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Ruperez C, Madeo F, de Cabo R, Kroemer G, Abdellatif M. Obesity accelerates cardiovascular ageing. Eur Heart J 2025:ehaf216. [PMID: 40197620 DOI: 10.1093/eurheartj/ehaf216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 12/11/2024] [Accepted: 03/17/2025] [Indexed: 04/10/2025] Open
Abstract
A global obesity pandemic, coupled with an increasingly ageing population, is exacerbating the burden of cardiovascular disease. Indeed, clinical and experimental evidence underscores a potential connection between obesity and ageing in the pathogenesis of various cardiovascular disorders. This is further supported by the notion that weight reduction not only effectively reduces major cardiovascular events in elderly individuals but is also considered the gold standard for lifespan extension, in obese and non-obese model organisms. This review evaluates the intricate interplay between obesity and ageing from molecular mechanisms to whole organ function within the cardiovascular system. By comparatively analysing their characteristic features, shared molecular and cell biological signatures between obesity and ageing are unveiled, with the intent to shed light on how obesity accelerates cardiovascular ageing. This review also elaborates on how emerging metabolic interventions targeting obesity might protect from cardiovascular diseases largely through antagonizing key molecular mechanisms of the ageing process itself. In sum, this review aims to provide valuable insight into how understanding these interconnected processes could guide the development of novel and effective cardiovascular therapeutics for a growing aged population with a concerning obesity problem.
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Affiliation(s)
- Celia Ruperez
- Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, Graz 8036, Austria
| | - Frank Madeo
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
- BioTechMed-Graz, 8010 Graz, Austria
- Field of Excellence BioHealth, University of Graz, 8010 Graz, Austria
| | - Rafael de Cabo
- Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, 15 Rue de l'École de Médecine, Paris 75006, France
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 114 Rue Edouard Vaillant, Villejuif 94805, France
- Department of Biology, Institut du Cancer Paris CARPEM, Hôpital Européen Georges Pompidou, AP-HP, 20 Rue Leblanc, Paris 75015, France
| | - Mahmoud Abdellatif
- Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, Graz 8036, Austria
- BioTechMed-Graz, 8010 Graz, Austria
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, 15 Rue de l'École de Médecine, Paris 75006, France
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 114 Rue Edouard Vaillant, Villejuif 94805, France
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2
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Cheng M, Zhu C, Liu H, Pu C, Hou Y. Effects of calorie restriction therapy on health-related outcomes in patients with heart failure, a systematic review and meta-analysis. Nutr Metab Cardiovasc Dis 2025; 35:103756. [PMID: 39455331 DOI: 10.1016/j.numecd.2024.09.026] [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: 02/19/2024] [Revised: 09/23/2024] [Accepted: 09/25/2024] [Indexed: 10/28/2024]
Abstract
AIMS We conducted this systematic review to comprehensively assess the impact of CRT on health-related outcomes among patients with HF. DATA SYNTHESIS In order to find studies investigating the effect of CRT on health-related outcomes among patients with HF, we performed a systematic search of PubMed, Cochrane Library, Embase, and Cumulative Index to Nursing and Allied Health Literature databases (inception until February 12th, 2023). A total of 10 studies including 933 individuals met the inclusion criteria. The systematic review indicated that 8 to 24 weeks of CRT intervention offered some health advantages for patients with HF. CRT significantly reduced patients' body weight (SMD = - 0.52, 95 % CI = - 0.99 to -0.04, P = 0.03, I2 = 77 %) and improved their quality of life (SMD = 0.35, 95 % CI = 0.12 to 0.58, P = 0.003, I2 = 0 %). However, CRT significantly increased the risk of mortality and HF-related rehospitalization, including combined events of all-cause mortality and HF-related rehospitalization within a year (CRT group: 20 % vs. control group: 5 %), mortality rate within 1.52 years (CRT group: 34 % vs. control group: 22 %), readmission rate (CRT group: 52 % vs. control group: 17 %), and length of stay after readmission (CRT group: 124 days vs. control group:18 days). CONCLUSION CRT provides no significant benefits in terms of health-related outcomes among patients with HF, hence most patients with HF might not be eligible for CRT treatments. Meanwhile, there are several methodological issues among the studies included in the review, resulting in a low-to-moderate quality of evidence. REGISTRATION The PROSPERO registration number of this review is CRD 42023413992.
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Affiliation(s)
- Ming Cheng
- Department of Nursing, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 95 Qingchun Street, Hangzhou, Zhejiang Province, China
| | - Chenya Zhu
- Intensive Care Unit (ICU), Department of Cardiac Surgery (East area), Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 9677 Jingshi Road, Jinan, 250021, China
| | - Huan Liu
- Department of Nursing, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 95 Qingchun Street, Hangzhou, Zhejiang Province, China
| | - Chenxi Pu
- Department of Nursing, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 95 Qingchun Street, Hangzhou, Zhejiang Province, China
| | - Yunying Hou
- School of Nursing, Suzhou Medical College of Soochow University, Suzhou, China.
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Wu X, Meier L, Liu TX, Toldo S, Poelzing S, Gourdie RG. Detection, Isolation and Quantification of Myocardial Infarct with Four Different Histological Staining Techniques. Diagnostics (Basel) 2024; 14:2325. [PMID: 39451648 PMCID: PMC11507200 DOI: 10.3390/diagnostics14202325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 10/14/2024] [Accepted: 10/15/2024] [Indexed: 10/26/2024] Open
Abstract
BACKGROUND/OBJECTIVES The precise quantification of myocardial infarction is crucial for evaluating therapeutic strategies. We developed a robust, color-based semi-automatic algorithm capable of infarct region detection, isolation and quantification with four different histological staining techniques, and of the isolation and quantification of diffuse fibrosis in the heart. METHODS Our method is developed based on the color difference in the infarct and non-infarct regions after histological staining. Mouse cardiac tissues stained with Masson's trichrome (MTS), hematoxylin and eosin (H&E), 2,3,5-Triphenyltetrazolium chloride and picrosirius red were included to demonstrate the performance of our method. RESULTS We demonstrate that our algorithm can effectively identify and produce a clear visualization of infarct tissue in the four staining techniques. Notably, the infarct region on an H&E-stained tissue section can be clearly visualized after processing. The MATLAB-based program we developed holds promise for infarct quantification. Additionally, our program can isolate and quantify diffuse fibrotic elements from an MTS-stained cardiac section, which suggests the algorithm's potential for evaluating pathological cardiac fibrosis in diseased cardiac tissues. CONCLUSIONS We demonstrate that this color-based algorithm is capable of accurately identifying, isolating and quantifying cardiac infarct regions with different staining techniques, as well as diffuse and patchy fibrosis in MTS-stained cardiac tissues.
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Affiliation(s)
- Xiaobo Wu
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, VA 24016, USA; (X.W.)
| | - Linnea Meier
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA 24061, USA
| | - Tom X. Liu
- Center for Artificial Intelligence, Bluhm Cardiovascular Institute, Northwestern University, Chicago, IL 60201, USA
| | - Stefano Toldo
- Robert M. Berne Cardiovascular Research Center, Department of Medicine, Division of Cardiovascular Medicine, University of Virginia, Charlottesville, VA 22908, USA
| | - Steven Poelzing
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, VA 24016, USA; (X.W.)
- Department of Biomedical Engineering and Mechanics, Virginia Tech, Blacksburg, VA 24061, USA
| | - Robert G. Gourdie
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, VA 24016, USA; (X.W.)
- Department of Biomedical Engineering and Mechanics, Virginia Tech, Blacksburg, VA 24061, USA
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Prvulovic M, Pavlovic S, Mitic SB, Simeunovic V, Vukojevic A, Todorovic S, Mladenovic A. Mitigating the effects of time in the heart and liver: the variable effects of short- and long-term caloric restriction. Mech Ageing Dev 2024:111992. [PMID: 39270803 DOI: 10.1016/j.mad.2024.111992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 09/10/2024] [Accepted: 09/10/2024] [Indexed: 09/15/2024]
Abstract
Caloric restriction (CR) is known for its anti-aging benefits, partly due to reduced oxidative stress and enhanced antioxidant defense. However, CR outcomes vary based on its intensity, timing, and duration. This study explored CR's effects on antioxidant activity in the heart and liver of male Wistar rats during aging. We investigated two CR paradigms: long-term CR (LTCR), started early in life, and short-term CR (STCR), initiated in middle or old age for 3 months. Contrary to previous findings of short-term CR deleterious effects of on the nervous system, our results revealed increased levels of key antioxidants after STCR. More specifically, we found an increase in GSH-Px and GSH under STCR that was particularly pronounced in the liver, while an increase in CAT and GR activities was observed in the heart of the STCR groups. Catalase was characterized as an enzyme particularly responsive to CR, as its activity was also increased in both the liver and heart after long-term caloric restriction. Our results highlight a significant tissue-specific response to CR and contribute to our understanding of the dynamic effects of CR, which in turn has implications for refining its therapeutic potential in combating age-related decline.
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Affiliation(s)
- Milica Prvulovic
- Department for Neurobiology, Institute for Biological Research "Sinisa Stankovic", National Institute of the Republic of Serbia, University of Belgrade, Bul. D. Stefana 142, 11108 Belgrade, Serbia
| | - Sladjan Pavlovic
- Department of Physiology, Institute for Biological Research "Sinisa Stankovic", National Institute of the Republic of Serbia, University of Belgrade, Bul. D. Stefana 142, 11108 Belgrade, Serbia
| | - Slavica Borkovic Mitic
- Department of Physiology, Institute for Biological Research "Sinisa Stankovic", National Institute of the Republic of Serbia, University of Belgrade, Bul. D. Stefana 142, 11108 Belgrade, Serbia
| | - Valentina Simeunovic
- Department for Neurobiology, Institute for Biological Research "Sinisa Stankovic", National Institute of the Republic of Serbia, University of Belgrade, Bul. D. Stefana 142, 11108 Belgrade, Serbia
| | - Andjela Vukojevic
- Department for Neurobiology, Institute for Biological Research "Sinisa Stankovic", National Institute of the Republic of Serbia, University of Belgrade, Bul. D. Stefana 142, 11108 Belgrade, Serbia
| | - Smilja Todorovic
- Department for Neurobiology, Institute for Biological Research "Sinisa Stankovic", National Institute of the Republic of Serbia, University of Belgrade, Bul. D. Stefana 142, 11108 Belgrade, Serbia
| | - Aleksandra Mladenovic
- Department for Neurobiology, Institute for Biological Research "Sinisa Stankovic", National Institute of the Republic of Serbia, University of Belgrade, Bul. D. Stefana 142, 11108 Belgrade, Serbia.
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Wu N, Zheng W, Zhou Y, Tian Y, Tang M, Feng X, Ashrafizadeh M, Wang Y, Niu X, Tambuwala M, Wang L, Tergaonkar V, Sethi G, Klionsky D, Huang L, Gu M. Autophagy in aging-related diseases and cancer: Principles, regulatory mechanisms and therapeutic potential. Ageing Res Rev 2024; 100:102428. [PMID: 39038742 DOI: 10.1016/j.arr.2024.102428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 07/05/2024] [Accepted: 07/15/2024] [Indexed: 07/24/2024]
Abstract
Macroautophagy/autophagy is primarily accountable for the degradation of damaged organelles and toxic macromolecules in the cells. Regarding the essential function of autophagy for preserving cellular homeostasis, changes in, or dysfunction of, autophagy flux can lead to disease development. In the current paper, the complicated function of autophagy in aging-associated pathologies and cancer is evaluated, highlighting the underlying molecular mechanisms that can affect longevity and disease pathogenesis. As a natural biological process, a reduction in autophagy is observed with aging, resulting in an accumulation of cell damage and the development of different diseases, including neurological disorders, cardiovascular diseases, and cancer. The MTOR, AMPK, and ATG proteins demonstrate changes during aging, and they are promising therapeutic targets. Insulin/IGF1, TOR, PKA, AKT/PKB, caloric restriction and mitochondrial respiration are vital for lifespan regulation and can modulate or have an interaction with autophagy. The specific types of autophagy, such as mitophagy that degrades mitochondria, can regulate aging by affecting these organelles and eliminating those mitochondria with genomic mutations. Autophagy and its specific types contribute to the regulation of carcinogenesis and they are able to dually enhance or decrease cancer progression. Cancer hallmarks, including proliferation, metastasis, therapy resistance and immune reactions, are tightly regulated by autophagy, supporting the conclusion that autophagy is a promising target in cancer therapy.
