surgery, Lucerne Cantonal Hospital, Lucerne, Switzerland
| | - Henryk Haffer
- Spine Care Institute, Hospital for Special Surgery, Weill Cornell Medicine, 535 East 70th Street, New York, NY, 10021, USA
- Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Berlin, Germany
| | - Yusuke Dodo
- Spine Care Institute, Hospital for Special Surgery, Weill Cornell Medicine, 535 East 70th Street, New York, NY, 10021, USA
| | - Dominik Adl Amini
- Spine Care Institute, Hospital for Special Surgery, Weill Cornell Medicine, 535 East 70th Street, New York, NY, 10021, USA
- Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Berlin, Germany
| | - John A Carrino
- Department of Radiology and Imaging, Hospital for Special Surgery, New York City, NY, USA
| | - Ek T Tan
- Department of Radiology and Imaging, Hospital for Special Surgery, New York City, NY, USA
| | - Jennifer Shue
- Spine Care Institute, Hospital for Special Surgery, Weill Cornell Medicine, 535 East 70th Street, New York, NY, 10021, USA
| | - Jiaqi Zhu
- Biostatistics Core, Hospital for Special Surgery, New York City, NY, USA
| | - Andrew A Sama
- Spine Care Institute, Hospital for Special Surgery, Weill Cornell Medicine, 535 East 70th Street, New York, NY, 10021, USA
| | - Frank P Cammisa
- Spine Care Institute, Hospital for Special Surgery, Weill Cornell Medicine, 535 East 70th Street, New York, NY, 10021, USA
| | - Federico P Girardi
- Spine Care Institute, Hospital for Special Surgery, Weill Cornell Medicine, 535 East 70th Street, New York, NY, 10021, USA
| | - Alexander P Hughes
- Spine Care Institute, Hospital for Special Surgery, Weill Cornell Medicine, 535 East 70th Street, New York, NY, 10021, USA.
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Liang Z, Zhang T, Liu H, Li Z, Peng L, Wang C, Wang T. Inflammaging: The ground for sarcopenia? Exp Gerontol 2022; 168:111931. [PMID: 35985553 DOI: 10.1016/j.exger.2022.111931] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 08/02/2022] [Accepted: 08/14/2022] [Indexed: 12/15/2022]
Abstract
Sarcopenia is a progressive skeletal muscle disease that occurs most commonly in the elderly population, contributing to increased costs and hospitalization. Exercise and nutritional therapy have been proven to be effective for sarcopenia, and some drugs can also alleviate declines in muscle mass and function due to sarcopenia. However, there is no specific pharmacological treatment for sarcopenia at present. This review will mainly discuss the relationship between inflammaging and sarcopenia. The increased secretion of proinflammatory cytokines with aging may be because of cellular senescence, immunosenescence, alterations in adipose tissue, damage-associated molecular patterns (DAMPs), and gut microbes due to aging. These sources of inflammaging can impact the sarcopenia process through direct or indirect pathways. Conversely, sarcopenia can also aggravate the process of inflammaging, creating a vicious cycle. Targeting sources of inflammaging can influence muscle function, which could be considered a therapeutic target for sarcopenia. Moreover, not only proinflammatory cytokines but also anti-inflammatory cytokines can influence muscle and inflammation and participate in the progression of sarcopenia. This review focuses on the effects of TNF-α, IL-6, and IL-10, which can be detected in plasma. Therefore, clearing chronic inflammation by targeting proinflammatory cytokines (TNF-α, IL-1, IL-6) and the inflammatory pathway (JAK/STAT, autophagy, NF-κB) may be effective in treating sarcopenia.
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Affiliation(s)
- Zejun Liang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Tianxiao Zhang
- School of Healthcare Sciences, Cardiff University, Health Park, CF14 4XN Wales, UK
| | - Honghong Liu
- West China School of Nursing/West China Hospital, Sichuan University, NO.37 Alley, Chengdu 610041, Sichuan, PR China
| | - Zhenlin Li
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Lihong Peng
- Department of Rehabilitation Medicine, West China Second University Hospital, Sichuan University, PR China
| | - Changyi Wang
- Department of Rehabilitation Medicine, Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China; Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Tiantian Wang
- Department of Rehabilitation Medicine, Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China; Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
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26
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Peraldi P, Loubat A, Chignon-Sicard B, Dani C, Ladoux A. Identification of Human Breast Adipose Tissue Progenitors Displaying Distinct Differentiation Potentials and Interactions with Cancer Cells. Biomedicines 2022; 10:biomedicines10081928. [PMID: 36009475 PMCID: PMC9406003 DOI: 10.3390/biomedicines10081928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/26/2022] [Accepted: 08/02/2022] [Indexed: 11/16/2022] Open
Abstract
Breast adipose tissue (AT) participates in the physiological evolution and remodeling of the mammary gland due to its high plasticity. It is also a favorable microenvironment for breast cancer progression. However, information on the properties of human breast adipose progenitor cells (APCs) involved in breast physiology or pathology is scant. We performed differential enzymatic dissociation of human breast AT lobules. We isolated and characterized two populations of APCs. Here we report that these distinct breast APC populations selectively expressed markers suitable for characterization. The population preferentially expressing ALPL (MSCA1) showed higher adipogenic potential. The population expressing higher levels of INHBA and CD142 acquired myofibroblast characteristics upon TGF-β treatment and a myo-cancer-associated fibroblast profile in the presence of breast cancer cells. This population expressed the immune checkpoint CD274 (PD-L1) and facilitated the expansion of breast cancer mammospheres compared with the adipogenic population. Indeed, the breast, as with other fat depots, contains distinct types of APCs with differences in their ability to specialize. This indicates that they were differentially involved in breast remodeling. Their interactions with breast cancer cells revealed differences in the potential for tumor dissemination and estrogen receptor expression, and these differences might be relevant to improve therapies targeting the tumor microenvironment.
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Affiliation(s)
- Pascal Peraldi
- CNRS, INSERM, iBV, Université Côte d’Azur, 06107 Nice, France
| | - Agnès Loubat
- CNRS, INSERM, iBV, Université Côte d’Azur, 06107 Nice, France
| | - Bérengère Chignon-Sicard
- CNRS, INSERM, iBV, Université Côte d’Azur, 06107 Nice, France
- Department of Plastic and Reconstructive Surgery, Pasteur 2 Hospital, Université Côte d’Azur, 06107 Nice, France
| | - Christian Dani
- CNRS, INSERM, iBV, Université Côte d’Azur, 06107 Nice, France
| | - Annie Ladoux
- CNRS, INSERM, iBV, Université Côte d’Azur, 06107 Nice, France
- CNRS, Institute of Biology Valrose (iBV), University of Nice Sophia-Antipolis, 28 Avenue de Valombrose, CEDEX 2, 06107 Nice, France
- Correspondence:
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27
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Obesity and Bone Health: A Complex Relationship. Int J Mol Sci 2022; 23:ijms23158303. [PMID: 35955431 PMCID: PMC9368241 DOI: 10.3390/ijms23158303] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/21/2022] [Accepted: 07/25/2022] [Indexed: 02/07/2023] Open
Abstract
Recent scientific evidence has shown an increased risk of fractures in patients with obesity, especially in those with a higher visceral adipose tissue content. This contradicts the old paradigm that obese patients were more protected than those with normal weight. Specifically, in older subjects in whom there is a redistribution of fat from subcutaneous adipose tissue to visceral adipose tissue and an infiltration of other tissues such as muscle with the consequent sarcopenia, obesity can accentuate the changes characteristic of this age group that predisposes to a greater risk of falls and fractures. Other factors that determine a greater risk in older subjects with obesity are chronic proinflammatory status, altered adipokine secretion, vitamin D deficiency, insulin resistance and reduced mobility. On the other hand, diagnostic tests may be influenced by obesity and its comorbidities as well as by body composition, and risk scales may underestimate the risk of fractures in these patients. Weight loss with physical activity programs and cessation of high-fat diets may reduce the risk. Finally, more research is needed on the efficacy of anti-osteoporotic treatments in obese patients.
