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Barayan D, Khalaf F, Rehou S, Tedesco DJ, Bhattachan P, Pond G, Abdullahi A, Jeschke MG. Metformin administration improves adverse outcomes in older adult burn patients: a single-centre cohort study. NPJ AGING 2025; 11:43. [PMID: 40419490 PMCID: PMC12106820 DOI: 10.1038/s41514-025-00224-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Accepted: 04/23/2025] [Indexed: 05/28/2025]
Abstract
This study assesses the safety and efficacy of metformin administration in older adult burn patients, a rapidly growing demographic with substantially poorer outcomes. This is a single-centre cohort study of older adults (≥60 years) admitted to a provincial burn center over 15 years. Clinical outcomes, laboratory measures, inflammatory markers, and adipose tissue single-nuclei RNA sequencing (SnRNA-seq) were compared among metformin-treated and non-treated controls. A total of 50 metformin-treated and 262 control older burn patients met the eligibility criteria. Despite pre-admission comorbidities, metformin-treated patients showed improved survival, no significant differences in the number of hypoglycemic episodes, a lower incidence of lactic acidosis, and reduced circulating levels of organ damage markers. SnRNA-Seq further revealed that metformin may exert its beneficial effects by local restoration of immune and inflammatory responses. In older burn patients, metformin was linked with improved outcomes and no adverse effects, underscoring its safety and efficacy in this population.
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Affiliation(s)
- Dalia Barayan
- Sunnybrook Research Institute, Toronto, ON, Canada
- Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Surgery, McMaster University, Hamilton, ON, Canada
- David Braley Research Institute, Hamilton, ON, Canada
- Hamilton Health Sciences, Hamilton, ON, Canada
| | - Fadi Khalaf
- David Braley Research Institute, Hamilton, ON, Canada
- Hamilton Health Sciences, Hamilton, ON, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
| | - Sarah Rehou
- Sunnybrook Research Institute, Toronto, ON, Canada
- David Braley Research Institute, Hamilton, ON, Canada
- Hamilton Health Sciences, Hamilton, ON, Canada
- Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Diana Julia Tedesco
- David Braley Research Institute, Hamilton, ON, Canada
- Hamilton Health Sciences, Hamilton, ON, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
| | - Punit Bhattachan
- Department of Surgery, McMaster University, Hamilton, ON, Canada
- David Braley Research Institute, Hamilton, ON, Canada
- Hamilton Health Sciences, Hamilton, ON, Canada
| | - Gregory Pond
- Hamilton Health Sciences, Hamilton, ON, Canada
- Department of Oncology, McMaster University, Hamilton, ON, Canada
| | - Abdikarim Abdullahi
- Sunnybrook Research Institute, Toronto, ON, Canada
- Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Surgery, McMaster University, Hamilton, ON, Canada
- David Braley Research Institute, Hamilton, ON, Canada
- Hamilton Health Sciences, Hamilton, ON, Canada
| | - Marc G Jeschke
- Sunnybrook Research Institute, Toronto, ON, Canada.
- Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
- Department of Surgery, McMaster University, Hamilton, ON, Canada.
- David Braley Research Institute, Hamilton, ON, Canada.
- Hamilton Health Sciences, Hamilton, ON, Canada.