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Affiliation(s)
- Na Wu
- Department of Infectious Diseases, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Wenhui Zheng
- Department of Anesthesiology, The Shengjing Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Yundong Zhou
- Department of Thoracic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang 315040, China
| | - Yu Tian
- School of Public Health, Benedictine University, No.5700 College Road, Lisle, IL 60532, USA; Research Center, the Huizhou Central People's Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Min Tang
- Department of Oncology, Chongqing General Hospital, Chongqing University, Chongqing 401120, China
| | - Xiaoqiang Feng
- Center of Stem Cell and Regenerative Medicine, Gaozhou People's Hospital, Gaozhou, Guangdong 525200, China
| | - Milad Ashrafizadeh
- Department of Radiation Oncology, Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China; Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yuzhuo Wang
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H3Z6, Canada
| | - Xiaojia Niu
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H3Z6, Canada
| | - Murtaza Tambuwala
- Lincoln Medical School, University of Lincoln, Brayford Pool Campus, Lincoln LN6 7TS, UK
| | - Lingzhi Wang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117600, Singapore
| | - Vinay Tergaonkar
- Laboratory of NF-κB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A⁎STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117600, Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.
| | - Daniel Klionsky
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
| | - Li Huang
- Center of Stem Cell and Regenerative Medicine, Gaozhou People's Hospital, Gaozhou, Guangdong 525200, China.
| | - Ming Gu
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
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Wu X, Meier L, Liu TX, Toldo S, Poelzing S, Gourdie RG. Detection, Isolation and Quantification of Myocardial Infarct with Four Different Histological Staining Techniques. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.16.608294. [PMID: 39229206 PMCID: PMC11370443 DOI: 10.1101/2024.08.16.608294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
Precise quantification of myocardial infarction is crucial for evaluating the therapeutic strategies. We developed a robust, color-based semi-automatic algorithm capable of infarct region detection, isolation and quantification with four different histological staining techniques, and the isolation and quantification of diffuse fibrosis in the heart. Our method is developed based on the color difference in the infarct and non-infarct regions after histological staining. Mouse cardiac tissues stained with Masson's trichrome (MTS), hematoxylin and eosin (H&E), 2,3,5-Triphenyltetrazolium chloride and picrosirius red were included to demonstrate the performance of our method. We demonstrate that our algorithm can effectively identify and produce a clear visualization of infarct tissue for the four staining techniques. Notably, the infarct region on a H&E-stained tissue section can be clearly visualized after processing. The MATLAB-based program we developed holds promise in the infarct quantification. Additionally, our program can isolate and quantify the diffuse fibrotic elements from an MTS-stained cardiac section, which suggested the algorithm's potential for evaluating pathological cardiac fibrosis in diseased cardiac tissues. In conclusion, we demonstrate that this color-based algorithm is capable of accurately identifying, isolating and quantifying cardiac infarct regions with different staining techniques, as well as the diffuse and patchy fibrosis in MTS-stained cardiac tissues.
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Affiliation(s)
- Xiaobo Wu
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, Virginia
| | - Linnea Meier
- Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia
| | - Tom X Liu
- Northwestern Medicine, Northwestern University, Chicago, Illinois
| | - Stefano Toldo
- Robert M. Berne Cardiovascular Research Center, Department of Medicine, Division of Cardiovascular Medicine, University of Virginia, Charlottesville, Virginia
| | - Steven Poelzing
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, Virginia
- Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, Virginia
| | - Robert G. Gourdie
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, Virginia
- Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, Virginia
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Alibhai FJ, Li RK. Rejuvenation of the Aging Heart: Molecular Determinants and Applications. Can J Cardiol 2024; 40:1394-1411. [PMID: 38460612 DOI: 10.1016/j.cjca.2024.03.004] [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: 12/03/2023] [Revised: 02/20/2024] [Accepted: 03/04/2024] [Indexed: 03/11/2024] Open
Abstract
In Canada and worldwide, the elderly population (ie, individuals > 65 years of age) is increasing disproportionately relative to the total population. This is expected to have a substantial impact on the health care system, as increased aged is associated with a greater incidence of chronic noncommunicable diseases. Within the elderly population, cardiovascular disease is a leading cause of death, therefore developing therapies that can prevent or slow disease progression in this group is highly desirable. Historically, aging research has focused on the development of anti-aging therapies that are implemented early in life and slow the age-dependent decline in cell and organ function. However, accumulating evidence supports that late-in-life therapies can also benefit the aged cardiovascular system by limiting age-dependent functional decline. Moreover, recent studies have demonstrated that rejuvenation (ie, reverting cellular function to that of a younger phenotype) of the already aged cardiovascular system is possible, opening new avenues to develop therapies for older individuals. In this review, we first provide an overview of the functional changes that occur in the cardiomyocyte with aging and how this contributes to the age-dependent decline in heart function. We then discuss the various anti-aging and rejuvenation strategies that have been pursued to improve the function of the aged cardiomyocyte, with a focus on therapies implemented late in life. These strategies include 1) established systemic approaches (caloric restriction, exercise), 2) pharmacologic approaches (mTOR, AMPK, SIRT1, and autophagy-targeting molecules), and 3) emerging rejuvenation approaches (partial reprogramming, parabiosis/modulation of circulating factors, targeting endogenous stem cell populations, and senotherapeutics). Collectively, these studies demonstrate the exciting potential and limitations of current rejuvenation strategies and highlight future areas of investigation that will contribute to the development of rejuvenation therapies for the aged heart.
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Affiliation(s)
- Faisal J Alibhai
- Toronto General Research Hospital Institute, University Health Network, Toronto, Ontario, Canada
| | - Ren-Ke Li
- Toronto General Research Hospital Institute, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Division of Cardiovascular Surgery, University of Toronto, Toronto, Ontario, Canada.
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Ozcan M, Abdellatif M, Javaheri A, Sedej S. Risks and Benefits of Intermittent Fasting for the Aging Cardiovascular System. Can J Cardiol 2024; 40:1445-1457. [PMID: 38354947 DOI: 10.1016/j.cjca.2024.02.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 02/08/2024] [Accepted: 02/08/2024] [Indexed: 02/16/2024] Open
Abstract
Population aging and the associated increase in cardiovascular disease rates pose serious threats to global public health. Different forms of fasting have become an increasingly attractive strategy to directly address aging and potentially limit or delay the onset of cardiovascular diseases. A growing number of experimental studies and clinical trials indicate that the amount and timing of food intake as well as the daily time window during which food is consumed, are crucial determinants of cardiovascular health. Indeed, intermittent fasting counteracts the molecular hallmarks of cardiovascular aging and promotes different aspects of cardiometabolic health, including blood pressure and glycemic control, as well as body weight reduction. In this report, we summarize current evidence from randomized clinical trials of intermittent fasting on body weight and composition as well as cardiovascular and metabolic risk factors. Moreover, we critically discuss the preventive and therapeutic potential of intermittent fasting, but also possible detrimental effects in the context of cardiovascular aging and related disease. We delve into the physiological mechanisms through which intermittent fasting might improve cardiovascular health, and raise important factors to consider in the design of clinical trials on the efficacy of intermittent fasting to reduce major adverse cardiovascular events among aged individuals at high risk of cardiovascular disease. We conclude that despite growing evidence and interest among the lay and scientific communities in the cardiovascular health-improving effects of intermittent fasting, further research efforts and appropriate caution are warranted before broadly implementing intermittent fasting regimens, especially in elderly persons.
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Affiliation(s)
- Mualla Ozcan
- Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
| | - Mahmoud Abdellatif
- Department of Cardiology, Medical University of Graz, Graz, Austria; BioTechMed Graz, Graz, Austria
| | - Ali Javaheri
- Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA; John J. Cochran Veterans Affairs Medical Center, St. Louis, Missouri, USA
| | - Simon Sedej
- Department of Cardiology, Medical University of Graz, Graz, Austria; BioTechMed Graz, Graz, Austria; Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia.
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9
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Parvaresh H, Paczek K, Al-Bari MAA, Eid N. Mechanistic insights into fasting-induced autophagy in the aging heart. World J Cardiol 2024; 16:109-117. [PMID: 38576517 PMCID: PMC10989221 DOI: 10.4330/wjc.v16.i3.109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 02/01/2024] [Accepted: 03/04/2024] [Indexed: 03/21/2024] Open
Abstract
Autophagy is a prosurvival mechanism for the clearance of accumulated abnormal proteins, damaged organelles, and excessive lipids within mammalian cells. A growing body of data indicates that autophagy is reduced in aging cells. This reduction leads to various diseases, such as myocardial hypertrophy, infarction, and atherosclerosis. Recent studies in animal models of an aging heart showed that fasting-induced autophagy improved cardiac function and longevity. This improvement is related to autophagic clearance of damaged cellular components via either bulk or selective autophagy (such as mitophagy). In this editorial, we summarize the mechanisms of autophagy in normal and aging hearts. In addition, the protective effect of fasting-induced autophagy in cardiac aging has been highlighted.
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Affiliation(s)
- Hannaneh Parvaresh
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad 9177948974, Iran
| | - Katarzyna Paczek
- Department of Chiropractic, International Medical University, Kuala Lumpur 57000, Malaysia
| | | | - Nabil Eid
- Department of Anatomy, Division of Human Biology, School of Medicine, International Medical University, Kuala Lumpur 57000, Malaysia.
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10
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Qiu Z, Li Y, Fu Y, Yang Y. Research progress of AMP-activated protein kinase and cardiac aging. Open Life Sci 2023; 18:20220710. [PMID: 37671091 PMCID: PMC10476487 DOI: 10.1515/biol-2022-0710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 07/27/2023] [Accepted: 08/05/2023] [Indexed: 09/07/2023] Open
Abstract
The process of aging is marked by a gradual deterioration in the physiological functions and functional reserves of various tissues and organs, leading to an increased susceptibility to diseases and even death. Aging manifests in a tissue- and organ-specific manner, and is characterized by varying rates and direct and indirect interactions among different tissues and organs. Cardiovascular disease (CVD) is the leading cause of death globally, with older adults (aged >70 years) accounting for approximately two-thirds of CVD-related deaths. The prevalence of CVD increases exponentially with an individual's age. Aging is a critical independent risk factor for the development of CVD. AMP-activated protein kinase (AMPK) activation exerts cardioprotective effects in the heart and restores cellular metabolic functions by modulating gene expression and regulating protein levels through its interaction with multiple target proteins. Additionally, AMPK enhances mitochondrial function and cellular energy status by facilitating the utilization of energy substrates. This review focuses on the role of AMPK in the process of cardiac aging and maintaining normal metabolic levels and redox homeostasis in the heart, particularly in the presence of oxidative stress and the invasion of inflammatory factors.