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28
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Elsharkasi HM, Chen SC, Steell L, Joseph S, Abdalrahaman N, McComb C, Johnston B, Foster J, Wong SC, Faisal Ahmed S. 3T-MRI-based age, sex and site-specific markers of musculoskeletal health in healthy children and young adults. Endocr Connect 2022; 11:e220034. [PMID: 35700237 PMCID: PMC9346338 DOI: 10.1530/ec-22-0034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 06/13/2022] [Indexed: 11/08/2022]
Abstract
Objective The aim of this study is to investigate the role of 3T-MRI in assessing musculoskeletal health in children and young people. Design Bone, muscle and bone marrow imaging was performed in 161 healthy participants with a median age of 15.0 years (range, 8.0, 30.0). Methods Detailed assessment of bone microarchitecture (constructive interference in the steady state (CISS) sequence, voxel size 0.2 × 0.2 × 0.4 mm3), bone geometry (T1-weighted turbo spin echo (TSE) sequence, voxel size 0.4 × 0.4 × 2 mm3) and bone marrow (1H-MRS, point resolved spectroscopy sequence (PRESS) (single voxel size 20 × 20 × 20 mm3) size and muscle adiposity (Dixon, voxel size 1.1 × 1.1 × 2 mm3). Results There was an inverse association of apparent bone volume/total volume (appBV/TV) with age (r = -0.5, P < 0.0005). Cortical area, endosteal and periosteal circumferences and muscle cross-sectional area showed a positive association to age (r > 0.49, P < 0.0001). In those over 17 years of age, these parameters were also higher in males than females (P < 0.05). This sex difference was also evident for appBV/TV and bone marrow adiposity (BMA) in the older participants (P < 0.05). AppBV/TV showed a negative correlation with BMA (r = -0.22, P = 0.01) which also showed an association with muscle adiposity (r = 0.24, P = 0.04). Cortical geometric parameters were highly correlated with muscle area (r > 0.57, P < 0.01). Conclusions In addition to providing deep insight into the normal relationships between bone, fat and muscle in young people, these novel data emphasize the role of MRI as a non-invasive method for performing a comprehensive and integrated assessment of musculoskeletal health in the growing skeleton.
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Affiliation(s)
- Huda M Elsharkasi
- Developmental Endocrinology Research Group, University of Glasgow, Glasgow, UK
| | - Suet C Chen
- Developmental Endocrinology Research Group, University of Glasgow, Glasgow, UK
| | - Lewis Steell
- Developmental Endocrinology Research Group, University of Glasgow, Glasgow, UK
| | - Shuko Joseph
- Developmental Endocrinology Research Group, University of Glasgow, Glasgow, UK
- Paediatric Neurosciences Research Group, Royal Hospital for Children, NHS Greater Glasgow & Clyde, Glasgow, UK
| | - Naiemh Abdalrahaman
- Developmental Endocrinology Research Group, University of Glasgow, Glasgow, UK
| | - Christie McComb
- Department of Clinical Physics, NHS Greater Glasgow & Clyde, Glasgow, UK
| | - Blair Johnston
- Department of Clinical Physics, NHS Greater Glasgow & Clyde, Glasgow, UK
| | - John Foster
- Department of Clinical Physics, NHS Greater Glasgow & Clyde, Glasgow, UK
| | - Sze Choong Wong
- Developmental Endocrinology Research Group, University of Glasgow, Glasgow, UK
| | - S Faisal Ahmed
- Developmental Endocrinology Research Group, University of Glasgow, Glasgow, UK
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29
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Ou MY, Zhang H, Tan PC, Zhou SB, Li QF. Adipose tissue aging: mechanisms and therapeutic implications. Cell Death Dis 2022; 13:300. [PMID: 35379822 PMCID: PMC8980023 DOI: 10.1038/s41419-022-04752-6] [Citation(s) in RCA: 114] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/03/2022] [Accepted: 03/18/2022] [Indexed: 01/10/2023]
Abstract
Adipose tissue, which is the crucial energy reservoir and endocrine organ for the maintenance of systemic glucose, lipid, and energy homeostasis, undergoes significant changes during aging. These changes cause physiological declines and age-related disease in the elderly population. Here, we review the age-related changes in adipose tissue at multiple levels and highlight the underlying mechanisms regulating the aging process. We also discuss the pathogenic pathways of age-related fat dysfunctions and their systemic negative consequences, such as dyslipidemia, chronic general inflammation, insulin resistance, and type 2 diabetes (T2D). Age-related changes in adipose tissue involve redistribution of deposits and composition, in parallel with the functional decline of adipocyte progenitors and accumulation of senescent cells. Multiple pathogenic pathways induce defective adipogenesis, inflammation, aberrant adipocytokine production, and insulin resistance, leading to adipose tissue dysfunction. Changes in gene expression and extracellular signaling molecules regulate the aging process of adipose tissue through various pathways. In addition, adipose tissue aging impacts other organs that are infiltrated by lipids, which leads to systemic inflammation, metabolic system disruption, and aging process acceleration. Moreover, studies have indicated that adipose aging is an early onset event in aging and a potential target to extend lifespan. Together, we suggest that adipose tissue plays a key role in the aging process and is a therapeutic target for the treatment of age-related disease, which deserves further study to advance relevant knowledge.
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Affiliation(s)
- Min-Yi Ou
- Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 200011, Shanghai, China
| | - Hao Zhang
- Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 200011, Shanghai, China
| | - Poh-Ching Tan
- Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 200011, Shanghai, China
| | - Shuang-Bai Zhou
- Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 200011, Shanghai, China.
| | - Qing-Feng Li
- Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 200011, Shanghai, China.
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30
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Kim M, Oh JH, Won CW. Sex-Specific Differences in Lower Body Fat Distribution and Association with Physical Performance among Healthy Community-Dwelling Older Adults: A Pilot Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19074201. [PMID: 35409882 PMCID: PMC8998698 DOI: 10.3390/ijerph19074201] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 12/02/2022]
Abstract
This study aims to examine sex-specific differences in body composition and lower extremity fat distribution and their association with physical performance among healthy older adults. The pilot study comprises 40 subjects (20 men and 20 women) matched by age and body mass index. The participants undergo dual-energy X-ray absorptiometry, magnetic resonance imaging, and proton magnetic resonance spectroscopy (1H-MRS) to assess body composition and lower extremity fat distribution. 1H-MRS is used to measure the extramyocellular lipid (EMCL) and intramyocellular lipid (IMCL) contents of the lower leg muscles (soleus and tibialis anterior) at the maximum circumference of the calf after overnight fasting. The tibialis anterior IMCL, as assessed by 1H-MRS, is negatively associated with the five-times sit-to-stand test scores (rs = 0.518, p = 0.023) in men, while the soleus IMCL content is negatively associated with the timed up-and-go test scores (rs = 0.472, p = 0.048) in women. However, the soleus EMCL content is positively associated with the five-times sit-to-stand test scores (rs = −0.488, p = 0.040) in women, but this association is not statistically significant in men. This study shows an inverse correlation between IMCL content and physical performance in healthy older individuals and lower leg muscle-specific IMCL based on sex differences. Furthermore, our results suggest that greater EMCL content in the soleus and calf subcutaneous fat might affect physical performance positively in women but not men.
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Affiliation(s)
- Miji Kim
- Department of Biomedical Science and Technology, College of Medicine, East-West Medical Research Institute, Kyung Hee University, Seoul 02447, Korea
- Correspondence: (M.K.); (C.W.W.); Tel.: +82-2-958-2840 (M.K.); +82-2-958-8700 (C.W.W.)
| | - Jang-Hoon Oh
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul 02447, Korea;
| | - Chang Won Won
- Department of Family Medicine, College of Medicine, Kyung Hee University, Seoul 02447, Korea
- Correspondence: (M.K.); (C.W.W.); Tel.: +82-2-958-2840 (M.K.); +82-2-958-8700 (C.W.W.)
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Bhalla S, Kuchel GA, Pandol S, Bishehsari F. Association of Pancreatic Fatty Infiltration With Age and Metabolic Syndrome Is Sex-Dependent. GASTRO HEP ADVANCES 2022; 1:344-349. [PMID: 39131675 PMCID: PMC11308813 DOI: 10.1016/j.gastha.2022.01.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 01/25/2022] [Indexed: 08/13/2024]
Abstract
Background and Aims Fatty infiltration of the pancreas has been shown to be associated with both precancerous pancreatic lesions and pancreatic ductal adenocarcinoma. We aim to determine predictors of fatty infiltration of the pancreas in United States adults. Methods In this retrospective cohort study conducted at a large academic hospital in Chicago, Illinois, we calculated the relative fatty infiltration of the pancreas (corrected to spleen) of 265 cancer-free individuals based on their cross-sectional imaging. Demographic data and relevant laboratory results were obtained from medical records. Results We found that age was the strongest predictor of fatty infiltration of the pancreas in our series (P < .01). Fatty infiltration of the pancreas was also significantly associated with body mass index (P < .01) and hyperlipidemia (P < .05). In women, in addition to age (P < .05), elevated body mass index (P = .023), hyperlipidemia (P = .013), and fatty liver (P = .017) were predictors of fat in pancreas. We found a sex-dependent association between pancreatic fat and metabolic syndrome including fatty liver (P = .002). Conclusion Fatty infiltration of the pancreas increases by age and components of metabolic syndrome. These assertions could be sex-dependent.