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
- Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
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Binsaleh AY, El-Haggar SM, Hegazy SK, Maher MM, Bahgat MM, Elmasry TA, Alrubia S, Alsegiani AS, Eldesoqui M, Bahaa MM. The adjunctive role of metformin in patients with mild to moderate ulcerative colitis: a randomized controlled study. Front Pharmacol 2025; 16:1507009. [PMID: 40191419 PMCID: PMC11969268 DOI: 10.3389/fphar.2025.1507009] [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: 10/06/2024] [Accepted: 02/14/2025] [Indexed: 04/09/2025] Open
Abstract
Background Metformin, hypoglycemic medication, is recognized for its diverse properties and its capacity to influence the inflammatory pathways. Medications with anti-inflammatory and anti-oxidative characteristics have been demonstrated to be able to elicit and sustain remission in ulcerative colitis (UC), chronic inflammatory disorder of the bowel. Studies in both preclinical and clinical settings have looked into the several metabolic pathways via which metformin protects against UC. Aim To assess efficacy of metformin as adjunctive therapy in patients with mild to moderate UC. Methods This clinical research was double-blinded, randomized, controlled, and involved 60 patients with mild to moderate UC. The participants were randomly assigned to one of two groups (n = 30). The control group was given 1 g of mesalamine three times a day (t.i.d.) for a period of 6 months (mesalamine group). The metformin group was given 500 mg of metformin twice daily and 1 g of mesalamine t. i.d. For a period of 6 months. Patients with UC were assessed by a gastroenterologist using the disease activity index (DAI) both at the beginning of treatment and 6 months thereafter. To evaluate the drug's biological efficacy, measurements of fecal calprotectin, serum C-reactive protein (CRP), interleukin 10 (IL-10), and nitric oxide (NO) were taken both before and after treatment. Study outcomes Decrease in DAI and change in the level of measured serum and fecal markers. Results The metformin group displayed a statistical reduction in DAI (p = 0.0001), serum CRP (p = 0.019), NO (p = 0.04), and fecal calprotectin (p = 0.027), as well as a significant increase in IL-10 (p = 0.04) when compared to the mesalamine group. There was a significant direct correlation between DAI and calprotectin (p < 0.0001, r = 0.551), and between DAI and CRP (p < 0.0001, r = 0.794). There was a significant negative correlation between DAI and IL-10 (p = 0.0003, r = 0.371). Conclusion Metformin may be an effective adjunct drug in management of patients with mild to moderate UC by decreasing DAI and other inflammatory markers that were involved in the pathogenesis of UC. Clinical Trial Registration identifier NCT05553704.
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Affiliation(s)
- Ammena Y. Binsaleh
- Department of Pharmacy Practice, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Sahar M. El-Haggar
- Clinical Pharmacy Department, Faculty of Pharmacy, Tanta University, El-Gharbia Government, Tanta, Egypt
| | - Sahar K. Hegazy
- Clinical Pharmacy Department, Faculty of Pharmacy, Tanta University, El-Gharbia Government, Tanta, Egypt
- Pharmacy Practice Department, Faculty of Pharmacy, Horus University, New Damietta, Egypt
| | - Maha M. Maher
- Internal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
- Internal Medicine Department, Faculty of Medicine, Horus University, New Damietta, Egypt
| | - Monir M. Bahgat
- Internal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Thanaa A. Elmasry
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Tanta University, Tanta, Al-Gharbia, Egypt
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Sinai University, Arish campus, Egypt
| | - Sarah Alrubia
- Pharmaceutical Chemistry Department, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Amsha S. Alsegiani
- Pharmaceutical Chemistry Department, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Mamdouh Eldesoqui
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh, Saudi Arabia
| | - Mostafa M. Bahaa
- Pharmacy Practice Department, Faculty of Pharmacy, Horus University, New Damietta, Egypt
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Hong H, Fu Q, Gu P, Zhao J, Dai J, Xu K, Yang T, Dai H, Shen S. Investigating the common genetic architecture and causality of metabolic disorders with neurodegenerative diseases. Diabetes Obes Metab 2025; 27:1337-1349. [PMID: 39703124 DOI: 10.1111/dom.16130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 12/03/2024] [Accepted: 12/03/2024] [Indexed: 12/21/2024]
Abstract
BACKGROUND The co-occurrence of metabolic dysfunction and neurodegenerative diseases suggests a genetic link, yet the shared genetic architecture and causality remain unclear. We aimed to comprehensively characterise these genetic relationships. METHODS We investigated genetic correlations among four neurodegenerative diseases and seven metabolic dysfunctions, followed by bidirectional Mendelian randomisation (MR) to assess potential causal relationships. Pleiotropy analysis (PLACO) was used to detect the pleiotropic effects of genetic variants. Significant pleiotropic loci were refined and annotated using functional mapping and annotation (FUMA) and Bayesian colocalisation analysis. We further explored mapped genes with tissue-specific expression and gene set enrichment analyses. RESULTS We identified significant genetic correlations in nine out of 28 trait pairs. MR suggested causal relationships between specific trait pairs. Pleiotropy analysis revealed 25 931 significant single-nucleotide polymorphisms, with 246 pleiotropic loci identified via FUMA and 55 causal loci through Bayesian colocalisation. These loci are involved in neurotransmitter transport and immune response mechanisms, notably the missense variant rs41286192 in SLC18B1. The tissue-specific analysis highlighted the pancreas, left ventricle, amygdala, and liver as critical organs in disease progression. Drug target analysis linked 74 unique genes to existing therapeutic agents, while gene set enrichment identified 189 pathways related to lipid metabolism, cell differentiation and immune responses. CONCLUSION Our findings reveal a shared genetic basis, pleiotropic loci, and potential causal relationships between metabolic dysfunction and neurodegenerative diseases. These insights highlight the biological connections underlying their phenotypic association and offer implications for future research to reduce the risk of neurodegenerative diseases.