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Affiliation(s)
- Zhengqi Qiu
- Faculty of Medicine, Macau University of Science and Technology, Taipa, Macao SAR 999078, China
| | - Yufei Li
- Faculty of Medicine, Macau University of Science and Technology, Taipa, Macao SAR 999078, China
| | - Yancheng Fu
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Carson International Cancer Center, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Health Science Center, Shenzhen University, Shenzhen518060, China
| | - Yanru Yang
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Carson International Cancer Center, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Health Science Center, Shenzhen University, Shenzhen518060, China
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11
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Uziel O, Dickstein H, Beery E, Lewis Y, Loewenthal R, Uziel E, Shochat Z, Weizman A, Stein D. Differences in Telomere Length between Adolescent Females with Anorexia Nervosa Restricting Type and Anorexia Nervosa Binge-Purge Type. Nutrients 2023; 15:2596. [PMID: 37299559 PMCID: PMC10255620 DOI: 10.3390/nu15112596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 05/29/2023] [Accepted: 05/29/2023] [Indexed: 06/12/2023] Open
Abstract
Physiological and psychological distress may accelerate cellular aging, manifested by shortening of telomere length (TL). The present study focused on TL shortening in anorexia nervosa (AN), an illness combining physiological and psychological distress. For that purpose, we measured TL in 44 female adolescents with AN at admission to inpatient treatment, in a subset of 18 patients also at discharge, and in 22 controls. No differences in TL were found between patients with AN and controls. At admission, patients with AN-binge/purge type (AN-B/P; n = 18) showed shorter TL compared with patients with AN-restricting type (AN-R; n = 26). No change in TL was found from admission to discharge, despite an improvement in body mass index standard deviation score (BMI-SDS) following inpatient treatment. Older age was the only parameter assessed to be correlated with greater TL shortening. Several methodological changes have to be undertaken to better understand the putative association of shorter TL with B/P behaviors, including increasing the sample size and the assessment of the relevant pathological eating disorder (ED) and non-ED psychological correlates in the two AN subtypes.
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Affiliation(s)
- Orit Uziel
- Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Petah Tikva 69978, Israel; (O.U.)
- Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Hadar Dickstein
- Safra Children’s Hospital, Sheba Medical Center, Ramat Gan 52621, Israel
| | - Einat Beery
- Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Petah Tikva 69978, Israel; (O.U.)
| | - Yael Lewis
- Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
- Shalvatah Mental Health Center, Hod Hasahron 45100, Israel
| | - Ron Loewenthal
- Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
- Safra Children’s Hospital, Sheba Medical Center, Ramat Gan 52621, Israel
| | - Eran Uziel
- Research Unit, Geha Mental Health Center, Petah Tikva 49100, Israel
| | - Zipi Shochat
- Research Unit, Geha Mental Health Center, Petah Tikva 49100, Israel
| | - Abraham Weizman
- Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Petah Tikva 69978, Israel; (O.U.)
- Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
- Statistical Service, Rabin Medical Center, Petah Tikva 49100, Israel
| | - Daniel Stein
- Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
- Safra Children’s Hospital, Sheba Medical Center, Ramat Gan 52621, Israel
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12
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Cho JM, Ghosh R, Mookherjee S, Boudina S, Symons JD. Reduce, Reuse, Recycle, Run ! : 4 Rs to improve cardiac health in advanced age. Aging (Albany NY) 2022; 14:9388-9392. [PMID: 36470665 PMCID: PMC9792203 DOI: 10.18632/aging.204415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 11/21/2022] [Indexed: 12/03/2022]
Abstract
During the aging process damaged/dysfunctional proteins and organelles accumulate and contribute to organ dysfunction. Luckily, there is a conserved intracellular process to reuse and recycle these dysregulated cellular components termed macroautophagy (autophagy). Unfortunately, strong evidence indicates autophagy is compromised with aging, protein quality control is jeopardized, and resultant proteotoxicity can contribute significantly to age-associated organ dysfunction. Are there interventions that can re-establish autophagic flux that is otherwise impaired with aging? With particular regard to the heart, here we review evidence that caloric-restriction, the polyamine spermidine, and the mTOR inhibitor rapamycin, even when initiated late-in-life, restore cardiomyocyte autophagy to an extent that lessens age-associated cardiac dysfunction. Cho et al. provide a physiological intervention to this list i.e., regular physical exercise initiated late-in-life boosts cardiomyocyte autophagic flux and rejuvenates cardiac function in male mice. While this study provides strong evidence for a mechanism whereby heightened physical activity can lead to improved heart health in the context of aging, (i) only male mice were studied; (ii) the intensity of exercise-training might not be suitable for all; and (iii) mice with aging-associated comorbidities were not investigated. Nonetheless, Cho et al. provide robust evidence that a low-cost and simple behavioral intervention initiated late-in-life improves cardiomyocyte autophagic flux and rejuvenates cardiac function.
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Affiliation(s)
- Jae Min Cho
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT 84112, USA
| | - Rajeshwary Ghosh
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT 84112, USA
| | - Sohom Mookherjee
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT 84112, USA
| | - Sihem Boudina
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT 84112, USA,Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112, USA
| | - J. David Symons
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT 84112, USA,Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112, USA
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13
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Wei X, Hou Y, Long M, Jiang L, Du Y. Advances in energy metabolism in renal fibrosis. Life Sci 2022; 312:121033. [PMID: 36270427 DOI: 10.1016/j.lfs.2022.121033] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/22/2022] [Accepted: 09/30/2022] [Indexed: 11/05/2022]
Abstract
Renal fibrosis is a common pathway toward chronic kidney disease (CKD) and is the main pathological predecessor for end-stage renal disease; thus, preventing progressive CKD and renal fibrosis is essential to reducing their consequential morbidity and mortality. Emerging evidence has connected renal fibrosis to metabolic reprogramming; abnormalities in energy metabolism pathways, such as glycolysis, the tricarboxylic acid cycle, and lipid metabolism, are known to cause diseases of diverse etiologies. Cytokine interventions in affected metabolic pathways may significantly reduce the degree of fibrosis, highlighting therapeutic targets for drug development for renal fibrosis. Here, we discuss the relationship between glycolysis, lipid metabolism, mitochondrial and peroxisome dysfunction, and renal fibrosis in detail and propose that targeted therapies for specific metabolic pathways are expected to represent the next generation of treatments for renal fibrosis.
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Affiliation(s)
- Xuejiao Wei
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Yue Hou
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Mengtuan Long
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Lili Jiang
- Department of Physical Examination Center, The First Hospital of Jilin University, Changchun, China
| | - Yujun Du
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China.
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14
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Rachakatla A, Kalashikam RR. Calorie Restriction-Regulated Molecular Pathways and Its Impact on Various Age Groups: An Overview. DNA Cell Biol 2022; 41:459-468. [PMID: 35451872 DOI: 10.1089/dna.2021.0922] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Calorie restriction (CR) if planned properly with regular exercise at different ages can result in healthy weight loss. CR can also have different beneficial effects on improving lifespan and decreasing the age-associated diseases by regulating physiological, biochemical, and molecular markers. The different pathways regulated by CR include:(1) AMP-activated protein kinase (AMPK), which involves PGC-1α, SIRT1, and SIRT3. AMPK also effects myocyte enhancer factor 2 (MEF2), peroxisome proliferator-activated receptor delta, and peroxisome proliferator-activated receptor alpha, which are involved in mitochondrial biogenesis and lipid oxidation; (2) Forkhead box transcription factor's signaling is related to the DNA repair, lipid metabolism, protection of protein structure, autophagy, and resistance to oxidative stress; (3) Mammalian target of rapamycin (mTOR) signaling, which involves key factors, such as S6 protein kinase-1 (S6K1), mTOR complex-1 (mTORC1), and 4E-binding protein (4E-BP). Under CR conditions, AMPK activation and mTOR inhibition helps in the activation of Ulk1 complex along with the acetyltransferase Mec-17, which is necessary for autophagy; (4) Insulin-like growth factor-1 (IGF-1) pathway downregulation protects against cancer and slows the aging process; (5) Nuclear factor kappa B pathway downregulation decreases the inflammation; and (6) c-Jun N-terminal kinase and p38 kinase regulation as a response to the stress. The acute and chronic CR both shows antidepression and anxiolytic action by effecting ghrelin/GHS-R1a signaling. CR also regulates GSK3β kinase and protects against age-related brain atrophy. CR at young age may show many deleterious effects by effecting different mechanisms. Parental CR before or during conception will also affect the health and development of the offspring by causing many epigenetic modifications that show transgenerational transmission. Maternal CR is associated with intrauterine growth retardation effecting the offspring in their adulthood by developing different metabolic syndromes. The epigenetic changes with response to paternal food supply also linked to offspring health. CR at middle and old age provides a significant preventive impact against the development of age-associated diseases.
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15
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Mehdizadeh M, Aguilar M, Thorin E, Ferbeyre G, Nattel S. The role of cellular senescence in cardiac disease: basic biology and clinical relevance. Nat Rev Cardiol 2022; 19:250-264. [PMID: 34667279 DOI: 10.1038/s41569-021-00624-2] [Citation(s) in RCA: 138] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/06/2021] [Indexed: 12/11/2022]
Abstract
Cellular senescence, classically defined as stable cell cycle arrest, is implicated in biological processes such as embryogenesis, wound healing and ageing. Senescent cells have a complex senescence-associated secretory phenotype (SASP), involving a range of pro-inflammatory factors with important paracrine and autocrine effects on cell and tissue biology. Clinical evidence and experimental studies link cellular senescence, senescent cell accumulation, and the production and release of SASP components with age-related cardiac pathologies such as heart failure, myocardial ischaemia and infarction, and cancer chemotherapy-related cardiotoxicity. However, the precise role of senescent cells in these conditions is unclear and, in some instances, both detrimental and beneficial effects have been reported. The involvement of cellular senescence in other important entities, such as cardiac arrhythmias and remodelling, is poorly understood. In this Review, we summarize the basic biology of cellular senescence and discuss what is known about the role of cellular senescence and the SASP in heart disease. We then consider the various approaches that are being developed to prevent the accumulation of senescent cells and their consequences. Many of these strategies are applicable in vivo and some are being investigated for non-cardiac indications in clinical trials. We end by considering important knowledge gaps, directions for future research and the potential implications for improving the management of patients with heart disease.
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Affiliation(s)
- Mozhdeh Mehdizadeh
- Research Center, Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.,Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada
| | - Martin Aguilar
- Research Center, Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.,Department of Medicine, Université de Montréal, Montreal, QC, Canada
| | - Eric Thorin
- Research Center, Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.,Department of Surgery, Université de Montréal, Montreal, QC, Canada
| | - Gerardo Ferbeyre
- Department of Biochemistry, Université de Montréal and CRCHUM, Montreal, QC, Canada
| | - Stanley Nattel
- Research Center, Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada. .,Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada. .,Department of Medicine, Université de Montréal, Montreal, QC, Canada. .,Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada. .,Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany. .,IHU LIRYC and Fondation Bordeaux, Université Bordeaux, Bordeaux, France.
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16
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AMPK Activation Is Indispensable for the Protective Effects of Caloric Restriction on Left Ventricular Function in Postinfarct Myocardium. BIOLOGY 2022; 11:biology11030448. [PMID: 35336822 PMCID: PMC8945456 DOI: 10.3390/biology11030448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 03/02/2022] [Accepted: 03/08/2022] [Indexed: 11/16/2022]
Abstract
Background: Caloric restriction (CR) extends lifespan in many species, including mammals. CR is cardioprotective in senescent myocardium by correcting pre-existing mitochondrial dysfunction and apoptotic activation. Furthermore, it confers cardioprotection against acute ischemia-reperfusion injury. Here, we investigated the role of AMP-activated protein kinase (AMPK) in mediating the cardioprotective CR effects in failing, postinfarct myocardium. Methods: Ligation of the left coronary artery or sham operation was performed in rats and mice. Four weeks after surgery, left ventricular (LV) function was analyzed by echocardiography, and animals were assigned to different feeding groups (control diet or 40% CR, 8 weeks) as matched pairs. The role of AMPK was investigated with an AMPK inhibitor in rats or the use of alpha 2 AMPK knock-out mice. Results: CR resulted in a significant improvement in LV function, compared to postinfarct animals receiving control diet in both species. The improvement in LV function was accompanied by a reduction in serum BNP, decrease in LV proapoptotic activation, and increase in mitochondrial biogenesis in the LV. Inhibition or loss of AMPK prevented most of these changes. Conclusions: The failing, postischemic heart is protected from progressive loss of LV systolic function by CR. AMPK activation is indispensable for these protective effects.