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Affiliation(s)
- Sameer Bhalla
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois
| | - George A. Kuchel
- UConn Center on Aging, University of Connecticut, Farmington, Connecticut
| | - Stephen Pandol
- Division of Digestive and Liver Disease, Cedars-Sinai Medical Center, Los Angeles, California
| | - Faraz Bishehsari
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, Illinois
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Espinosa De Ycaza AE, Søndergaard E, Morgan-Bathke M, Lytle K, Delivanis DA, Ramos P, Carranza Leon BG, Jensen MD. Adipose Tissue Inflammation Is Not Related to Adipose Insulin Resistance in Humans. Diabetes 2022; 71:381-393. [PMID: 34857544 PMCID: PMC8893944 DOI: 10.2337/db21-0609] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 11/18/2021] [Indexed: 11/13/2022]
Abstract
The role of adipose tissue (AT) inflammation in AT function in humans is unclear. We tested whether AT macrophage (ATM) content, cytokine gene expression, and senescent cell burden (markers of AT inflammation) predict AT insulin resistance measured as the insulin concentration that suppresses lipolysis by 50% (IC50). We studied 86 volunteers with normal weight or obesity at baseline and a subgroup of 25 volunteers with obesity before and after weight loss. There was a strong positive relationship between IC50 and abdominal subcutaneous and femoral fat cell size (FCS). The positive, univariate relationships between IC50 and abdominal AT inflammatory markers CD68, CD14, CD206 ATM/100 adipocytes, senescent cells, IL-6, and TNF-α mRNA were not significant after adjustment for FCS. A 10% weight loss significantly reduced IC50; however, there was no reduction in adipose ATM content, senescent cells, or cytokine gene expression. Our study suggests that commonly used markers of AT inflammation are not causally linked to AT insulin resistance, whereas FCS is a strong predictor of AT insulin resistance with respect to lipolysis.
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Affiliation(s)
- Ana Elena Espinosa De Ycaza
- Endocrine Research Unit, Mayo Clinic, Rochester, MN
- Facultad de Medicina, Universidad de Panamá, Panama City, Republic of Panama
- Panamanian Institute of Biological Research, Panama City, Republic of Panama
| | - Esben Søndergaard
- Endocrine Research Unit, Mayo Clinic, Rochester, MN
- Steno Diabetes Center Aarhus, Aarhus, Denmark
- The Danish Diabetes Academy, Odense, Denmark
| | - Maria Morgan-Bathke
- Endocrine Research Unit, Mayo Clinic, Rochester, MN
- Nutrition and Dietetics, Viterbo University, La Crosse, WI
| | - Kelli Lytle
- Endocrine Research Unit, Mayo Clinic, Rochester, MN
| | | | - Paola Ramos
- Endocrine Research Unit, Mayo Clinic, Rochester, MN
| | - Barbara Gisella Carranza Leon
- Endocrine Research Unit, Mayo Clinic, Rochester, MN
- Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN
| | - Michael D. Jensen
- Endocrine Research Unit, Mayo Clinic, Rochester, MN
- Corresponding author: Michael D. Jensen,
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Campos JTADM, Oliveira MSD, Soares LP, Medeiros KAD, Campos LRDS, Lima JG. DNA repair-related genes and adipogenesis: Lessons from congenital lipodystrophies. Genet Mol Biol 2022; 45:e20220086. [DOI: 10.1590/1678-4685-gmb-2022-0086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 09/20/2022] [Indexed: 11/09/2022] Open
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Senolytic effects of quercetin in an in vitro model of pre-adipocytes and adipocytes induced senescence. Sci Rep 2021; 11:23237. [PMID: 34853352 PMCID: PMC8636588 DOI: 10.1038/s41598-021-02544-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 11/03/2021] [Indexed: 12/25/2022] Open
Abstract
The dysfunction of adipose tissue with aging and the accumulation of senescent cells has been implicated in the pathophysiology of chronic diseases. Recently interventions capable of reducing the burden of senescent cells and in particular the identification of a new class of drugs termed senolytics have been object of extensive investigation. We used an in vitro model of induced senescence by treating both pre-adipocytes as well as mature adipocytes with hydrogen peroxide (H2O2) at a sub-lethal concentration for 3 h for three consecutive days, and hereafter with 20 uM quercetin at a dose that in preliminary experiments resulted to be senolytic without cytotoxicity. H2O2 treated pre-adipocytes and adipocytes showed typical senescence-associated features including increased beta-galactosidase activity (SA-ß-gal) and p21, activation of ROS and increased expression of pro-inflammatory cytokines. The treatment with quercetin in senescent pre-adipocytes and adipocytes was associated to a significant decrease in the number of the SA-β-gal positive cells along with the suppression of ROS and of inflammatory cytokines. Besides, quercetin treatment decreased miR-155-5p expression in both models, with down-regulation of p65 and a trend toward an up-regulation of SIRT-1 in complete cell extracts. The senolytic compound quercetin could affect AT ageing by reducing senescence, induced in our in vitro model by oxidative stress. The downregulation of miRNA-155-5p, possibly through the modulation of NF-κB and SIRT-1, could have a key role in the effects of quercetin on both pre-adipocytes and adipocytes.
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Ma XY, Chen FQ. Effects of anti-diabetic drugs on sarcopenia: Best treatment options for elderly patients with type 2 diabetes mellitus and sarcopenia. World J Clin Cases 2021; 9:10064-10074. [PMID: 34904076 PMCID: PMC8638038 DOI: 10.12998/wjcc.v9.i33.10064] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/22/2021] [Accepted: 09/30/2021] [Indexed: 02/06/2023] Open
Abstract
Human life expectancy increases as society becomes more developed. This increased life expectancy poses challenges associated with the rapid aging of the population. Sarcopenia, an age-related disease, has become a worldwide health issue. Patients with sarcopenia experience decreases in muscle mass and function, becoming frail and eventually bedridden. Type 2 diabetes mellitus (T2DM) is also a major health issue; the incidence of T2DM increases with aging. T2DM is associated with reduced muscle strength and poor muscle quality and may contribute to acceleration of the aging process, augmenting age-related sarcopenia. Recent studies indicate that elderly patients with diabetes are at an increased risk for sarcopenia. Therefore, these older diabetic patients with sarcopenia need specific anti-diabetic therapies targeting not only glycemic control but also sarcopenia, with the goal of preventing sarcopenia in pre-sarcopenic patients. Presently, various types of hypoglycemic drugs are available, but which hypoglycemic drugs are better suited for geriatric T2DM patients with sarcopenia remains undetermined. In this review, we discuss the association between diabetes and sarcopenia in geriatric patients, and how anti-diabetic drugs may influence sarcopenia outcomes. This review will guide clinical workers in the selection of drugs best suited for this patient population.
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Affiliation(s)
- Xiao-Yu Ma
- Department of Geriatrics, The First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning Province, China
| | - Fen-Qin Chen
- Department of Geriatrics, The First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning Province, China
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Kim M, Ladomersky E, Mozny A, Kocherginsky M, O'Shea K, Reinstein ZZ, Zhai L, Bell A, Lauing KL, Bollu L, Rabin E, Dixit K, Kumthekar P, Platanias LC, Hou L, Zheng Y, Wu J, Zhang B, Hrachova M, Merrill SA, Mrugala MM, Prabhu VC, Horbinski C, James CD, Yamini B, Ostrom QT, Johnson MO, Reardon DA, Lukas RV, Wainwright DA. Glioblastoma as an age-related neurological disorder in adults. Neurooncol Adv 2021; 3:vdab125. [PMID: 34647022 PMCID: PMC8500689 DOI: 10.1093/noajnl/vdab125] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background Advanced age is a major risk factor for the development of many diseases including those affecting the central nervous system. Wild-type isocitrate dehydrogenase glioblastoma (IDHwt GBM) is the most common primary malignant brain cancer and accounts for ≥90% of all adult GBM diagnoses. Patients with IDHwt GBM have a median age of diagnosis at 68–70 years of age, and increasing age is associated with an increasingly worse prognosis for patients with this type of GBM. Methods The Surveillance, Epidemiology, and End Results, The Cancer Genome Atlas, and the Chinese Glioma Genome Atlas databases were analyzed for mortality indices. Meta-analysis of 80 clinical trials was evaluated for log hazard ratio for aging to tumor survivorship. Results Despite significant advances in the understanding of intratumoral genetic alterations, molecular characteristics of tumor microenvironments, and relationships between tumor molecular characteristics and the use of targeted therapeutics, life expectancy for older adults with GBM has yet to improve. Conclusions Based upon the results of our analysis, we propose that age-dependent factors that are yet to be fully elucidated, contribute to IDHwt GBM patient outcomes.