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Affiliation(s)
- Hao Hong
- Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Qi Fu
- Department of Endocrinology and Metabolism, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Pan Gu
- Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jingyi Zhao
- Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jinglan Dai
- Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Kuanfeng Xu
- Department of Endocrinology and Metabolism, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Tao Yang
- Department of Endocrinology and Metabolism, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hao Dai
- Department of Endocrinology and Metabolism, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Sipeng Shen
- Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
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Daka Q, Neziri B, Lindner E, Azuara Blanco A. Metformin in Glaucoma Treatment. J Glaucoma 2024; 33:387-393. [PMID: 38536124 DOI: 10.1097/ijg.0000000000002387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 03/07/2024] [Indexed: 06/01/2024]
Abstract
PRCIS Rigorous trials are essential to develop comprehensive treatment strategies that fully exploit the therapeutic potential of metformin in the treatment of glaucoma. OBJECTIVE The objective of this study was to evaluate the potentially beneficial effect of metformin on glaucoma risk factors and to investigate the underlying mechanisms. The aim is to contribute to the development of new treatment strategies for glaucoma. METHODS We searched for studies that assessed the effects of metformin on glaucoma risk factors and the associated underlying mechanisms. Our search included electronic databases such as PUBMED, EMBASE, and clinicaltrials.gov. RESULTS Unfortunately, we did not find any clinical trials that specifically investigated the impact of metformin on glaucoma. However, data from experimental studies demonstrated the capability of metformin to modulate various pathways that could contribute to neuroprotection in glaucoma. CONCLUSION In order to develop comprehensive treatment strategies that fully exploit the therapeutic potential of metformin in the treatment of glaucoma, rigorous trials are essential. These studies are necessary to demonstrate both the safety and efficacy of metformin in the context of glaucoma treatment.
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Affiliation(s)
- Qëndresë Daka
- Department of Pathophysiology, Medical Faculty, University of Prishtina, Prishtinë, Kosovo
- Department of Ophthalmology, University Clinical Centre of Kosova, Prishtinë, Kosovo
| | - Burim Neziri
- Department of Pathophysiology, Medical Faculty, University of Prishtina, Prishtinë, Kosovo
| | - Ewald Lindner
- Department of Ophthalmology, Medical University of Granz, Auenbruggerplatz, Granz, Austria
| | - Augusto Azuara Blanco
- Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, UK
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Zhou SM, Yao XM, Cheng Y, Xing YJ, Sun Y, Hua Q, Wan SJ, Meng XJ. Metformin enhances METTL14-Mediated m6A methylation to alleviate NIT-1 cells apoptosis induced by hydrogen peroxide. Heliyon 2024; 10:e24432. [PMID: 38312705 PMCID: PMC10835167 DOI: 10.1016/j.heliyon.2024.e24432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 01/08/2024] [Accepted: 01/09/2024] [Indexed: 02/06/2024] Open
Abstract
Injuries to pancreatic β-cells are intricately linked to the onset of diabetes mellitus (DM). Metformin (Met), one of the most widely prescribed medications for diabetes and metabolic disorders, has been extensively studied for its antioxidant, anti-aging, anti-glycation, and hepatoprotective activities. N6-methyladenosine (m6A) plays a crucial role in the regulation of β-cell growth and development, and its dysregulation is associated with metabolic disorders. This study aimed to elucidate the mechanistic basis of m6A involvement in the protective effects of Met against oxidative damage in pancreatic β-cells. Hydrogen peroxide (H2O2) was employed to induce β-cell damage. Remarkably, Met treatment effectively increased methylation levels and the expression of the methyltransferase METTL14, subsequently reducing H2O2-induced apoptosis. Knocking down METTL14 expression using siRNA significantly compromised cell viability. Conversely, targeted overexpression of METTL14 specifically in β-cells substantially enhanced their capacity to withstand H2O2-induced stress. Molecular evidence suggests that the anti-apoptotic properties of Met may be mediated through Bcl-xL and Bim proteins. In conclusion, our findings indicate that Met induces METTL14-mediated alterations in m6A methylation levels, thereby shielding β-cells from apoptosis and oxidative damage induced by oxidative stress.