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17
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Li SJ, Lin YH, Chiang CH, Wang PY, Chen CY. Early-onset dietary restriction maintains mitochondrial health, autophagy and ER function in the left ventricle during aging. J Nutr Biochem 2022; 101:108944. [PMID: 35017002 DOI: 10.1016/j.jnutbio.2022.108944] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 12/06/2021] [Indexed: 12/11/2022]
Abstract
Dietary restriction (DR) exerts healthy benefits, including heart functions. However, the cardioprotective role of DR is till controversial among researchers due to the variation of DR conditions. The present study focuses on the protective effect of early-onset DR on cardiac injury using mitochondrial structure and expression of protein associated with mitochondrial homeostasis, autophagy and endoplasmic reticulum (ER) function as measures. METHODS Two-month-old mice were fed with a breeding diet ad libitum (AL) or DR (60% of AL) for 3 (Young) or 20 (Aged) months. RESULTS Body weight increased with aging, whereas DR treatment kept body weight consistent. DR mice exhibited a higher relative heart weight than AL mice. DR mice displayed lower plasma glucose levels, compared with AL groups. Furthermore, Aged-AL, but not Aged-DR mice, had increased collagen content and morphological distortions in the left ventricle (LV). Aged-DR mice had a higher ATP and lower TBARS in the LV than Aged-AL mice. Mitochondrial morphology was detected by electron microscopy; Aged-AL mice had increased abnormal morphology of mitochondria. Treatment with DR reduced abnormal mitochondrial accumulation. Aging elevated the protein expressions of mitochondrial functions and ER-induced apoptosis. Aging downregulated autophagy-related proteins and chaperones in the heart. Dietary restriction reversed those protein expressions. CONCLUSIONS The present study demonstrated a beneficial effect of early onset DR on cardiac aging. The age-dependent mitochondrial dysfunction and protein quality control dysregulation was significantly reversed by long-term DR, demonstrating a concordance with the beneficial effect in the heart.
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Affiliation(s)
- Sin-Jin Li
- Department of Animal Science and Technology, National Taiwan University, No. 50, Lane 155, Sec 3, Keelung Rd, Taipei, 10672, Taiwan
| | - Yu-Han Lin
- General Research Service Center/ Department of Animal Science, National Pingtung University of Science and Technology, No. 1, Shuefu Rd, Neipu, Pingtung, 912301, Taiwan
| | - Chun-Hsien Chiang
- Department of Animal Science and Technology, National Taiwan University, No. 50, Lane 155, Sec 3, Keelung Rd, Taipei, 10672, Taiwan
| | - Pei-Yu Wang
- Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ching-Yi Chen
- Department of Animal Science and Technology, National Taiwan University, No. 50, Lane 155, Sec 3, Keelung Rd, Taipei, 10672, Taiwan.
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18
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Abstract
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the general population. Energy metabolism disturbance is one of the early abnormalities in CVDs, such as coronary heart disease, diabetic cardiomyopathy, and heart failure. To explore the role of myocardial energy homeostasis disturbance in CVDs, it is important to understand myocardial metabolism in the normal heart and their function in the complex pathophysiology of CVDs. In this article, we summarized lipid metabolism/lipotoxicity and glucose metabolism/insulin resistance in the heart, focused on the metabolic regulation during neonatal and ageing heart, proposed potential metabolic mechanisms for cardiac regeneration and degeneration. We provided an overview of emerging molecular network among cardiac proliferation, regeneration, and metabolic disturbance. These novel targets promise a new era for the treatment of CVDs.
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Affiliation(s)
- Lu-Yun WANG
- Division of Cardiology, Tongji Hospital, Tongji Medical College and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan, China
| | - Chen CHEN
- Division of Cardiology, Tongji Hospital, Tongji Medical College and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan, China
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19
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Yeh CH, Chou YJ, Chu TK, Tsai TF. Rejuvenating the Aging Heart by Enhancing the Expression of the Cisd2 Prolongevity Gene. Int J Mol Sci 2021; 22:ijms222111487. [PMID: 34768917 PMCID: PMC8583758 DOI: 10.3390/ijms222111487] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 10/21/2021] [Accepted: 10/22/2021] [Indexed: 02/07/2023] Open
Abstract
Aging is the major risk factor for cardiovascular disease, which is the leading cause of mortality worldwide among aging populations. Cisd2 is a prolongevity gene that mediates lifespan in mammals. Previously, our investigations revealed that a persistently high level of Cisd2 expression in mice is able to prevent age-associated cardiac dysfunction. This study was designed to apply a genetic approach that induces cardiac-specific Cisd2 overexpression (Cisd2 icOE) at a late-life stage, namely a time point immediately preceding the onset of old age, and evaluate the translational potential of this approach. Several discoveries are pinpointed. Firstly, Cisd2 is downregulated in the aging heart. This decrease in Cisd2 leads to cardiac dysfunction and impairs electromechanical performance. Intriguingly, Cisd2 icOE prevents an exacerbation of age-associated electromechanical dysfunction. Secondly, Cisd2 icOE ameliorates cardiac fibrosis and improves the integrity of the intercalated discs, thereby reversing various structural abnormalities. Finally, Cisd2 icOE reverses the transcriptomic profile of the aging heart, changing it from an older-age pattern to a younger pattern. Intriguingly, Cisd2 icOE modulates a number of aging-related pathways, namely the sirtuin signaling, autophagy, and senescence pathways, to bring about rejuvenation of the heart as it enters old age. Our findings highlight Cisd2 as a novel molecular target for developing therapies targeting cardiac aging.
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Affiliation(s)
- Chi-Hsiao Yeh
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan;
- Department of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan
| | - Yi-Ju Chou
- Institute of Molecular and Genomic Medicine, National Health Research Institute, Zhunan, Miaoli 350, Taiwan;
| | - Ting-Kuan Chu
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
| | - Ting-Fen Tsai
- Institute of Molecular and Genomic Medicine, National Health Research Institute, Zhunan, Miaoli 350, Taiwan;
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
- Aging and Health Research Center, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Correspondence: ; Tel.: +886-2-28267293
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20
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Cho JM, Park S, Ghosh R, Ly K, Ramous C, Thompson L, Hansen M, Mattera MSDLC, Pires KM, Ferhat M, Mookherjee S, Whitehead KJ, Carter K, Buffolo M, Boudina S, Symons JD. Late-in-life treadmill training rejuvenates autophagy, protein aggregate clearance, and function in mouse hearts. Aging Cell 2021; 20:e13467. [PMID: 34554626 PMCID: PMC8520717 DOI: 10.1111/acel.13467] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 07/08/2021] [Accepted: 08/05/2021] [Indexed: 01/18/2023] Open
Abstract
Protein quality control mechanisms decline during the process of cardiac aging. This enables the accumulation of protein aggregates and damaged organelles that contribute to age-associated cardiac dysfunction. Macroautophagy is the process by which post-mitotic cells such as cardiomyocytes clear defective proteins and organelles. We hypothesized that late-in-life exercise training improves autophagy, protein aggregate clearance, and function that is otherwise dysregulated in hearts from old vs. adult mice. As expected, 24-month-old male C57BL/6J mice (old) exhibited repressed autophagosome formation and protein aggregate accumulation in the heart, systolic and diastolic dysfunction, and reduced exercise capacity vs. 8-month-old (adult) mice (all p < 0.05). To investigate the influence of late-in-life exercise training, additional cohorts of 21-month-old mice did (old-ETR) or did not (old-SED) complete a 3-month progressive resistance treadmill running program. Body composition, exercise capacity, and soleus muscle citrate synthase activity improved in old-ETR vs. old-SED mice at 24 months (all p < 0.05). Importantly, protein expression of autophagy markers indicate trafficking of the autophagosome to the lysosome increased, protein aggregate clearance improved, and overall function was enhanced (all p < 0.05) in hearts from old-ETR vs. old-SED mice. These data provide the first evidence that a physiological intervention initiated late-in-life improves autophagic flux, protein aggregate clearance, and contractile performance in mouse hearts.
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Affiliation(s)
- Jae Min Cho
- Nutrition and Integrative Physiology University of Utah Salt Lake City Utah USA
| | - Seul‐Ki Park
- Nutrition and Integrative Physiology University of Utah Salt Lake City Utah USA
| | - Rajeshwary Ghosh
- Nutrition and Integrative Physiology University of Utah Salt Lake City Utah USA
| | - Kellsey Ly
- Nutrition and Integrative Physiology University of Utah Salt Lake City Utah USA
| | - Caroline Ramous
- Nutrition and Integrative Physiology University of Utah Salt Lake City Utah USA
| | - Lauren Thompson
- Nutrition and Integrative Physiology University of Utah Salt Lake City Utah USA
| | - Michele Hansen
- Nutrition and Integrative Physiology University of Utah Salt Lake City Utah USA
| | | | - Karla Maria Pires
- Nutrition and Integrative Physiology University of Utah Salt Lake City Utah USA
| | - Maroua Ferhat
- Nutrition and Integrative Physiology University of Utah Salt Lake City Utah USA
| | - Sohom Mookherjee
- Nutrition and Integrative Physiology University of Utah Salt Lake City Utah USA
| | - Kevin J. Whitehead
- Molecular Medicine Program University of Utah Salt Lake City Utah USA
- Division of Cardiovascular Medicine and Pediatric Cardiology University of Utah Salt Lake City Utah USA
- George E Wahlen VA Medical Center University of Utah Salt Lake City Utah USA
| | - Kandis Carter
- Molecular Medicine Program University of Utah Salt Lake City Utah USA
| | - Márcio Buffolo
- Nutrition and Integrative Physiology University of Utah Salt Lake City Utah USA
| | - Sihem Boudina
- Nutrition and Integrative Physiology University of Utah Salt Lake City Utah USA
- Molecular Medicine Program University of Utah Salt Lake City Utah USA
| | - J. David Symons
- Nutrition and Integrative Physiology University of Utah Salt Lake City Utah USA
- Molecular Medicine Program University of Utah Salt Lake City Utah USA
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21
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Zambrano E, Lomas-Soria C, Nathanielsz PW. Rodent studies of developmental programming and ageing mechanisms: Special issue: In utero and early life programming of ageing and disease. Eur J Clin Invest 2021; 51:e13631. [PMID: 34061987 DOI: 10.1111/eci.13631] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/30/2021] [Accepted: 05/30/2021] [Indexed: 12/31/2022]
Abstract
Compelling evidence exists indicating that developmental programming influences ageing. Programming alters life-course phenotype in multiple organs, predisposing to diseases such as diabetes, obesity and cardiovascular disease that shorten lifespan. This review describes studies in rodents, the most commonly studied species, addressing interactions of programming challenges with ageing. We first consider ageing and programming of insulin function that has been clearly shown to decrease with age. It is important to evaluate ageing in pancreatic islets isolated from other systems. Studies discussed show premature pancreatic islet ageing resulting from both maternal under- and overnutrition. New ways to determine programming of adipose tissue and effects on fat storage are explored. Oxidative stress is a major factor that regulates ageing in tissues. Oxidative stress is discussed in relation to reproductive and cardiovascular ageing. Premature ageing is associated with both low and high glucocorticoid function. Both over and undernutrition have offspring sex-specific programming effects on life-course glucocorticoid concentrations. Evidence is provided that maternal age at conception affects offspring endocrine and metabolism ageing. Finally, the importance of matching foetal nutrition and energy availability with composition and energy content in the post-weaning diet is demonstrated. This mismatch can lead to a greatly shortened lifespan. General principles are discussed throughout. For example, sexual dimorphism of age-related outcomes can be marked. Accelerated ageing occurs early in life. Improving knowledge on programming ageing interactions will improve health span as well as lifespan. Finally, there are considerable similarities in outcomes programmed by maternal undernutrition and overnutrition.