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Affiliation(s)
- Miri Kim
- Department of Neurological Surgery, Loyola University Medical Center, Maywood, Illinois, USA.,Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Erik Ladomersky
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Andreas Mozny
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Masha Kocherginsky
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Kaitlyn O'Shea
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Zachary Z Reinstein
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Lijie Zhai
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - April Bell
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Kristen L Lauing
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Lakshmi Bollu
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Erik Rabin
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Karan Dixit
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Priya Kumthekar
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Leonidas C Platanias
- Department of Medicine, Division of Hematology-Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Lifang Hou
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Yinan Zheng
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Jennifer Wu
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Bin Zhang
- Department of Medicine, Division of Hematology-Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Maya Hrachova
- Division of Neuro-Oncology, Department of Neurology, Mayo Clinic, Phoenix, Arizona, USA
| | - Sarah A Merrill
- Division of Neuro-Oncology, Department of Neurology, Mayo Clinic, Phoenix, Arizona, USA
| | - Maciej M Mrugala
- Division of Neuro-Oncology, Department of Neurology, Mayo Clinic, Phoenix, Arizona, USA
| | - Vikram C Prabhu
- Department of Neurological Surgery, Loyola University Medical Center, Maywood, Illinois, USA
| | - Craig Horbinski
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Charles David James
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Bakhtiar Yamini
- Department of Neurological Surgery, University of Chicago Medical Center & Biological Sciences, Chicago, Illinois, USA
| | - Quinn T Ostrom
- Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USA
| | - Margaret O Johnson
- Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USA
| | - David A Reardon
- Dana-Farber/Harvard Cancer Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Rimas V Lukas
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Derek A Wainwright
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.,Department of Medicine, Division of Hematology-Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.,Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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Mancini C, Gohlke S, Garcia-Carrizo F, Zagoriy V, Stephanowitz H, Schulz TJ. Identification of biomarkers of brown adipose tissue aging highlights the role of dysfunctional energy and nucleotide metabolism pathways. Sci Rep 2021; 11:19928. [PMID: 34620947 PMCID: PMC8497523 DOI: 10.1038/s41598-021-99362-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Accepted: 09/23/2021] [Indexed: 12/25/2022] Open
Abstract
Brown adipose tissue function declines during aging and may contribute to the onset of metabolic disorders such as diabetes and obesity. Only limited understanding of the mechanisms leading to the metabolic impairment of brown adipocytes during aging exists. To this end, interscapular brown adipose tissue samples were collected from young and aged mice for quantification of differential gene expression and metabolite levels. To identify potential processes involved in brown adipocyte dysfunction, metabolite concentrations were correlated to aging and significantly changed candidates were subsequently integrated with a non-targeted proteomic dataset and gene expression analyses. Our results include novel age-dependent correlations of polar intermediates in brown adipose tissue. Identified metabolites clustered around three biochemical processes, specifically energy metabolism, nucleotide metabolism and vitamin metabolism. One mechanism of brown adipose tissue dysfunction may be linked to mast cell activity, and we identify increased histamine levels in aged brown fat as a potential biomarker. In addition, alterations of genes involved in synthesis and degradation of many metabolites were mainly observed in the mature brown adipocyte fraction as opposed to the stromal vascular fraction. These findings may provide novel insights on the molecular mechanisms contributing to the impaired thermogenesis of brown adipocytes during aging.
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Affiliation(s)
- Carola Mancini
- Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, 114-116 Arthur-Scheunert-Allee, 14558, Nuthetal, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Sabrina Gohlke
- Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, 114-116 Arthur-Scheunert-Allee, 14558, Nuthetal, Germany
| | - Francisco Garcia-Carrizo
- Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, 114-116 Arthur-Scheunert-Allee, 14558, Nuthetal, Germany
| | | | - Heike Stephanowitz
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
| | - Tim J Schulz
- Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, 114-116 Arthur-Scheunert-Allee, 14558, Nuthetal, Germany. .,German Center for Diabetes Research (DZD), München-Neuherberg, Germany. .,Institute of Nutritional Science, University of Potsdam, Potsdam-Rehbrücke, Nuthetal, Germany.
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Age and Sex: Impact on adipose tissue metabolism and inflammation. Mech Ageing Dev 2021; 199:111563. [PMID: 34474078 DOI: 10.1016/j.mad.2021.111563] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 08/19/2021] [Accepted: 08/26/2021] [Indexed: 02/08/2023]
Abstract
Age associated chronic inflammation is a major contributor to diseases with advancing age. Adipose tissue function is at the nexus of processes contributing to age-related metabolic disease and mediating longevity. Hormonal fluctuations in aging potentially regulate age-associated visceral adiposity and metabolic dysfunction. Visceral adiposity in aging is linked to aberrant adipogenesis, insulin resistance, lipotoxicity and altered adipokine secretion. Age-related inflammatory phenomena depict sex differences in macrophage polarization, changes in T and B cell numbers, and types of dendritic cells. Sex differences are also observed in adipose tissue remodeling and cellular senescence suggesting a role for sex steroid hormones in the regulation of the adipose tissue microenvironment. It is crucial to investigate sex differences in aging clinical outcomes to identify and better understand physiology in at-risk individuals. Early interventions aimed at targets involved in adipose tissue adipogenesis, remodeling and inflammation in aging could facilitate a profound impact on health span and overcome age-related functional decline.
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Uddin MS, Yu WS, Lim LW. Exploring ER stress response in cellular aging and neuroinflammation in Alzheimer's disease. Ageing Res Rev 2021; 70:101417. [PMID: 34339860 DOI: 10.1016/j.arr.2021.101417] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 07/27/2021] [Accepted: 07/28/2021] [Indexed: 02/06/2023]
Abstract
One evident hallmark of Alzheimer's disease (AD) is the irregular accumulation of proteins due to changes in proteostasis involving endoplasmic reticulum (ER) stress. To alleviate ER stress and reinstate proteostasis, cells undergo an integrated signaling cascade called the unfolded protein response (UPR) that reduces the number of misfolded proteins and inhibits abnormal protein accumulation. Aging is associated with changes in the expression of ER chaperones and folding enzymes, leading to the impairment of proteostasis, and accumulation of misfolded proteins. The disrupted initiation of UPR prevents the elimination of unfolded proteins, leading to ER stress. In AD, the accumulation of misfolded proteins caused by sustained cellular stress leads to neurodegeneration and neuronal death. Current research has revealed that ER stress can trigger an inflammatory response through diverse transducers of UPR. Although the involvement of a neuroinflammatory component in AD has been documented for decades, whether it is a contributing factor or part of the neurodegenerative events is so far unknown. Besides, a feedback loop occurs between neuroinflammation and ER stress, which is strongly associated with neurodegenerative processes in AD. In this review, we focus on the current research on ER stress and UPR in cellular aging and neuroinflammatory processes, leading to memory impairment and synapse dysfunction in AD.
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Bilbao-Malavé V, González-Zamora J, de la Puente M, Recalde S, Fernandez-Robredo P, Hernandez M, Layana AG, Saenz de Viteri M. Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Age Related Macular Degeneration, Role in Pathophysiology, and Possible New Therapeutic Strategies. Antioxidants (Basel) 2021; 10:1170. [PMID: 34439418 PMCID: PMC8388889 DOI: 10.3390/antiox10081170] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/14/2021] [Accepted: 07/20/2021] [Indexed: 02/07/2023] Open
Abstract
Age related macular degeneration (AMD) is the main cause of legal blindness in developed countries. It is a multifactorial disease in which a combination of genetic and environmental factors contributes to increased risk of developing this vision-incapacitating condition. Oxidative stress plays a central role in the pathophysiology of AMD and recent publications have highlighted the importance of mitochondrial dysfunction and endoplasmic reticulum stress in this disease. Although treatment with vascular endothelium growth factor inhibitors have decreased the risk of blindness in patients with the exudative form of AMD, the search for new therapeutic options continues to prevent the loss of photoreceptors and retinal pigment epithelium cells, characteristic of late stage AMD. In this review, we explain how mitochondrial dysfunction and endoplasmic reticulum stress participate in AMD pathogenesis. We also discuss a role of several antioxidants (bile acids, resveratrol, melatonin, humanin, and coenzyme Q10) in amelioration of AMD pathology.