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Affiliation(s)
- Si-Min Zhou
- Department of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Wannan Medical College, Wuhu, 241002, China
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241002, China
| | - Xin-Ming Yao
- Department of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Wannan Medical College, Wuhu, 241002, China
| | - Yi Cheng
- Department of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Wannan Medical College, Wuhu, 241002, China
| | - Yu-Jie Xing
- Department of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Wannan Medical College, Wuhu, 241002, China
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241002, China
| | - Yue Sun
- Department of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Wannan Medical College, Wuhu, 241002, China
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241002, China
| | - Qiang Hua
- Department of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Wannan Medical College, Wuhu, 241002, China
| | - Shu-Jun Wan
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241002, China
| | - Xiang-Jian Meng
- Department of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Wannan Medical College, Wuhu, 241002, China
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Nassar K, El-Mekawey D, Elmasry AE, Refaey MS, El-Sayed Ghoneim M, Elshaier YAMM. The significance of caloric restriction mimetics as anti-aging drugs. Biochem Biophys Res Commun 2024; 692:149354. [PMID: 38091837 DOI: 10.1016/j.bbrc.2023.149354] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 11/26/2023] [Accepted: 11/30/2023] [Indexed: 01/06/2024]
Abstract
Aging is an intricate process characterized by the gradual deterioration of the physiological integrity of a living organism. This unfortunate phenomenon inevitably leads to a decline in functionality and a heightened susceptibility to the ultimate fate of mortality. Therefore, it is of utmost importance to implement interventions that possess the capability to reverse or preempt age-related pathology. Caloric restriction mimetics (CRMs) refer to a class of molecules that have been observed to elicit advantageous outcomes on both health and longevity in various model organisms and human subjects. Notably, these compounds offer a promising alternative to the arduous task of adhering to a caloric restriction diet and mitigate the progression of the aging process and extend the duration of life in laboratory animals and human population. A plethora of molecular signals have been linked to the practice of caloric restriction, encompassing Insulin-like Growth Factor 1 (IGF1), Mammalian Target of Rapamycin (mTOR), the Adenosine Monophosphate-Activated Protein Kinase (AMPK) pathway, and Sirtuins, with particular emphasis on SIRT1. Therefore, this review will center its focus on several compounds that act as CRMs, highlighting their molecular targets, chemical structures, and mechanisms of action. Moreover, this review serves to underscore the significant relationship between post COVID-19 syndrome, antiaging, and importance of utilizing CRMs. This particular endeavor will serve as a comprehensive guide for medicinal chemists and other esteemed researchers, enabling them to meticulously conceive and cultivate novel molecular entities with the potential to function as efficacious antiaging pharmaceutical agents.
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Affiliation(s)
- Khloud Nassar
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Menoufia, 32897, Egypt
| | - Doaa El-Mekawey
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Sadat City, Menoufia, 32897, Egypt
| | - Ahmed E Elmasry
- Department Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Menoufia, 32897, Egypt
| | - Mohamed S Refaey
- Department of Pharmacognosy, Faculty of Pharmacy, University of Sadat City, Menoufia, 32897, Egypt
| | - Mai El-Sayed Ghoneim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Sadat City, Menoufia, 32897, Egypt.