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Affiliation(s)
- Elena Zambrano
- Reproductive Biology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, México
| | - Consuelo Lomas-Soria
- Reproductive Biology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, México.,Reproductive Biology Department, CONACyT-Cátedras, Instituto Nacional de Ciencias Médicas y Nutrición SZ, Mexico City, México
| | - Peter W Nathanielsz
- Department of Animal Science, Texas Pregnancy and Life-course Health Center, University of Wyoming, Laramie, WY, USA
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22
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Sheng Y, Xia F, Chen L, Lv Y, Lv S, Yu J, Liu J, Ding G. Differential Responses of White Adipose Tissue and Brown Adipose Tissue to Calorie Restriction During Aging. J Gerontol A Biol Sci Med Sci 2021; 76:393-399. [PMID: 32222773 DOI: 10.1093/gerona/glaa070] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Indexed: 01/15/2023] Open
Abstract
Age-related adipose tissue dysfunction is potentially important in the development of insulin resistance and metabolic disorder. Caloric restriction (CR) is a robust intervention to reduce adiposity, improve metabolic health, and extend healthy life span. Both white adipose tissue (WAT) and brown adipose tissue (BAT) are involved in energy homeostasis. CR triggers the beiging of WAT in young mice; however, the effects of CR on beiging of WAT and function of BAT during aging are unclear. This study aimed to investigate how age and CR impact the beiging of WAT, the function of BAT, and metabolic health in mice. C57BL/6 mice were fed CR diet (40% less than the ad libitum [AL] diet) for 3 months initiated in young (3 months), middle-aged (12 months), and old (19 months) stage. We found age-related changes in different types of adipose tissue, including adipocyte enlargement, declined beiging of WAT, and declined thermogenic and β-oxidational function of BAT. Moreover, CR attenuated age-associated adipocyte enlargement and prevented the age-related decline in beiging potential of WAT. These protective effects on the beiging potential were significant in inguinal WAT at all three ages, which were significant in epididymal WAT at young and old age. In contrast, thermogenic and β-oxidational function of BAT further declined after CR in the young age group. In conclusion, our findings reveal the contribution of WAT beiging decline to age-related metabolic disorder and suggest nutritional intervention, specifically targeting WAT beiging, as an effective approach to metabolic health during aging.
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Affiliation(s)
- Yunlu Sheng
- Division of Geriatric Endocrinology, the First Affiliated Hospital of Nanjing Medical University, People's Republic of China
| | - Fan Xia
- Division of Geriatric Endocrinology, the First Affiliated Hospital of Nanjing Medical University, People's Republic of China
| | - Lei Chen
- Division of Geriatric Respiratory, the First Affiliated Hospital of Nanjing Medical University, People's Republic of China
| | - Yifan Lv
- Division of Geriatric Endocrinology, the First Affiliated Hospital of Nanjing Medical University, People's Republic of China
| | - Shan Lv
- Division of Geriatric Endocrinology, the First Affiliated Hospital of Nanjing Medical University, People's Republic of China
| | - Jing Yu
- Division of Geriatric Endocrinology, the First Affiliated Hospital of Nanjing Medical University, People's Republic of China
| | - Juan Liu
- Division of Geriatric Endocrinology, the First Affiliated Hospital of Nanjing Medical University, People's Republic of China
| | - Guoxian Ding
- Division of Geriatric Endocrinology, the First Affiliated Hospital of Nanjing Medical University, People's Republic of China
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23
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Liao CY, Kummert OMP, Bair AM, Alavi N, Alavi J, Miller DM, Bagga I, Schempf AM, Hsu YM, Woods Ii BD, Brown Mayfield SM, Mitchell AN, Tannady G, Talbot AR, Dueck AM, Barrera Ovando R, Parker HD, Wang J, Schoeneweis JK, Kennedy BK. The autophagy inducer spermidine protects against metabolic dysfunction during overnutrition. J Gerontol A Biol Sci Med Sci 2021; 76:1714-1725. [PMID: 34060628 DOI: 10.1093/gerona/glab145] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Indexed: 12/16/2022] Open
Abstract
Autophagy, a process catabolizing intracellular components to maintain energy homeostasis, impacts aging and metabolism. Spermidine, a natural polyamine and autophagy activator, extends lifespan across a variety of species, including mice. In addition to protecting cardiac and liver tissue, spermidine also affects adipose tissue through unexplored mechanisms. Here, we examined spermidine in the links between autophagy and systemic metabolism. Consistently, daily injection of spermidine delivered even at late life is sufficient to cause a trend in lifespan extension in wild type mice. We further found that spermidine has minimal metabolic effects in young and old mice under normal nutrition. However, spermidine counteracts HFD (high-fat diet)-induced obesity by increasing lipolysis in visceral fat. Mechanistically, spermidine increases the hepatokine FGF21 expression in liver without reducing food intake. Spermidine also modulates FGF21 in adipose tissues, elevating FGF21 expression in subcutaneous fat, but reducing it in visceral fat. Despite this, FGF21 is not required for spermidine action, since Fgf21 -/- mice were still protected from HFD. Furthermore, the enhanced lipolysis by spermidine was also independent of autophagy in adipose tissue, given that adipose-specific autophagy deficient (Beclin-1 flox/+ Fabp4-cre) mice remained spermidine-responsive under HFD. Our results suggest that the metabolic effects of spermidine occurs through systemic changes in metabolism, involving multiple mechanistic pathways.
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Affiliation(s)
- Chen-Yu Liao
- Buck Institute for Research on Aging, Novato, CA, USA
| | | | - Amanda M Bair
- Buck Institute for Research on Aging, Novato, CA, USA
| | - Nora Alavi
- Buck Institute for Research on Aging, Novato, CA, USA
| | - Josef Alavi
- Buck Institute for Research on Aging, Novato, CA, USA
| | | | - Isha Bagga
- Buck Institute for Research on Aging, Novato, CA, USA
| | | | - Yueh-Mei Hsu
- Buck Institute for Research on Aging, Novato, CA, USA
| | | | | | | | | | | | - Aaron M Dueck
- Buck Institute for Research on Aging, Novato, CA, USA
| | | | | | - Junying Wang
- Buck Institute for Research on Aging, Novato, CA, USA
| | | | - Brian K Kennedy
- Buck Institute for Research on Aging, Novato, CA, USA.,Healthy Longevity Programme, Yong Loo Lin of Medicine, National University Singapore.,Centre for Healthy Longevity, National University Health System, Singapore.,Singapore Institute for Clinical Sciences, Singapore
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24
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Yan M, Sun S, Xu K, Huang X, Dou L, Pang J, Tang W, Shen T, Li J. Cardiac Aging: From Basic Research to Therapeutics. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:9570325. [PMID: 33777324 PMCID: PMC7969106 DOI: 10.1155/2021/9570325] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 02/07/2021] [Accepted: 02/11/2021] [Indexed: 01/12/2023]
Abstract
With research progress on longevity, we have gradually recognized that cardiac aging causes changes in heart structure and function, including progressive myocardial remodeling, left ventricular hypertrophy, and decreases in systolic and diastolic function. Elucidating the regulatory mechanisms of cardiac aging is a great challenge for biologists and physicians worldwide. In this review, we discuss several key molecular mechanisms of cardiac aging and possible prevention and treatment methods developed in recent years. Insights into the process and mechanism of cardiac aging are necessary to protect against age-related diseases, extend lifespan, and reduce the increasing burden of cardiovascular disease in elderly individuals. We believe that research on cardiac aging is entering a new era of unique significance for the progress of clinical medicine and social welfare.
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Affiliation(s)
- Mingjing Yan
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China
- Peking University Fifth School of Clinical Medicine, Beijing 100730, China
| | - Shenghui Sun
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Kun Xu
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Xiuqing Huang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Lin Dou
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Jing Pang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Weiqing Tang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Tao Shen
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China
- Peking University Fifth School of Clinical Medicine, Beijing 100730, China
| | - Jian Li
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China
- Peking University Fifth School of Clinical Medicine, Beijing 100730, China
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25
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Liśkiewicz AD, Marczak Ł, Bogus K, Liśkiewicz D, Przybyła M, Lewin-Kowalik J. Proteomic and Structural Manifestations of Cardiomyopathy in Rat Models of Obesity and Weight Loss. Front Endocrinol (Lausanne) 2021; 12:568197. [PMID: 33716957 PMCID: PMC7945951 DOI: 10.3389/fendo.2021.568197] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 01/05/2021] [Indexed: 12/12/2022] Open
Abstract
Obesity cardiomyopathy increases the risk of heart failure and death. Obesity is curable, leading to the restoration of the heart phenotype, but it is not clear if there are any after-effects of obesity present after weight loss. We characterize the proteomic landscape of obesity cardiomyopathy with an evaluation of whether the cardiac phenotype is still shaped after weight loss. Cardiomyopathy was validated by cardiac hypertrophy, fibrosis, oversized myocytes, and mTOR upregulation in a rat model of cafeteria diet-induced developmental obesity. By global proteomic techniques (LC-MS/MS) a plethora of molecular changes was observed in the heart and circulation of obese animals, suggesting abnormal utilization of metabolic substrates. This was confirmed by increased levels of cardiac ACSL-1, a key enzyme for fatty acid degradation and decreased GLUT-1, a glucose transporter in obese rats. Calorie restriction and weight loss led to the normalization of the heart's size, but fibrosis was still excessive. The proteomic compositions of cardiac tissue and plasma were different after weight loss as compared to control. In addition to morphological consequences, obesity cardiomyopathy involves many proteomic changes. Weight loss provides for a partial repair of the heart's architecture, but the trace of fibrotic deposition and proteomic alterations may occur.
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Affiliation(s)
- Arkadiusz D. Liśkiewicz
- Department of Physiology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
- Laboratory of Molecular Biology, Institute of Physiotherapy and Health Sciences, The Jerzy Kukuczka Academy of Physical Education, Katowice, Poland
| | - Łukasz Marczak
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
| | - Katarzyna Bogus
- Department of Histology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Daniela Liśkiewicz
- Laboratory of Molecular Biology, Institute of Physiotherapy and Health Sciences, The Jerzy Kukuczka Academy of Physical Education, Katowice, Poland
- Department for Experimental Medicine, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Marta Przybyła
- Department for Experimental Medicine, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Joanna Lewin-Kowalik
- Department of Physiology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
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26
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Autophagy and Mitophagy as Essential Components of Atherosclerosis. Cells 2021; 10:cells10020443. [PMID: 33669743 PMCID: PMC7922388 DOI: 10.3390/cells10020443] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/12/2021] [Accepted: 02/16/2021] [Indexed: 12/23/2022] Open
Abstract
Cardiovascular disease (CVD) is one of the greatest health problems affecting people worldwide. Atherosclerosis, in turn, is one of the most common causes of cardiovascular disease. Due to the high mortality rate from cardiovascular diseases, prevention and treatment at the earliest stages become especially important. This requires developing a deep understanding of the mechanisms underlying the development of atherosclerosis. It is well-known that atherogenesis is a complex multi-component process that includes lipid metabolism disorders, inflammation, oxidative stress, autophagy disorders and mitochondrial dysfunction. Autophagy is a cellular control mechanism that is critical to maintaining health and survival. One of the specific forms of autophagy is mitophagy, which aims to control and remove defective mitochondria from the cell. Particularly defective mitophagy has been shown to be associated with atherogenesis. In this review, we consider the role of autophagy, focusing on a special type of it—mitophagy—in the context of its role in the development of atherosclerosis.
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27
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Role of FoxO transcription factors in aging-associated cardiovascular diseases. VITAMINS AND HORMONES 2021; 115:449-475. [PMID: 33706958 DOI: 10.1016/bs.vh.2020.12.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Aging constitutes a major risk factor toward the development of cardiovascular diseases (CVDs). The aging heart undergoes several changes at the molecular, cellular and physiological levels, which diminishes its contractile function and weakens stress tolerance. Further, old age increases the exposure to risk factors such as hypertension, diabetes and hypercholesterolemia. Notably, research in the past decades have identified FoxO subfamily of the forkhead transcription factors as key players in regulating diverse cellular processes linked to cardiac aging and diseases. In the present chapter, we discuss the important role of FoxO in the development of various aging-associated cardiovascular complications such as cardiac hypertrophy, cardiac fibrosis, heart failure, vascular dysfunction, atherosclerosis, hypertension and myocardial ischemia. Besides, we will also discuss the role of FoxO in cardiometabolic alterations, autophagy and proteasomal degradation, which are implicated in aging-associated cardiac dysfunction.