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Affiliation(s)
- Valentina Bilbao-Malavé
- Department of Opthalmology, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (V.B.-M.); (J.G.-Z.); (M.d.l.P.); (A.G.L.)
| | - Jorge González-Zamora
- Department of Opthalmology, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (V.B.-M.); (J.G.-Z.); (M.d.l.P.); (A.G.L.)
| | - Miriam de la Puente
- Department of Opthalmology, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (V.B.-M.); (J.G.-Z.); (M.d.l.P.); (A.G.L.)
| | - Sergio Recalde
- Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Universidad de Navarra, 31008 Pamplona, Spain; (S.R.); (P.F.-R.); (M.H.)
- Navarra Institute for Health Research, IdiSNA, 31008 Pamplona, Spain
- Red Temática de Investigación Cooperativa en Salud: ‘Prevention, Early Detection, and Treatment of the Prevalent Degenerative and Chronic Ocular Pathology’ from (RD16/0008/0011), Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Patricia Fernandez-Robredo
- Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Universidad de Navarra, 31008 Pamplona, Spain; (S.R.); (P.F.-R.); (M.H.)
- Navarra Institute for Health Research, IdiSNA, 31008 Pamplona, Spain
- Red Temática de Investigación Cooperativa en Salud: ‘Prevention, Early Detection, and Treatment of the Prevalent Degenerative and Chronic Ocular Pathology’ from (RD16/0008/0011), Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - María Hernandez
- Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Universidad de Navarra, 31008 Pamplona, Spain; (S.R.); (P.F.-R.); (M.H.)
- Navarra Institute for Health Research, IdiSNA, 31008 Pamplona, Spain
- Red Temática de Investigación Cooperativa en Salud: ‘Prevention, Early Detection, and Treatment of the Prevalent Degenerative and Chronic Ocular Pathology’ from (RD16/0008/0011), Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Alfredo Garcia Layana
- Department of Opthalmology, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (V.B.-M.); (J.G.-Z.); (M.d.l.P.); (A.G.L.)
- Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Universidad de Navarra, 31008 Pamplona, Spain; (S.R.); (P.F.-R.); (M.H.)
- Navarra Institute for Health Research, IdiSNA, 31008 Pamplona, Spain
- Red Temática de Investigación Cooperativa en Salud: ‘Prevention, Early Detection, and Treatment of the Prevalent Degenerative and Chronic Ocular Pathology’ from (RD16/0008/0011), Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Manuel Saenz de Viteri
- Department of Opthalmology, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (V.B.-M.); (J.G.-Z.); (M.d.l.P.); (A.G.L.)
- Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Universidad de Navarra, 31008 Pamplona, Spain; (S.R.); (P.F.-R.); (M.H.)
- Navarra Institute for Health Research, IdiSNA, 31008 Pamplona, Spain
- Red Temática de Investigación Cooperativa en Salud: ‘Prevention, Early Detection, and Treatment of the Prevalent Degenerative and Chronic Ocular Pathology’ from (RD16/0008/0011), Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III, 28029 Madrid, Spain
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Kirstein AS, Kehr S, Nebe M, Hanschkow M, Barth LAG, Lorenz J, Penke M, Breitfeld J, Le Duc D, Landgraf K, Körner A, Kovacs P, Stadler PF, Kiess W, Garten A. PTEN regulates adipose progenitor cell growth, differentiation, and replicative aging. J Biol Chem 2021; 297:100968. [PMID: 34273354 PMCID: PMC8350019 DOI: 10.1016/j.jbc.2021.100968] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/17/2021] [Accepted: 07/13/2021] [Indexed: 12/12/2022] Open
Abstract
The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates the insulin signaling pathway. Germline PTEN pathogenic variants cause PTEN hamartoma tumor syndrome (PHTS), associated with lipoma development in children. Adipose progenitor cells (APCs) lose their capacity to differentiate into adipocytes during continuous culture, whereas APCs from lipomas of patients with PHTS retain their adipogenic potential over a prolonged period. It remains unclear which mechanisms trigger this aberrant adipose tissue growth. To investigate the role of PTEN in adipose tissue development, we performed functional assays and RNA-Seq of control and PTEN knockdown APCs. Reduction of PTEN levels using siRNA or CRISPR led to enhanced proliferation and differentiation of APCs. Forkhead box protein O1 (FOXO1) transcriptional activity is known to be regulated by insulin signaling, and FOXO1 was downregulated at the mRNA level while its inactivation through phosphorylation increased. FOXO1 phosphorylation initiates the expression of the lipogenesis-activating transcription factor sterol regulatory element-binding protein 1 (SREBP1). SREBP1 levels were higher after PTEN knockdown and may account for the observed enhanced adipogenesis. To validate this, we overexpressed constitutively active FOXO1 in PTEN CRISPR cells and found reduced adipogenesis, accompanied by SREBP1 downregulation. We observed that PTEN CRISPR cells showed less senescence compared with controls and the senescence marker CDKN1A (p21) was downregulated in PTEN knockdown cells. Cellular senescence was the most significantly enriched pathway found in RNA-Seq of PTEN knockdown versus control cells. These results provide evidence that PTEN is involved in the regulation of APC proliferation, differentiation, and senescence, thereby contributing to aberrant adipose tissue growth in patients with PHTS.
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Affiliation(s)
- Anna S Kirstein
- University Hospital for Children & Adolescents, Center for Pediatric Research, Leipzig University, Leipzig, Germany.
| | - Stephanie Kehr
- Bioinformatics Group, Department of Computer Science and Interdisciplinary Center for Bioinformatics, Leipzig University, Leipzig, Germany
| | - Michèle Nebe
- University Hospital for Children & Adolescents, Center for Pediatric Research, Leipzig University, Leipzig, Germany
| | - Martha Hanschkow
- University Hospital for Children & Adolescents, Center for Pediatric Research, Leipzig University, Leipzig, Germany
| | - Lisa A G Barth
- University Hospital for Children & Adolescents, Center for Pediatric Research, Leipzig University, Leipzig, Germany
| | - Judith Lorenz
- University Hospital for Children & Adolescents, Center for Pediatric Research, Leipzig University, Leipzig, Germany
| | - Melanie Penke
- University Hospital for Children & Adolescents, Center for Pediatric Research, Leipzig University, Leipzig, Germany
| | - Jana Breitfeld
- Medical Department III-Endocrinology, Nephrology, Rheumatology, Leipzig University Medical Center, Leipzig, Germany
| | - Diana Le Duc
- Institute of Human Genetics, Leipzig University Medical Center, Leipzig, Germany; Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany
| | - Kathrin Landgraf
- University Hospital for Children & Adolescents, Center for Pediatric Research, Leipzig University, Leipzig, Germany
| | - Antje Körner
- University Hospital for Children & Adolescents, Center for Pediatric Research, Leipzig University, Leipzig, Germany
| | - Peter Kovacs
- Medical Department III-Endocrinology, Nephrology, Rheumatology, Leipzig University Medical Center, Leipzig, Germany
| | - Peter F Stadler
- Bioinformatics Group, Department of Computer Science and Interdisciplinary Center for Bioinformatics, Leipzig University, Leipzig, Germany; Max Planck Institute for Mathematics in the Sciences, Leipzig, Germany
| | - Wieland Kiess
- University Hospital for Children & Adolescents, Center for Pediatric Research, Leipzig University, Leipzig, Germany
| | - Antje Garten
- University Hospital for Children & Adolescents, Center for Pediatric Research, Leipzig University, Leipzig, Germany; Institute for Metabolism and Systems Research, University of Birmingham, Birmingham, UK
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42
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Caverzan J, Mussi L, Sufi B, Padovani G, Nazato L, Camargo FB, Magalhães WV, Di Stasi LC. A new phytocosmetic preparation from Thymus vulgaris stimulates adipogenesis and controls skin aging process: In vitro studies and topical effects in a double-blind placebo-controlled clinical trial. J Cosmet Dermatol 2021; 20:2190-2202. [PMID: 33169920 DOI: 10.1111/jocd.13818] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 10/14/2020] [Accepted: 10/22/2020] [Indexed: 12/26/2022]
Abstract
BACKGROUND The use of the injectable products for soft tissue augmentation and treatment of skin aging is an uncomfortable, invasive and related to several complications, and chronic reactions, mainly after long-term application. Efforts to develop new topically active anti-aging products with fewer adverse effects are a huge challenge that should be faced. AIMS We evaluated the anti-aging effects of a phytocosmetic preparation containing Thymus vulgaris associated with lecithin (ThymLec) on the facial wrinkles, expression lines, and face oval remodeling using a double-blind placebo-controlled clinical trial and in vitro cell culture assays. METHODS A clinical trial was conducted to evaluate the effects of ThymLec 2% on the area, length, and depth of the perioral and crow's feet wrinkles, nasolabial and smile lines, as well as face oval remodeling in female volunteers using a sophisticated Bio3D Structured-light Scanner. In the in vitro studies using 3T3-L1 mouse embryonic fibroblasts, adiponectin was measured by immunoenzymatic assay, adipogenesis by the AdipoRed reagent method, and the PPAR-γ expression by RT-PCR analysis. RESULTS Topical treatment with ThymLec 2% reduced facial wrinkles and expression lines promoting a face oval remodeling. In the in vitro studies, ThymLec upregulated the PPAR-γ expression increasing adiponectin production and stimulating the adipogenesis process. CONCLUSIONS The phytocosmetic preparation containing Thymus vulgaris and lecithin is an innovative and safe topical anti-aging product promoting fat tissue augmentation by adipogenesis stimulation via the upregulation of PPAR-γ expression and adiponectin production.