| | - Yaseen A M M Elshaier
- Department Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Menoufia, 32897, Egypt
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7
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Geiger M, Gorica E, Mohammed SA, Mongelli A, Mengozi A, Delfine V, Ruschitzka F, Costantino S, Paneni F. Epigenetic Network in Immunometabolic Disease. Adv Biol (Weinh) 2024; 8:e2300211. [PMID: 37794610 DOI: 10.1002/adbi.202300211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 09/08/2023] [Indexed: 10/06/2023]
Abstract
Although a large amount of data consistently shows that genes affect immunometabolic characteristics and outcomes, epigenetic mechanisms are also heavily implicated. Epigenetic changes, including DNA methylation, histone modification, and noncoding RNA, determine gene activity by altering the accessibility of chromatin to transcription factors. Various factors influence these alterations, including genetics, lifestyle, and environmental cues. Moreover, acquired epigenetic signals can be transmitted across generations, thus contributing to early disease traits in the offspring. A closer investigation is critical in this aspect as it can help to understand the underlying molecular mechanisms further and gain insights into potential therapeutic targets for preventing and treating diseases arising from immuno-metabolic dysregulation. In this review, the role of chromatin alterations in the transcriptional modulation of genes involved in insulin resistance, systemic inflammation, macrophage polarization, endothelial dysfunction, metabolic cardiomyopathy, and nonalcoholic fatty liver disease (NAFLD), is discussed. An overview of emerging chromatin-modifying drugs and the importance of the individual epigenetic profile for personalized therapeutic approaches in patients with immuno-metabolic disorders is also presented.
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Affiliation(s)
- Martin Geiger
- Center for Translational and Experimental Cardiology, University Hospital Zürich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
| | - Era Gorica
- Center for Translational and Experimental Cardiology, University Hospital Zürich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
| | - Shafeeq Ahmed Mohammed
- Center for Translational and Experimental Cardiology, University Hospital Zürich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
| | - Alessia Mongelli
- Center for Translational and Experimental Cardiology, University Hospital Zürich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
| | - Alessandro Mengozi
- Center for Translational and Experimental Cardiology, University Hospital Zürich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
| | - Valentina Delfine
- Center for Translational and Experimental Cardiology, University Hospital Zürich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
| | - Frank Ruschitzka
- Center for Translational and Experimental Cardiology, University Hospital Zürich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
| | - Sarah Costantino
- Center for Translational and Experimental Cardiology, University Hospital Zürich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
- University Heart Center, University Hospital Zurich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
| | - Francesco Paneni
- Center for Translational and Experimental Cardiology, University Hospital Zürich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
- University Heart Center, University Hospital Zurich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
- Department of Research and Education, University Hospital Zurich and University of Zürich, Wagistrasse 12, Schlieren, Zurich, 8952, Switzerland
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8
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Kuntic M, Kuntic I, Hahad O, Lelieveld J, Münzel T, Daiber A. Impact of air pollution on cardiovascular aging. Mech Ageing Dev 2023; 214:111857. [PMID: 37611809 DOI: 10.1016/j.mad.2023.111857] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 08/19/2023] [Indexed: 08/25/2023]
Abstract
The world population is aging rapidly, and by some estimates, the number of people older than 60 will double in the next 30 years. With the increase in life expectancy, adverse effects of environmental exposures start playing a more prominent role in human health. Air pollution is now widely considered the most detrimental of all environmental risk factors, with some studies estimating that almost 20% of all deaths globally could be attributed to poor air quality. Cardiovascular diseases are the leading cause of death worldwide and will continue to account for the most significant percentage of non-communicable disease burden. Cardiovascular aging with defined pathomechanisms is a major trigger of cardiovascular disease in old age. Effects of environmental risk factors on cardiovascular aging should be considered in order to increase the health span and reduce the burden of cardiovascular disease in older populations. In this review, we explore the effects of air pollution on cardiovascular aging, from the molecular mechanisms to cardiovascular manifestations of aging and, finally, the age-related cardiovascular outcomes. We also explore the distinction between the effects of air pollution on healthy aging and disease progression. Future efforts should focus on extending the health span rather than the lifespan.
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Affiliation(s)
- Marin Kuntic
- University Medical Center Mainz, Department for Cardiology 1, Molecular Cardiology, Mainz, Germany
| | - Ivana Kuntic
- University Medical Center Mainz, Department for Cardiology 1, Molecular Cardiology, Mainz, Germany
| | - Omar Hahad
- University Medical Center Mainz, Department for Cardiology 1, Molecular Cardiology, Mainz, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, Germany
| | - Jos Lelieveld
- Max Planck Institute for Chemistry, Atmospheric Chemistry, Mainz, Germany
| | - Thomas Münzel
- University Medical Center Mainz, Department for Cardiology 1, Molecular Cardiology, Mainz, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, Germany.
| | - Andreas Daiber
- University Medical Center Mainz, Department for Cardiology 1, Molecular Cardiology, Mainz, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, Germany.