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28
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Sciarretta S, Forte M, Castoldi F, Frati G, Versaci F, Sadoshima J, Kroemer G, Maiuri MC. Caloric restriction mimetics for the treatment of cardiovascular diseases. Cardiovasc Res 2020; 117:1434-1449. [PMID: 33098415 DOI: 10.1093/cvr/cvaa297] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 10/09/2020] [Indexed: 12/25/2022] Open
Abstract
Caloric restriction mimetics (CRMs) are emerging as potential therapeutic agents for the treatment of cardiovascular diseases. CRMs include natural and synthetic compounds able to inhibit protein acetyltransferases, to interfere with acetyl coenzyme A biosynthesis, or to activate (de)acetyltransferase proteins. These modifications mimic the effects of caloric restriction, which is associated with the activation of autophagy. Previous evidence demonstrated the ability of CRMs to ameliorate cardiac function and reduce cardiac hypertrophy and maladaptive remodelling in animal models of ageing, mechanical overload, chronic myocardial ischaemia, and in genetic and metabolic cardiomyopathies. In addition, CRMs were found to reduce acute ischaemia-reperfusion injury. In many cases, these beneficial effects of CRMs appeared to be mediated by autophagy activation. In the present review, we discuss the relevant literature about the role of different CRMs in animal models of cardiac diseases, emphasizing the molecular mechanisms underlying the beneficial effects of these compounds and their potential future clinical application.
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Affiliation(s)
- Sebastiano Sciarretta
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 40100 Latina, Italy.,Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS), Italy
| | - Maurizio Forte
- Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS), Italy
| | - Francesca Castoldi
- Centre de Recherche des Cordeliers, Team "Metabolism, Cancer & Immunity", INSERM UMRS1138, Université de Paris, Sorbonne Université, 75006 Paris, France.,Cell Biology and Metabolomics platforms, Gustave Roussy Cancer Campus, 94805 Villejuif, France
| | - Giacomo Frati
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 40100 Latina, Italy.,Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS), Italy
| | - Francesco Versaci
- Division of Cardiology, S. Maria Goretti Hospital, 04100 Latina, Italy
| | - Junichi Sadoshima
- Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, 185 South Orange Avenue, G-609, Newark, NJ 07103, USA
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Team "Metabolism, Cancer & Immunity", INSERM UMRS1138, Université de Paris, Sorbonne Université, 75006 Paris, France.,Cell Biology and Metabolomics platforms, Gustave Roussy Cancer Campus, 94805 Villejuif, France.,Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France.,Suzhou Institute for Systems Medicine, Chinese Academy of Sciences, Suzhou Jiangsu 215163, China.,Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, 17176 Stockholm, Sweden
| | - Maria Chiara Maiuri
- Centre de Recherche des Cordeliers, Team "Metabolism, Cancer & Immunity", INSERM UMRS1138, Université de Paris, Sorbonne Université, 75006 Paris, France.,Cell Biology and Metabolomics platforms, Gustave Roussy Cancer Campus, 94805 Villejuif, France
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29
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Under construction: The dynamic assembly, maintenance, and degradation of the cardiac sarcomere. J Mol Cell Cardiol 2020; 148:89-102. [PMID: 32920010 DOI: 10.1016/j.yjmcc.2020.08.018] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/20/2020] [Accepted: 08/22/2020] [Indexed: 12/11/2022]
Abstract
The sarcomere is the basic contractile unit of striated muscle and is a highly ordered protein complex with the actin and myosin filaments at its core. Assembling the sarcomere constituents into this organized structure in development, and with muscle growth as new sarcomeres are built, is a complex process coordinated by numerous factors. Once assembled, the sarcomere requires constant maintenance as its continuous contraction is accompanied by elevated mechanical, thermal, and oxidative stress, which predispose proteins to misfolding and toxic aggregation. To prevent protein misfolding and maintain sarcomere integrity, the sarcomere is monitored by an assortment of protein quality control (PQC) mechanisms. The need for effective PQC is heightened in cardiomyocytes which are terminally differentiated and must survive for many years while preserving optimal mechanical output. To prevent toxic protein aggregation, molecular chaperones stabilize denatured sarcomere proteins and promote their refolding. However, when old and misfolded proteins cannot be salvaged by chaperones, they must be recycled via degradation pathways: the calpain and ubiquitin-proteasome systems, which operate under basal conditions, and the stress-responsive autophagy-lysosome pathway. Mutations to and deficiency of the molecular chaperones and associated factors charged with sarcomere maintenance commonly lead to sarcomere structural disarray and the progression of heart disease, highlighting the necessity of effective sarcomere PQC for maintaining cardiac function. This review focuses on the dynamic regulation of assembly and turnover at the sarcomere with an emphasis on the chaperones involved in these processes and describes the alterations to chaperones - through mutations and deficient expression - implicated in disease progression to heart failure.
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30
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Di W, Lv Y, Xia F, Sheng Y, Liu J, Ding G. Improvement of intestinal stem cells and barrier function via energy restriction in middle-aged C57BL/6 mice. Nutr Res 2020; 81:47-57. [PMID: 32877836 DOI: 10.1016/j.nutres.2020.06.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 05/14/2020] [Accepted: 06/22/2020] [Indexed: 01/21/2023]
Abstract
This study aimed to reveal the impact of energy restriction on the intestine via structural and molecular changes in terms of intestinal stem cell (ISC) function, ISC niche, intestinal epithelial barrier function, and intestinal immune function. Female C57BL/6J mice, aged 12 months, fed a commercial chow were used in this study. The ISC function, ISC niche, intestinal epithelial barrier function, and intestinal immune function were assessed. Energy restriction reversed aging-induced intestinal shortening and made the crypts shallower. The intestinal epithelial cells isolated from the intestine showed a significant increase in the expression levels of stem cell-associated genes in small intestinal epithelial cells as detected by flow cytometry. Despite the increase in the number of stem cells and the expression levels of markers, no increase or decrease was found in the enteroid complexity of the small intestine and colonic enteroid formation in vitro. The colonic mucous layer was measured in mice of the energy restricted (ER)-treated group to investigate the epithelial barrier function in the colon. The results revealed that the barrier was more complete. The fluorescence intensity of tight junction markers claudin-2 and zonula occludens-1 increased and the mRNA expression profiles of monocyte chemotactic protein 1 and interleukin-6 decreased in the colon of mice in the ER-treated group. The beneficial effects of ER on the colon in terms of the integrity of the mucosal barrier and alleviation of inflammation were confirmed, thus highlighting the importance of modulating the intestinal function in developing effective antiaging dietary interventions.
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Affiliation(s)
- Wenjuan Di
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yifan Lv
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Fan Xia
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yunlu Sheng
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Juan Liu
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Guoxian Ding
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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31
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Kirkham AA, Beka V, Prado CM. The effect of caloric restriction on blood pressure and cardiovascular function: A systematic review and meta-analysis of randomized controlled trials. Clin Nutr 2020; 40:728-739. [PMID: 32675017 DOI: 10.1016/j.clnu.2020.06.029] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 06/15/2020] [Accepted: 06/26/2020] [Indexed: 01/03/2023]
Abstract
BACKGROUND & AIMS Preclinical evidence suggests that caloric restriction is an effective therapy for a number of cardiovascular insults. Whether caloric restriction has cardio-protective effects in humans is not well understood. The aim was to systematically review and meta-analyze human randomized control trials (RCTs) testing the effect of caloric restriction on blood pressure (BP) and cardiovascular function. METHODS A systematic review was performed using Medline, EMBASE, CINAHL (up to June 2017) to search for RCTs of adults receiving a calorie-restricted intervention versus a control/standard diet. Random-effect meta-analyses were performed to calculate weighted mean difference and 95% CI. RESULTS Thirty-two RCTs with 1722 participants assessing BP (n = 29 studies), heart rate (n = 10), VO2peak (n = 8), muscle sympathetic nerve activity (MSNA, n = 4), and endothelial function (n = 4) were included. Calorie-restricted interventions lasting 1-4 weeks had the largest effect on systolic (-5.5 mmHg, p < 0.001, 95% CI: -3.8, -7.1) and diastolic (-2.9 mmHg, p = 0.005, 95% CI: -5.0, -0.9) BP, but no effect on HR. Interventions lasting 1.5-6 months had similar effects on BP, and reduced HR (-4.4 beats/minute, p < 0.001, 95% CI: -6.1,-2.8). Relative VO2peak improved (1.8 mL/kg/min, p < 0.001, 95% CI: 1.3, 2.2). There were also potential positive effects on MSNA and endothelial function. CONCLUSIONS The effect of 1-4 weeks of calorie restriction on BP was similar to that expected with medications, and larger than that reported for other lifestyle interventions or supplements. Cardiovascular risk could be further reduced by caloric restriction lasting up to six months to lower heart rate and improve VO2peak.
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Affiliation(s)
- Amy A Kirkham
- Faculty of Kinesiology and Physical Education, University of Toronto, Toronto, M5S 2C9, Canada.
| | - Vanesa Beka
- Faculty of Nursing, University of Alberta, Edmonton, T6G 2R3, Canada.
| | - Carla M Prado
- Department of Agricultural Food and Nutritional Science, University of Alberta, Edmonton, T6G 2R3, Canada.
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32
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Celebi-Birand D, Ardic NI, Karoglu-Eravsar ET, Sengul GF, Kafaligonul H, Adams MM. Dietary and Pharmacological Interventions That Inhibit Mammalian Target of Rapamycin Activity Alter the Brain Expression Levels of Neurogenic and Glial Markers in an Age-and Treatment-Dependent Manner. Rejuvenation Res 2020; 23:485-497. [PMID: 32279604 DOI: 10.1089/rej.2019.2297] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Intermittent fasting (IF) and its mimetic, rapamycin extend lifespan and healthspan through mechanisms that are not fully understood. We investigated different short-term durations of IF and rapamycin on cellular and molecular changes in the brains of young (6-10 months) and old (26-31 months) zebrafish. Interestingly, our results showed that IF significantly lowered glucose levels while increasing DCAMKL1 in both young and old animals. This proliferative effect of IF was supported by the upregulation of foxm1 transcript in old animals. Rapamycin did not change glucose levels in young and old animals but had differential effects depending on age. In young zebrafish, proliferating cell nuclear antigen and the LC3-II/LC3-I ratio was decreased, whereas glial fibrillary acidic protein and gephyrin were decreased in old animals. The changes in proliferative markers and a marker of autophagic flux suggest an age-dependent interplay between autophagy and cell proliferation. Additionally, changes in glia and inhibitory tone suggest a suppressive effect on neuroinflammation but may push the brain toward a more excitable state. Mammalian target of rapamycin (mTOR) activity in the brain following the IF and rapamycin treatment was differentially regulated by age. Interestingly, rapamycin inhibited mTOR more potently in young animals than IF. Principal component analysis supported our conclusion that the regulatory effects of IF and rapamycin were age-specific, since we observed different patterns in the expression levels and clustering of young and old animals. Taken together, our results suggest that even a short-term duration of IF and rapamycin have significant effects in the brain at young and old ages, and that these are age and treatment dependent.