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Affiliation(s)
- Jeanifer Caverzan
- Research and Development Department, Chemyunion Química Ltda, Sorocaba, Brazil
| | - Lilian Mussi
- Research and Development Department, Chemyunion Química Ltda, Sorocaba, Brazil
| | - Bianca Sufi
- Research and Development Department, Chemyunion Química Ltda, Sorocaba, Brazil
| | - Giovana Padovani
- Research and Development Department, Chemyunion Química Ltda, Sorocaba, Brazil
| | - Lucas Nazato
- Research and Development Department, Chemyunion Química Ltda, Sorocaba, Brazil
| | - Flavio B Camargo
- Research and Development Department, Chemyunion Química Ltda, Sorocaba, Brazil
| | - Wagner V Magalhães
- Research and Development Department, Chemyunion Química Ltda, Sorocaba, Brazil
| | - Luiz C Di Stasi
- Laboratory of Phytomedicines, Pharmacology and Biotechnology (PhytoPharmaTech), Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University (Unesp), Botucatu, Brazil
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43
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Song S, Luo Z, Li C, Huang X, Shiroma EJ, Simonsick EM, Chen H. Changes in Body Composition Before and After Parkinson's Disease Diagnosis. Mov Disord 2021; 36:1617-1623. [PMID: 33615545 PMCID: PMC10775470 DOI: 10.1002/mds.28536] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/24/2021] [Accepted: 01/27/2021] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND Weight loss is common in Parkinson's disease (PD). However, little is known about when it starts, how PD changes as it progresses, and whether there is a differential loss of lean or fat mass. The objective of this study was to examine how body composition changes before and after PD diagnosis. METHODS In the Health, Aging, and Body Composition study (n = 3075; age range, 70-79 years), body composition was assessed using dual-energy x-ray absorptiometry on an annual or biennial basis from year 1 to year 10. For each PD case each year, we calculated the difference between their actual body composition measures and expected values had they not developed PD. Using linear mixed models with crossed random effects, we further examined the trend of change in body composition measures before and after PD diagnosis. RESULTS A total of 80 PD cases were identified in this cohort. Compared with their expected values, PD cases began to lose total and fat mass about 6-7 years before diagnosis, although the differences were not statistically significant until 3-5 years after diagnosis. The loss was substantial and persistent, with statistically significant trends of loss for total body mass (P = 0.008), fat mass (P = 0.001), and percentage fat (P < 0.001). In comparison, lean mass was stable throughout the follow-up (P = 0.16). Overall, 96% of the body mass loss in PD cases was from the loss of fat mass. CONCLUSIONS In this longitudinal analysis with objective measures of body composition, we found persistent weight loss in PD cases, predominantly in fat mass, starting a few years before diagnosis. © 2021 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Shengfang Song
- Department of Epidemiology and Biostatistics, College of Human Medicine, Michigan State University, East Lansing, Michigan, USA
| | - Zhehui Luo
- Department of Epidemiology and Biostatistics, College of Human Medicine, Michigan State University, East Lansing, Michigan, USA
| | - Chenxi Li
- Department of Epidemiology and Biostatistics, College of Human Medicine, Michigan State University, East Lansing, Michigan, USA
| | - Xuemei Huang
- Department of Neurology, Hersey Medical Center, Pennsylvania State University, Hersey, Pennsylvania, USA
| | - Eric J. Shiroma
- Laboratory of Epidemiology and Population Science, Intramural Research Program of the National Institutes of Health, National Institute on Aging, Bethesda, Maryland, USA
| | - Eleanor M. Simonsick
- Laboratory of Epidemiology and Population Science, Intramural Research Program of the National Institutes of Health, National Institute on Aging, Bethesda, Maryland, USA
| | - Honglei Chen
- Department of Epidemiology and Biostatistics, College of Human Medicine, Michigan State University, East Lansing, Michigan, USA
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Nguyen HP, Lin F, Yi D, Xie Y, Dinh J, Xue P, Sul HS. Aging-dependent regulatory cells emerge in subcutaneous fat to inhibit adipogenesis. Dev Cell 2021; 56:1437-1451.e3. [PMID: 33878347 PMCID: PMC8137669 DOI: 10.1016/j.devcel.2021.03.026] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 12/10/2020] [Accepted: 03/23/2021] [Indexed: 12/11/2022]
Abstract
Adipose tissue mass and adiposity change throughout the lifespan. During aging, while visceral adipose tissue (VAT) tends to increase, peripheral subcutaneous adipose tissue (SAT) decreases significantly. Unlike VAT, which is linked to metabolic diseases, including type 2 diabetes, SAT has beneficial effects. However, the molecular details behind the aging-associated loss of SAT remain unclear. Here, by comparing scRNA-seq of total stromal vascular cells of SAT from young and aging mice, we identify an aging-dependent regulatory cell (ARC) population that emerges only in SAT of aged mice and humans. ARCs express adipose progenitor markers but lack adipogenic capacity; they secrete high levels of pro-inflammatory chemokines, including Ccl6, to inhibit proliferation and differentiation of neighboring adipose precursors. We also found Pu.1 to be a driving factor for ARC development. We identify an ARC population and its capacity to inhibit differentiation of neighboring adipose precursors, correlating with aging-associated loss of SAT.
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Affiliation(s)
- Hai P Nguyen
- Department of Nutritional Sciences & Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Frances Lin
- Department of Nutritional Sciences & Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Danielle Yi
- Department of Nutritional Sciences & Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Program, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Ying Xie
- Department of Nutritional Sciences & Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Jennie Dinh
- Department of Nutritional Sciences & Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Pengya Xue
- Department of Nutritional Sciences & Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Hei Sook Sul
- Department of Nutritional Sciences & Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Program, University of California, Berkeley, Berkeley, CA 94720, USA.
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45
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Crippa S, Santi L, Berti M, De Ponti G, Bernardo ME. Role of ex vivo Expanded Mesenchymal Stromal Cells in Determining Hematopoietic Stem Cell Transplantation Outcome. Front Cell Dev Biol 2021; 9:663316. [PMID: 34017834 PMCID: PMC8129582 DOI: 10.3389/fcell.2021.663316] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023] Open
Abstract
Overall, the human organism requires the production of ∼1 trillion new blood cells per day. Such goal is achieved via hematopoiesis occurring within the bone marrow (BM) under the tight regulation of hematopoietic stem and progenitor cell (HSPC) homeostasis made by the BM microenvironment. The BM niche is defined by the close interactions of HSPCs and non-hematopoietic cells of different origin, which control the maintenance of HSPCs and orchestrate hematopoiesis in response to the body’s requirements. The activity of the BM niche is regulated by specific signaling pathways in physiological conditions and in case of stress, including the one induced by the HSPC transplantation (HSCT) procedures. HSCT is the curative option for several hematological and non-hematological diseases, despite being associated with early and late complications, mainly due to a low level of HSPC engraftment, impaired hematopoietic recovery, immune-mediated graft rejection, and graft-versus-host disease (GvHD) in case of allogenic transplant. Mesenchymal stromal cells (MSCs) are key elements of the BM niche, regulating HSPC homeostasis by direct contact and secreting several paracrine factors. In this review, we will explore the several mechanisms through which MSCs impact on the supportive activity of the BM niche and regulate HSPC homeostasis. We will further discuss how the growing understanding of such mechanisms have impacted, under a clinical point of view, on the transplantation field. In more recent years, these results have instructed the design of clinical trials to ameliorate the outcome of HSCT, especially in the allogenic setting, and when low doses of HSPCs were available for transplantation.