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9
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Liu B, Meng Q, Gao X, Sun H, Xu Z, Wang Y, Zhou H. Lipid and glucose metabolism in senescence. Front Nutr 2023; 10:1157352. [PMID: 37680899 PMCID: PMC10481967 DOI: 10.3389/fnut.2023.1157352] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 08/09/2023] [Indexed: 09/09/2023] Open
Abstract
Senescence is an inevitable biological process. Disturbances in glucose and lipid metabolism are essential features of cellular senescence. Given the important roles of these types of metabolism, we review the evidence for how key metabolic enzymes influence senescence and how senescence-related secretory phenotypes, autophagy, apoptosis, insulin signaling pathways, and environmental factors modulate glucose and lipid homeostasis. We also discuss the metabolic alterations in abnormal senescence diseases and anti-cancer therapies that target senescence through metabolic interventions. Our work offers insights for developing pharmacological strategies to combat senescence and cancer.
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Affiliation(s)
- Bin Liu
- Department of Urology II, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Qingfei Meng
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, Jilin, China
| | - Xin Gao
- Department of Urology II, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Huihui Sun
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, Jilin, China
| | - Zhixiang Xu
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, Jilin, China
| | - Yishu Wang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, Jilin, China
| | - Honglan Zhou
- Department of Urology II, The First Hospital of Jilin University, Changchun, Jilin, China
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Mallick AM, Biswas A, Mishra S, Jadhav S, Chakraborty K, Tripathi A, Mukherjee A, Roy RS. Engineered vitamin E-tethered non-immunogenic facial lipopeptide for developing improved siRNA based combination therapy against metastatic breast cancer. Chem Sci 2023; 14:7842-7866. [PMID: 37502330 PMCID: PMC10370593 DOI: 10.1039/d3sc01071f] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Accepted: 06/30/2023] [Indexed: 07/29/2023] Open
Abstract
RNA interference based therapeutic gene silencing is an emerging platform for managing highly metastatic breast cancer. Cytosolic delivery of functional siRNA remains the key obstacle for efficient RNAi therapy. To overcome the challenges of siRNA delivery, we have engineered a vitamin E-tethered, short, optimum protease stabilized facial lipopeptide based non-immunogenic, biocompatible siRNA transporter to facilitate the clinical translation in future. Our designed lipopeptide has an Arginine-Sarcosine-Arginine segment for providing optimum protease-stability, minimizing adjacent arginine-arginine repulsion and reducing intermolecular aggregation and α-tocopherol as the lipidic moiety for facilitating cellular permeabilization. Interestingly, our designed non-immunogenic siRNA transporter has exhibited significantly better long term transfection efficiency than HiPerFect and can transfect hard to transfect primary cell line, HUVEC. Our engineered siRNA therapeutics demonstrated high efficacy in managing metastasis against triple negative breast cancer by disrupting the crosstalk of endothelial cells and MDA-MB-231 and reduced stemness and metastatic markers, as evidenced by downregulating critical oncogenic pathways. Our study aimed at silencing Notch1 signalling to achieve "multi-targeted" therapy with a single putative molecular medicine. We have further developed mechanistically rational combination therapy combining Notch1 silencing with a repurposed drug m-TOR inhibitor, metformin, which demonstrated synergistic interaction and enhanced antitumor efficacy against cancer metastasis.