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Affiliation(s)
- Dilan Celebi-Birand
- Interdisciplinary Graduate Program in Neuroscience, Aysel Sabuncu Brain Research Center, Bilkent University, Ankara, Turkey.,UNAM-Institute of Materials Science and Nanotechnology, Bilkent University, Ankara, Turkey.,Zebrafish Facility, Bilkent University Molecular Biology and Genetics, Ankara, Turkey
| | - Narin Ilgim Ardic
- Interdisciplinary Graduate Program in Neuroscience, Aysel Sabuncu Brain Research Center, Bilkent University, Ankara, Turkey.,UNAM-Institute of Materials Science and Nanotechnology, Bilkent University, Ankara, Turkey.,Zebrafish Facility, Bilkent University Molecular Biology and Genetics, Ankara, Turkey
| | - Elif Tugce Karoglu-Eravsar
- Interdisciplinary Graduate Program in Neuroscience, Aysel Sabuncu Brain Research Center, Bilkent University, Ankara, Turkey.,UNAM-Institute of Materials Science and Nanotechnology, Bilkent University, Ankara, Turkey.,Zebrafish Facility, Bilkent University Molecular Biology and Genetics, Ankara, Turkey
| | - Goksemin Fatma Sengul
- Interdisciplinary Graduate Program in Neuroscience, Aysel Sabuncu Brain Research Center, Bilkent University, Ankara, Turkey.,UNAM-Institute of Materials Science and Nanotechnology, Bilkent University, Ankara, Turkey.,Zebrafish Facility, Bilkent University Molecular Biology and Genetics, Ankara, Turkey.,Department of Cellular Biochemistry, Universitätsmedizin Göttingen, Göttingen, Germany
| | - Hulusi Kafaligonul
- Interdisciplinary Graduate Program in Neuroscience, Aysel Sabuncu Brain Research Center, Bilkent University, Ankara, Turkey.,Zebrafish Facility, Bilkent University Molecular Biology and Genetics, Ankara, Turkey.,National Magnetic Resonance Research Center (UMRAM), Bilkent University, Ankara, Turkey
| | - Michelle M Adams
- Interdisciplinary Graduate Program in Neuroscience, Aysel Sabuncu Brain Research Center, Bilkent University, Ankara, Turkey.,UNAM-Institute of Materials Science and Nanotechnology, Bilkent University, Ankara, Turkey.,Zebrafish Facility, Bilkent University Molecular Biology and Genetics, Ankara, Turkey.,Department of Psychology, Bilkent University, Ankara, Turkey
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33
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Abdellatif M, Ljubojevic-Holzer S, Madeo F, Sedej S. Autophagy in cardiovascular health and disease. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2020; 172:87-106. [PMID: 32620252 DOI: 10.1016/bs.pmbts.2020.04.022] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Autophagy is a cellular housekeeping and quality control mechanism that is essential for homeostasis and survival. By virtue of this role, any perturbations to the flow of this process in cardiac or vascular cells can elicit harmful effects on the cardiovascular system, and subsequently affect whole organismal health. In this chapter, we summarize the preclinical evidence supporting the role of autophagy in sustaining cardiovascular health during homeostasis and disease. Furthermore, we discuss how autophagy activation by dietary, genetic and pharmaceutical interventions can be exploited to counteract common cardiovascular disorders, including atherosclerosis, coronary artery disease, diabetic cardiomyopathy, arrhythmia, chemotherapy-induced cardiotoxicity and heart failure.
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Affiliation(s)
| | - Senka Ljubojevic-Holzer
- Department of Cardiology, Medical University of Graz, Graz, Austria; BioTechMed Graz, Graz, Austria
| | - Frank Madeo
- BioTechMed Graz, Graz, Austria; Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
| | - Simon Sedej
- Department of Cardiology, Medical University of Graz, Graz, Austria; BioTechMed Graz, Graz, Austria; Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia.
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Protein and Mitochondria Quality Control Mechanisms and Cardiac Aging. Cells 2020; 9:cells9040933. [PMID: 32290135 PMCID: PMC7226975 DOI: 10.3390/cells9040933] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 04/07/2020] [Accepted: 04/07/2020] [Indexed: 12/31/2022] Open
Abstract
Cardiovascular disease (CVD) is the number one cause of death in the United States. Advancing age is a primary risk factor for developing CVD. Estimates indicate that 20% of the US population will be ≥65 years old by 2030. Direct expenditures for treating CVD in the older population combined with indirect costs, secondary to lost wages, are predicted to reach $1.1 trillion by 2035. Therefore, there is an eminent need to discover novel therapeutic targets and identify new interventions to delay, lessen the severity, or prevent cardiovascular complications associated with advanced age. Protein and organelle quality control pathways including autophagy/lysosomal and the ubiquitin-proteasome systems, are emerging contributors of age-associated myocardial dysfunction. In general, two findings have sparked this interest. First, strong evidence indicates that cardiac protein degradation pathways are altered in the heart with aging. Second, it is well accepted that damaged and misfolded protein aggregates and dysfunctional mitochondria accumulate in the heart with age. In this review, we will: (i) define the different protein and mitochondria quality control mechanisms in the heart; (ii) provide evidence that each quality control pathway becomes dysfunctional during cardiac aging; and (iii) discuss current advances in targeting these pathways to maintain cardiac function with age.
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Grilo GA, Shaver PR, Stoffel HJ, Morrow CA, Johnson OT, Iyer RP, de Castro Brás LE. Age- and sex-dependent differences in extracellular matrix metabolism associate with cardiac functional and structural changes. J Mol Cell Cardiol 2020; 139:62-74. [PMID: 31978395 PMCID: PMC11017332 DOI: 10.1016/j.yjmcc.2020.01.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 12/19/2019] [Accepted: 01/10/2020] [Indexed: 01/08/2023]
Abstract
Age-related remodeling of the heart causes structural and functional changes in the left ventricle (LV) that are associated with a high index of morbidities and mortality worldwide. Some cardiac pathologies in the elderly population vary between genders revealing that cardiac remodeling during aging may be sex-dependent. Herein, we analyzed the effects of cardiac aging in male and female C57Bl/6 mice in four age groups, 3, 6, 12, and 18 month old (n = 6-12 animals/sex/age), to elucidate which age-related characteristics of LV remodeling are sex-specific. We focused particularly in parameters associated with age-dependent remodeling of the LV extracellular matrix (ECM) that are involved in collagen metabolism. LV function and anatomical structure were assessed both by conventional echocardiography and speckle tracking echocardiography (STE). We then measured ECM proteins that directly affect LV contractility and remodeling. All data were analyzed across ages and between sexes and were directly linked to LV functional changes. Echocardiography confirmed an age-dependent decrease in chamber volumes and LV internal diameters, indicative of concentric remodeling. As in humans, animals displayed preserved ejection fraction with age. Notably, changes to chamber dimensions and volumes were temporally distinct between sexes. Complementary to the traditional echocardiography, STE revealed that circumferential strain rate declined in 18 month old females, compared to younger animals, but not in males, suggesting STE as an earlier indicator for changes in cardiac function between sexes. Age-dependent collagen deposition and expression in the endocardium did not differ between sexes; however, other factors involved in collagen metabolism were sex-specific. Specifically, while decorin, osteopontin, Cthrc1, and Ddr1 expression were age-dependent but sex-independent, periostin, lysyl oxidase, and Mrc2 displayed age-dependent and sex-specific differences. Moreover, our data also suggest that with age males and females have distinct TGFβ signaling pathways. Overall, our results give evidence of sex-specific molecular changes during physiological cardiac remodeling that associate with age-dependent structural and functional dysfunction. These data highlight the importance of including sex-differences analysis when studying cardiac aging.
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Affiliation(s)
- Gabriel A Grilo
- Department of Physiology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States of America
| | - Patti R Shaver
- Department of Physiology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States of America
| | - Hamilton J Stoffel
- Department of Physiology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States of America
| | - Caleb Anthony Morrow
- Department of Physiology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States of America
| | - Octavious T Johnson
- Department of Physiology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States of America
| | - Rugmani P Iyer
- Department of Physiology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States of America
| | - Lisandra E de Castro Brás
- Department of Physiology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States of America; Department of Cardiovascular Sciences, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States of America.
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Abstract
Cardiovascular diseases are the most prominent maladies in aging societies. Indeed, aging promotes the structural and functional declines of both the heart and the blood circulation system. In this review, we revise the contribution of known longevity pathways to cardiovascular health and delineate the possibilities to interfere with them. In particular, we evaluate autophagy, the intracellular catabolic recycling system associated with life- and health-span extension. We present genetic models, pharmacological interventions, and dietary strategies that block, reduce, or enhance autophagy upon age-related cardiovascular deterioration. Caloric restriction or caloric restriction mimetics like metformin, spermidine, and rapamycin (all of which trigger autophagy) are among the most promising cardioprotective interventions during aging. We conclude that autophagy is a fundamental process to ensure cardiac and vascular health during aging and outline its putative therapeutic importance.
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Affiliation(s)
- Mahmoud Abdellatif
- From the Department of Cardiology, Medical University of Graz, Austria (M.A., S.S.)
| | - Simon Sedej
- From the Department of Cardiology, Medical University of Graz, Austria (M.A., S.S.).,BioTechMed Graz, Austria (S.S., D.C.-G., F.M.)
| | - Didac Carmona-Gutierrez
- BioTechMed Graz, Austria (S.S., D.C.-G., F.M.).,Institute of Molecular Biosciences, NAWI Graz, University of Graz, Austria (D.C.-G., F.M.)
| | - Frank Madeo
- BioTechMed Graz, Austria (S.S., D.C.-G., F.M.).,Institute of Molecular Biosciences, NAWI Graz, University of Graz, Austria (D.C.-G., F.M.)
| | - Guido Kroemer
- Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France (G.K.).,Cell Biology and Metabolomics Platforms, Gustave Roussy Comprehensive Cancer Center, Villejuif, France (G.K.).,INSERM, U1138, Paris, France (G.K.).,Université Paris Descartes, Sorbonne Paris Cité, France (G.K.).,Université Pierre et Marie Curie, Paris, France (G.K.).,Pôle de Biologie, Hôpital Européen Georges Pompidou, Paris, France (G.K.).,Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden (G.K.)
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Transcriptional profiling identifies strain-specific effects of caloric restriction and opposite responses in human and mouse white adipose tissue. Aging (Albany NY) 2019; 10:701-746. [PMID: 29708498 PMCID: PMC5940131 DOI: 10.18632/aging.101424] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 04/20/2018] [Indexed: 12/13/2022]
Abstract
Caloric restriction (CR) has been extensively studied in rodents as an intervention to improve lifespan and healthspan. However, effects of CR can be strain- and species-specific. This study used publically available microarray data to analyze expression responses to CR in males from 7 mouse strains (C57BL/6J, BALB/c, C3H, 129, CBA, DBA, B6C3F1) and 4 tissues (epididymal white adipose tissue (eWAT), muscle, heart, cortex). In each tissue, the largest number of strain-specific CR responses was identified with respect to the C57BL/6 strain. In heart and cortex, CR responses in C57BL/6 mice were negatively correlated with responses in other strains. Strain-specific CR responses involved genes associated with olfactory receptors (Olfr1184, Olfr910) and insulin/IGF-1 signaling (Igf1, Irs2). In each strain, CR responses in eWAT were negatively correlated with those in human subcutaneous WAT (scWAT). In human scWAT, CR increased expression of genes associated with stem cell maintenance and vascularization. However, orthologous genes linked to these processes were down-regulated in mouse. These results identify strain-specific CR responses limiting generalization across mouse strains. Differential CR responses in mouse versus human WAT may be due to differences in the depots examined and/or the presence of “thrifty genes” in humans that resist adipose breakdown despite caloric deficit.