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Affiliation(s)
- Stefania Crippa
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Ludovica Santi
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Margherita Berti
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giada De Ponti
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Centro Ricerca M. Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Monza, Italy
| | - Maria Ester Bernardo
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy.,University Vita-Salute San Raffaele, Faculty of Medicine, Milan, Italy
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46
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Waters DL, Aguirre L, Gurney AB, Sinacore DR, Fowler K, Gregori G, Armamento-Villareal R, Qualls C, Villareal DT. Effect of Aerobic or Resistance Exercise, or Both, on Intermuscular and Visceral Fat and Physical and Metabolic Function in Older Adults with Obesity While Dieting. J Gerontol A Biol Sci Med Sci 2021; 77:131-139. [PMID: 33839788 DOI: 10.1093/gerona/glab111] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Obesity exacerbates age-related effects on body composition, physical and metabolic function. Which exercise mode is most effective in mitigating these deleterious changes in dieting obese older adults is unknown. METHODS In a randomized controlled trial, we performed a head-to-head comparison of aerobic (AEX), resistance (REX), or combination (COMB) exercise during matched weight loss in 160 obese older adults. Prespecified analyses compared 6-month changes in intermuscular adipose tissue (IMAT) and visceral adipose tissue (VAT) assessed using MRI, insulin sensitivity index (ISI) by oral glucose tolerance test, physical function using Modified Physical Performance Test (PPT), VO2peak, gait-speed, and knee strength by dynamometry. RESULTS IMAT and VAT decreased more in COMB than AEX and REX groups (IMAT; -41% vs. -28% and -23% and VAT: -36% vs. -19% and -21%; p=.003 to .01); IMAT and VAT decreased in all groups more than control (CON) (between-group p<.001). ISI increased more in COMB than AEX and REX groups (86% vs. 50% and 39%; p=.005 to .03). PPT improved more in COMB than AEX and REX groups, while VO2peak improved more in COMB and AEX than REX group (all p<.05). Knee strength improved more in COMB and REX than AEX group (all p<.05). Changes in IMAT and VAT correlated with PPT (r=-.28 and -.39), VO2peak (r=-.49 and -.52), gait-speed (r=-.25 and -.36), and ISI (r=-.49 and -.52) (all p<.05). CONCLUSIONS Weight loss plus combination aerobic and resistance exercise was most effective in improving ectopic fat deposition and physical and metabolic function in older adults with obesity.
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Affiliation(s)
- Debra L Waters
- Department of Internal Medicine, School of Medicine, University of New Mexico, Albuquerque, New Mexico.,Department of Medicine, School of Physiotherapy, University of Otago, Dunedin, New Zealand.,New Mexico Veterans Affairs Health Care System, Albuquerque, New Mexico
| | - Lina Aguirre
- Department of Internal Medicine, School of Medicine, University of New Mexico, Albuquerque, New Mexico.,New Mexico Veterans Affairs Health Care System, Albuquerque, New Mexico
| | - A Burke Gurney
- Division of Physical Therapy, School of Medicine, University of New Mexico, Albuquerque, New Mexico
| | - David R Sinacore
- Department of Physical Therapy, High Point University, High Point, North Carolina and Program in Physical Therapy, Washington University School of Medicine, St Louis, Missouri
| | - Kenneth Fowler
- New Mexico Veterans Affairs Health Care System, Albuquerque, New Mexico
| | - Giulia Gregori
- Division of Endocrinology, Diabetes, and Metabolism, Baylor College of Medicine, Houston, Texas.,Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Reina Armamento-Villareal
- Division of Endocrinology, Diabetes, and Metabolism, Baylor College of Medicine, Houston, Texas.,Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Clifford Qualls
- Department of Mathematics and Statistics, School of Medicine, University of New Mexico, Albuquerque, New Mexico
| | - Dennis T Villareal
- Division of Endocrinology, Diabetes, and Metabolism, Baylor College of Medicine, Houston, Texas.,Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
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47
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Wu C, Yu P, Sun R. Adipose tissue and age‑dependent insulin resistance: New insights into WAT browning (Review). Int J Mol Med 2021; 47:71. [PMID: 33693956 PMCID: PMC7952244 DOI: 10.3892/ijmm.2021.4904] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 02/03/2021] [Indexed: 12/19/2022] Open
Abstract
Insulin resistance (IR) is defined as impaired insulin function, reduced glucose uptake and increased glucose production, which can result in type II diabetes, metabolic syndrome and even bone metabolic disorders. A possible reason for the increasing incidence of IR is population aging. Adipose tissue (AT) is an important endocrine organ that serves a crucial role in whole-body energy homeostasis. AT can be divided into white AT (WAT), beige AT and brown AT (BAT). Several mechanisms have been previously associated with age-dependent IR in WAT. However, BAT, a metabolically active tissue, controls the levels of plasma glucose and triglyceride metabolism. Therefore, the present review aimed to summarize the mechanisms of age-dependent IR induced by AT and to determine the role of WAT browning in achieving positive therapeutic outcomes in age-dependent IR.
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Affiliation(s)
- Chuanlong Wu
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China
| | - Pei Yu
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China
| | - Ruixin Sun
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, P.R. China
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48
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Mandl M, Wagner SA, Hatzmann FM, Ejaz A, Ritthammer H, Baumgarten S, Viertler HP, Springer J, Zwierzina ME, Mattesich M, Brucker C, Waldegger P, Pierer G, Zwerschke W. Sprouty1 Prevents Cellular Senescence Maintaining Proliferation and Differentiation Capacity of Human Adipose Stem/Progenitor Cells. J Gerontol A Biol Sci Med Sci 2021; 75:2308-2319. [PMID: 32304210 PMCID: PMC7662188 DOI: 10.1093/gerona/glaa098] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Indexed: 12/25/2022] Open
Abstract
The role of Ras-Mitogen-activated protein kinase (MAPK) signaling in cellular aging is not precisely understood. Recently, we identified Sprouty1 (SPRY1) as a weight-loss target gene in human adipose stem/progenitor cells (ASCs) and showed that Sprouty1 is important for proper regulation of adipogenesis. In the present study, we show that loss-of-function of Sprouty1 by CRISPR/Cas9-mediated genome editing in human ASCs leads to hyper-activation of MAPK signaling and a senescence phenotype. Sprouty1 knockout ASCs undergo an irreversible cell cycle arrest, become enlarged and stain positive for senescence-associated β-galactosidase. Sprouty1 down-regulation leads to DNA double strand breaks, a considerably increased number of senescence-associated heterochromatin foci and induction of p53 and p21Cip1. In addition, we detect an increase of hypo-phosphorylated Retinoblastoma (Rb) protein in SPRY1 knockout ASCs. p16Ink4A is not induced. Moreover, we show that Sprouty1 knockout leads to induction of a senescence-associated secretory phenotype as indicated by the activation of the transcription factors NFκB and C/EBPβ and a significant increase in mRNA expression and secretion of interleukin-8 (IL-8) and CXCL1/GROα. Finally, we demonstrate that adipogenesis is abrogated in senescent SPRY1 knockout ASCs. In conclusion, this study reveals a novel mechanism showing the importance of Sprouty1 for the prevention of senescence and the maintenance of the proliferation and differentiation capacity of human ASCs.
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Affiliation(s)
- Markus Mandl
- Division of Cell Metabolism and Differentiation Research, Research Institute for Biomedical Aging Research, University of Innsbruck, Austria.,Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Austria
| | - Sonja A Wagner
- Division of Cell Metabolism and Differentiation Research, Research Institute for Biomedical Aging Research, University of Innsbruck, Austria.,Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Austria
| | - Florian M Hatzmann
- Division of Cell Metabolism and Differentiation Research, Research Institute for Biomedical Aging Research, University of Innsbruck, Austria.,Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Austria
| | - Asim Ejaz
- Division of Cell Metabolism and Differentiation Research, Research Institute for Biomedical Aging Research, University of Innsbruck, Austria
| | - Heike Ritthammer
- Division of Cell Metabolism and Differentiation Research, Research Institute for Biomedical Aging Research, University of Innsbruck, Austria
| | - Saphira Baumgarten
- Division of Cell Metabolism and Differentiation Research, Research Institute for Biomedical Aging Research, University of Innsbruck, Austria
| | - Hans P Viertler
- Division of Cell Metabolism and Differentiation Research, Research Institute for Biomedical Aging Research, University of Innsbruck, Austria.,Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Austria
| | - Jochen Springer
- Division of Cell Metabolism and Differentiation Research, Research Institute for Biomedical Aging Research, University of Innsbruck, Austria
| | - Marit E Zwierzina
- Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Austria
| | - Monika Mattesich
- Department of Plastic and Reconstructive Surgery, Innsbruck Medical University, Austria
| | - Camille Brucker
- Division of Cell Metabolism and Differentiation Research, Research Institute for Biomedical Aging Research, University of Innsbruck, Austria.,Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Austria
| | - Petra Waldegger
- Division of Cell Metabolism and Differentiation Research, Research Institute for Biomedical Aging Research, University of Innsbruck, Austria.,Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Austria
| | - Gerhard Pierer
- Department of Plastic and Reconstructive Surgery, Innsbruck Medical University, Austria
| | - Werner Zwerschke
- Division of Cell Metabolism and Differentiation Research, Research Institute for Biomedical Aging Research, University of Innsbruck, Austria.,Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Austria
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49
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Shirasawa H, Matsumura N, Yoda M, Okubo K, Shimoda M, Uezumi A, Matsumoto M, Nakamura M, Horiuchi K. Retinoic Acid Receptor Agonists Suppress Muscle Fatty Infiltration in Mice. Am J Sports Med 2021; 49:332-339. [PMID: 33428447 DOI: 10.1177/0363546520984122] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND The infiltration of fat tissue into skeletal muscle, a condition referred to as muscle fatty infiltration or fatty degeneration, is regarded as an irreversible event that significantly compromises the motor function of skeletal muscle. PURPOSE To investigate the effect of retinoic acid receptor (RAR) agonists in suppressing the adipogenic differentiation of fibroadipogenic progenitors (FAPs) in vitro and fatty infiltration after rotator cuff tear in mice. STUDY DESIGN Controlled laboratory study. METHODS FAPs isolated from mouse skeletal muscle were cultured in adipogenic differentiation medium in the presence or absence of an RAR agonist. At the end of cell culture, adipogenic differentiation was evaluated by gene expression analysis and oil red O staining. A mouse model of fatty infiltration-which includes the resection of the rotator cuff, removal of the humeral head, and denervation the supraspinatus muscle-was used to induce fatty infiltration in the supraspinatus muscle. The mice were orally or intramuscularly administered with an RAR agonist after the surgery. Muscle fatty infiltration was evaluated by histology and gene expression analysis. RESULTS RAR agonists effectively inhibited the adipogenic differentiation of FAPs in vitro. Oral and intramuscular administration of RAR agonists suppressed the development of muscle fatty infiltration in the mice after rotator cuff tear. In accordance, we found a significant decrease in the number of intramuscular fat cells and suppressed expression in adipogenic markers. RAR agonists also increased the expression of the transcripts for collagens; however, an accumulation of collagenous tissues was not histologically evident in the present model. CONCLUSION Muscle fatty infiltration can be alleviated by RAR agonists through suppressing the adipogenic differentiation of FAPs. The results also suggest that RAR agonists are potential therapeutic agents for treating patients who are at risk of developing muscle fatty infiltration. The consequence of the increased expression of collagen transcripts by RAR agonists needs to be clarified. CLINICAL RELEVANCE RAR agonists can be used to prevent the development of muscle fatty infiltration after rotator cuff tear. Nevertheless, further studies are mandatory in a large animal model to examine the safety and efficacy of intramuscular injection of RAR agonists.
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Affiliation(s)
- Hideyuki Shirasawa
- Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Noboru Matsumura
- Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Masaki Yoda
- Laboratory of Cell and Tissue Biology, School of Medicine, Keio University, Tokyo, Japan
| | - Kazumasa Okubo
- Pharmacology, Pharmaceutical Research Department, Sato Pharmaceutical Co, Ltd, Tokyo, Japan
| | - Masayuki Shimoda
- Department of Pathology, School of Medicine, Keio University, Tokyo, Japan
| | - Akiyoshi Uezumi
- Department of Geriatric Medicine, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Morio Matsumoto
- Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Masaya Nakamura
- Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Keisuke Horiuchi
- Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan.,Department of Orthopedic Surgery, National Defense Medical College, Saitama, Japan
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Tang CY, Wu M, Zhao D, Edwards D, McVicar A, Luo Y, Zhu G, Wang Y, Zhou HD, Chen W, Li YP. Runx1 is a central regulator of osteogenesis for bone homeostasis by orchestrating BMP and WNT signaling pathways. PLoS Genet 2021; 17:e1009233. [PMID: 33476325 PMCID: PMC7819607 DOI: 10.1371/journal.pgen.1009233] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 10/29/2020] [Indexed: 12/23/2022] Open
Abstract
Runx1 is highly expressed in osteoblasts, however, its function in osteogenesis is unclear. We generated mesenchymal progenitor-specific (Runx1f/fTwist2-Cre) and osteoblast-specific (Runx1f/fCol1α1-Cre) conditional knockout (Runx1 CKO) mice. The mutant CKO mice with normal skeletal development displayed a severe osteoporosis phenotype at postnatal and adult stages. Runx1 CKO resulted in decreased osteogenesis and increased adipogenesis. RNA-sequencing analysis, Western blot, and qPCR validation of Runx1 CKO samples showed that Runx1 regulates BMP signaling pathway and Wnt/β-catenin signaling pathway. ChIP assay revealed direct binding of Runx1 to the promoter regions of Bmp7, Alk3, and Atf4, and promoter mapping demonstrated that Runx1 upregulates their promoter activity through the binding regions. Bmp7 overexpression rescued Alk3, Runx2, and Atf4 expression in Runx1-deficient BMSCs. Runx2 expression was decreased while Runx1 was not changed in Alk3 deficient osteoblasts. Atf4 overexpression in Runx1-deficient BMSCs did not rescue expression of Runx1, Bmp7, and Alk3. Smad1/5/8 activity was vitally reduced in Runx1 CKO cells, indicating Runx1 positively regulates the Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 signaling pathway. Notably, Runx1 overexpression in Runx2-/- osteoblasts rescued expression of Atf4, OCN, and ALP to compensate Runx2 function. Runx1 CKO mice at various osteoblast differentiation stages reduced Wnt signaling and caused high expression of C/ebpα and Pparγ and largely increased adipogenesis. Co-culture of Runx1-deficient and wild-type cells demonstrated that Runx1 regulates osteoblast-adipocyte lineage commitment both cell-autonomously and non-autonomously. Notably, Runx1 overexpression rescued bone loss in OVX-induced osteoporosis. This study focused on the role of Runx1 in different cell populations with regards to BMP and Wnt signaling pathways and in the interacting network underlying bone homeostasis as well as adipogenesis, and has provided new insight and advancement of knowledge in skeletal development. Collectively, Runx1 maintains adult bone homeostasis from bone loss though up-regulating Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 and WNT/β-Catenin signaling pathways, and targeting Runx1 potentially leads to novel therapeutics for osteoporosis.
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Affiliation(s)
- Chen-Yi Tang
- Department of Pathology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America
- Department of Metabolism & Endocrinology, Hunan provincial Key Laboratory of Metabolic Bone Diseases, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Mengrui Wu
- Department of Pathology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America
- Institute of Genetics, Life Science College, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Dongfeng Zhao
- Department of Pathology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America
- Shanghai University of Traditional Chinese Medicine, Pudong, Shanghai, China P.R
| | - Diep Edwards
- Department of Pathology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America
| | - Abigail McVicar
- Department of Pathology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America
| | - Yuan Luo
- Department of Pathology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America
| | - Guochun Zhu
- Department of Pathology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America
| | - Yongjun Wang
- Shanghai University of Traditional Chinese Medicine, Pudong, Shanghai, China P.R
| | - Hou-De Zhou
- Department of Metabolism & Endocrinology, Hunan provincial Key Laboratory of Metabolic Bone Diseases, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wei Chen
- Department of Pathology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America
- * E-mail: (WC); (Y-PL)
| | - Yi-Ping Li
- Department of Pathology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America
- * E-mail: (WC); (Y-PL)
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