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Wierich MC, Schipke J, Brandenberger C, Abdellatif M, Eisenberg T, Madeo F, Sedej S, Mühlfeld C. Cardioprotection by spermidine does not depend on structural characteristics of the myocardial microcirculation in aged mice. Exp Gerontol 2019; 119:82-88. [PMID: 30703435 DOI: 10.1016/j.exger.2019.01.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 01/21/2019] [Accepted: 01/25/2019] [Indexed: 11/17/2022]
Abstract
AIMS Ageing is associated with cardiovascular disease and reduced cardiac function. This cardiac functional decline is accompanied by cardiac remodeling and alterations in cardiomyocyte composition. Recently, it was shown that the natural polyamine spermidine preserves cardiac function and cardiomyocyte composition in old mice. As cardiac function critically relies on blood supply, we tested whether spermidine has also beneficial effects on ageing-associated changes of the myocardial microcirculation. METHODS Using transmission electron microscopy, the left ventricular capillaries of young (4-months old) and aged (24-months old) C57BL/6J male mice were investigated by stereology. Aged mice were subdivided into an untreated group and a group that was fed spermidine late in life for 6 months. Specifically, total volume, surface area and length of capillaries as well as endothelial thickness were estimated. Additionally, the total length of precapillary arterioles was assessed. The protein level of VEGF-A was measured using Western blot. RESULTS Ageing was associated with whole heart and left ventricular hypertrophy. All total capillary-related values (including volume, surface area and length) were significantly higher in 24-month-old mice compared with 4-month-old mice. Moreover, VEGF-A expression was significantly enhanced in aged mice. The mean thickness of the endothelium was not different, but the mean area of myocardium supplied by capillaries was smaller in old mice. Spermidine treatment had no significant effect on the ageing-associated structural changes or VEGF-A expression. CONCLUSIONS In conclusion, in the left ventricles of aged mice the growth of capillaries and arterioles supplying cardiomyocytes were in proportion to whole organ hypertrophy. Spermidine had no effect on quantitative characteristics of capillaries or arterioles, suggesting that the beneficial effects of spermidine on the ageing heart do not depend on the quantitative structural characteristics of the microcirculation which does not exclude potential functional differences between the groups.
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Affiliation(s)
- Marie-Christin Wierich
- Institute of Functional and Applied Anatomy, Hannover Medical School, 30625 Hannover, Germany
| | - Julia Schipke
- Institute of Functional and Applied Anatomy, Hannover Medical School, 30625 Hannover, Germany; Cluster of Excellence REBIRTH (From Regenerative Biology to Reconstructive Therapy), Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany
| | - Christina Brandenberger
- Institute of Functional and Applied Anatomy, Hannover Medical School, 30625 Hannover, Germany; Cluster of Excellence REBIRTH (From Regenerative Biology to Reconstructive Therapy), Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany
| | | | - Tobias Eisenberg
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
| | - Frank Madeo
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria; BioTechMed, Graz, Austria
| | - Simon Sedej
- Department of Cardiology, Medical University of Graz, Graz, Austria; BioTechMed, Graz, Austria
| | - Christian Mühlfeld
- Institute of Functional and Applied Anatomy, Hannover Medical School, 30625 Hannover, Germany; Cluster of Excellence REBIRTH (From Regenerative Biology to Reconstructive Therapy), Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany.
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Møller P, Wils RS, Jensen DM, Andersen MHG, Roursgaard M. Telomere dynamics and cellular senescence: an emerging field in environmental and occupational toxicology. Crit Rev Toxicol 2018; 48:761-788. [DOI: 10.1080/10408444.2018.1538201] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Peter Møller
- Department of Public Health, Section of Environmental Health, University of Copenhagen, Copenhagen, Denmark
| | - Regitze Sølling Wils
- Department of Public Health, Section of Environmental Health, University of Copenhagen, Copenhagen, Denmark
| | - Ditte Marie Jensen
- Department of Public Health, Section of Environmental Health, University of Copenhagen, Copenhagen, Denmark
| | | | - Martin Roursgaard
- Department of Public Health, Section of Environmental Health, University of Copenhagen, Copenhagen, Denmark
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Gu C, Li T, Jiang S, Yang Z, Lv J, Yi W, Yang Y, Fang M. AMP-activated protein kinase sparks the fire of cardioprotection against myocardial ischemia and cardiac ageing. Ageing Res Rev 2018; 47:168-175. [PMID: 30110651 DOI: 10.1016/j.arr.2018.08.002] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Revised: 06/28/2018] [Accepted: 08/07/2018] [Indexed: 12/12/2022]
Abstract
AMP-activated protein kinase (AMPK) is a pivotal regulator of some endogenous defensive molecules in various pathological processes, particularly myocardial ischemia (MI), a high risk of myocardial infarction. Thereby it is of great significance to explore the inherent mechanism between AMPK and myocardial infarction. In this review, we first introduce the structure and role of AMPK in the heart. Next, we introduce the mechanisms of AMPK in the heart; followed by the energy regulation of AMPK in MI. Lastly, the attention will be expanded to some potential directions and further perspectives. The information compiled here will be helpful for further research and drug design in the future before AMPK might be considered as a therapeutic target of MI.
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Affiliation(s)
- Chunhu Gu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an 710069, China; Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China
| | - Tian Li
- School of Basic Medicine, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Shuai Jiang
- Department of Aerospace Medicine, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Zhi Yang
- School of Basic Medicine, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Jianjun Lv
- School of Basic Medicine, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Wei Yi
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China
| | - Yang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an 710069, China.
| | - Minfeng Fang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an 710069, China.
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Mani K, Javaheri A, Diwan A. Lysosomes Mediate Benefits of Intermittent Fasting in Cardiometabolic Disease: The Janitor Is the Undercover Boss. Compr Physiol 2018; 8:1639-1667. [PMID: 30215867 DOI: 10.1002/cphy.c180005] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Adaptive responses that counter starvation have evolved over millennia to permit organismal survival, including changes at the level of individual organelles, cells, tissues, and organ systems. In the past century, a shift has occurred away from disease caused by insufficient nutrient supply toward overnutrition, leading to obesity and diabetes, atherosclerosis, and cardiometabolic disease. The burden of these diseases has spurred interest in fasting strategies that harness physiological responses to starvation, thus limiting tissue injury during metabolic stress. Insights gained from animal and human studies suggest that intermittent fasting and chronic caloric restriction extend lifespan, decrease risk factors for cardiometabolic and inflammatory disease, limit tissue injury during myocardial stress, and activate a cardioprotective metabolic program. Acute fasting activates autophagy, an intricately orchestrated lysosomal degradative process that sequesters cellular constituents for degradation, and is critical for cardiac homeostasis during fasting. Lysosomes are dynamic cellular organelles that function as incinerators to permit autophagy, as well as degradation of extracellular material internalized by endocytosis, macropinocytosis, and phagocytosis. The last decade has witnessed an explosion of knowledge that has shaped our understanding of lysosomes as central regulators of cellular metabolism and the fasting response. Intriguingly, lysosomes also store nutrients for release during starvation; and function as a nutrient sensing organelle to couple activation of mammalian target of rapamycin to nutrient availability. This article reviews the evidence for how the lysosome, in the guise of a janitor, may be the "undercover boss" directing cellular processes for beneficial effects of intermittent fasting and restoring homeostasis during feast and famine. © 2018 American Physiological Society. Compr Physiol 8:1639-1667, 2018.
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Affiliation(s)
- Kartik Mani
- John Cochran VA Medical Center, St. Louis, Missouri, USA.,Center for Cardiovascular Research and Division of Cardiology in Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Ali Javaheri
- Center for Cardiovascular Research and Division of Cardiology in Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Abhinav Diwan
- Center for Cardiovascular Research and Division of Cardiology in Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.,Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA
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42
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Bianchi VE. Impact of Nutrition on Cardiovascular Function. Curr Probl Cardiol 2018; 45:100391. [PMID: 30318107 DOI: 10.1016/j.cpcardiol.2018.08.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 08/31/2018] [Indexed: 12/11/2022]
Abstract
The metabolic sources of energy for myocardial contractility include mainly free fatty acids (FFA) for 95%, and in lesser amounts for 5% from glucose and minimal contributions from other substrates such lactate, ketones, and amino acids. However, myocardial efficiency is influenced by metabolic condition, overload, and ischemia. During cardiac stress, cardiomyocytes increase glucose oxidation and reduce FFA oxidation. In patients with ischemic coronary disease and heart failure, the low oxygen availability limits myocardial reliance on FFA and glucose utilization must increase. Although glucose uptake is fundamental to cardiomyocyte function, an excessive intracellular glucose level is detrimental. Insulin plays a fundamental role in maintaining myocardial efficiency and in reducing glycemia and inflammation; this is particularly evident in obese and type-2 diabetic patients. An excess of F availability increase fat deposition within cardiomyocytes and reduces glucose oxidation. In patients with high body mass index, a restricted diet or starvation have positive effects on cardiac metabolism and function while, in patients with low body mass index, restrictive diets, or starvation have a deleterious effect. Thus, weight loss in obese patients has positive impacts on ventricular mass and function, whereas, in underweight heart failure patients, such weight reduction adds to the risk of heart damage, predisposing to cachexia. Nutrition plays an essential role in the evolution of cardiovascular disease and should be taken into account. An energy-restricted diet improves myocardial efficiency but can represent a potential risk of heart damage, particularly in patients affected by cardiovascular disease. Micronutrient integration has a marginal effect on cardiovascular efficiency.
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Zullo A, Simone E, Grimaldi M, Musto V, Mancini FP. Sirtuins as Mediator of the Anti-Ageing Effects of Calorie Restriction in Skeletal and Cardiac Muscle. Int J Mol Sci 2018; 19:E928. [PMID: 29561771 PMCID: PMC5979282 DOI: 10.3390/ijms19040928] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Revised: 03/14/2018] [Accepted: 03/20/2018] [Indexed: 12/17/2022] Open
Abstract
Fighting diseases and controlling the signs of ageing are the major goals of biomedicine. Sirtuins, enzymes with mainly deacetylating activity, could be pivotal targets of novel preventive and therapeutic strategies to reach such aims. Scientific proofs are accumulating in experimental models, but, to a minor extent, also in humans, that the ancient practice of calorie restriction could prove an effective way to prevent several degenerative diseases and to postpone the detrimental signs of ageing. In the present review, we summarize the evidence about the central role of sirtuins in mediating the beneficial effects of calorie restriction in skeletal and cardiac muscle since these tissues are greatly damaged by diseases and advancing years. Moreover, we entertain the possibility that the identification of sirtuin activators that mimic calorie restriction could provide the benefits without the inconvenience of this dietary style.
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Affiliation(s)
- Alberto Zullo
- Department of Sciences and Technologies, University of Sannio, 82100 Benevento, Italy.
- CEINGE Biotecnologie Avanzate s.c.ar.l., 80145 Naples, Italy.
| | - Emanuela Simone
- Department of Sciences and Technologies, University of Sannio, 82100 Benevento, Italy.
| | - Maddalena Grimaldi
- Department of Pediatric Oncology and Hematology, Charité University Hospital, 13353 Berlin, Germany.
| | - Vincenzina Musto
- Department of Sciences and Technologies, University of Sannio, 82100 Benevento, Italy.
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Xin Z, Ma Z, Hu W, Jiang S, Yang Z, Li T, Chen F, Jia G, Yang Y. FOXO1/3: Potential suppressors of fibrosis. Ageing Res Rev 2018; 41:42-52. [PMID: 29138094 DOI: 10.1016/j.arr.2017.11.002] [Citation(s) in RCA: 105] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 10/07/2017] [Accepted: 11/08/2017] [Indexed: 02/06/2023]
Abstract
Fibrosis is a universally age-related disease that involves nearly all organs. It is typically initiated by organic injury and eventually results in organ failure. There are still few effective therapeutic strategy targets for fibrogenesis. Forkhead box proteins O1 and O3 (FOXO1/3) have been shown to have favorable inhibitory effects on fibroblast activation and subsequent extracellular matrix production and can ameliorate fibrosis levels in numerous organs, including the heart, liver, lung, and kidney; they are therefore promising targets for anti-fibrosis therapy. Moreover, we can develop appropriate strategies to make the best use of FOXO1/3's anti-fibrosis properties. The information reviewed here should be significant for understanding the roles of FOXO1/3 in fibrosis and should contribute to the design of further studies related to FOXO1/3 and the fibrotic response and shed light on a potential treatment for fibrosis.
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Affiliation(s)
- Zhenlong Xin
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an 710069, China; Department of Occupational and Environmental Health and The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Zhiqiang Ma
- Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China
| | - Wei Hu
- Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Shuai Jiang
- Department of Aerospace Medicine, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Zhi Yang
- Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Tian Li
- Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Fulin Chen
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an 710069, China
| | - Guozhan Jia
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China
| | - Yang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an 710069, China; Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China.
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