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Affiliation(s)
- Argha Mario Mallick
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata Mohanpur 741246 India
| | - Abhijit Biswas
- Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata Mohanpur 741246 India
| | - Sukumar Mishra
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata Mohanpur 741246 India
| | - Sonali Jadhav
- Department of Chemistry, Indian Institute of Science Education and Research Pune Pune 411008 India
| | - Kasturee Chakraborty
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata Mohanpur 741246 India
| | - Archana Tripathi
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata Mohanpur 741246 India
| | - Arnab Mukherjee
- Department of Chemistry, Indian Institute of Science Education and Research Pune Pune 411008 India
| | - Rituparna Sinha Roy
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata Mohanpur 741246 India
- Centre for Advanced Functional Materials, Indian Institute of Science Education and Research Kolkata Mohanpur 741246 India
- Centre for Climate and Environmental Studies, Indian Institute of Science Education and Research Kolkata Mohanpur 741246 India
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11
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Starr MR, Dalvin LA, AbouChehade JE, Damento GM, Garcia M, Shah SM, Hodge DO, Iezzi R, Bakri SJ. Incidence of metformin use in patients with age-related macular degeneration versus normal controls: A population-based study in Olmsted County, Minnesota. Eye (Lond) 2023; 37:1861-1865. [PMID: 36151313 PMCID: PMC10275985 DOI: 10.1038/s41433-022-02245-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 08/12/2022] [Accepted: 09/05/2022] [Indexed: 11/08/2022] Open
Abstract
PURPOSE The purpose of this study is to compare the use of metformin in patients with both exudative and non-exudative age-related macular degeneration (AMD) versus control populations. DESIGN Retrospective review of three age- and sex-matched cohorts from 1/1/2004 to 12/31/2013: patients with exudative AMD, a cohort of dry AMD patients, and a cohort of patients without AMD. The primary endpoint was the incidence of metformin use in all of the cohorts. RESULTS There were 1512 patients, with 504 in each of the three cohorts. There was no difference in the prevalence of diabetes between cohorts. Compared to patients with dry AMD, patients with no AMD had increased likelihood of metformin use (p = 0.0168, OR 1.66 (1.09-2.51). There was no difference in the likelihood of metformin use between exudative AMD patients and non-AMD controls. CONCLUSIONS There appears to be an increased incidence of metformin use in patients without AMD compared to patients with dry AMD. Metformin's current role in the treatment of anti-aging diseases makes it a plausible target for use in the treatment of AMD, particularly dry AMD.
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Affiliation(s)
- Matthew R Starr
- Department of Ophthalmology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Lauren A Dalvin
- Department of Ophthalmology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Jackson E AbouChehade
- Department of Ophthalmology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Gena M Damento
- Mayo Clinic School of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Maria Garcia
- Department of Ophthalmology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Saumya M Shah
- Department of Ophthalmology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - David O Hodge
- Department of Health Sciences Research/Biomedical Statistics and Informatics, Mayo Clinic, 4500 San Pablo Rd S, Jacksonville, FL, 32224, USA
| | - Raymond Iezzi
- Department of Ophthalmology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
| | - Sophie J Bakri
- Department of Ophthalmology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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12
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Anwar L, Ali SA, Khan S, Uzairullah MM, Mustafa N, Ali UA, Siddiqui F, Bhatti HA, Rehmani SJ, Abbas G. Fenugreek seed ethanolic extract inhibited formation of advanced glycation end products via scavenging reactive carbonyl intermediates. Heliyon 2023; 9:e16866. [PMID: 37484294 PMCID: PMC10360956 DOI: 10.1016/j.heliyon.2023.e16866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 05/17/2023] [Accepted: 05/31/2023] [Indexed: 07/25/2023] Open
Abstract
Senescence is a natural phenomenon of growing old. It accelerates under certain conditions like diabetes mellitus resulting in early decline of bodily functions, which can be avoided by many claimed functional foods. The present study aims to investigate the anti-aging ability of Fenugreek seeds (Trigonellafoenum-graecum); a common ingredient of Indo-Pak cuisines. Briefly, the Fenugreek seeds extract (FgSE) in concentrationsof0.1, 0.5 and 1 mg/ml inhibited the formation of Advanced Glycation End products (AGEs) and fructosamine adducts in Bovine serum albumin (BSA)/fructose model in vitro. The BSA conformational analysis via Circular Dichorism and Congo red assays showed that it preserves secondary structure of BSA in aforementioned model. Although mechanistic studies revealed insignificant lysine blocking ability of Fenugreek by OPA assay, however carbonyl entrapping was found to be 24%, 34% and 42% at 0.1, 0.5 and 1 mg/ml, respectively. In vivo model of High Fructose diet (HFD) induced glycation, FgSE treatment in doses of 10, 25 & 50 mg/kg markedly improved Escape latency (p < 0.01) and preserved cognition in Morris Water Maze. Our data further exhibits significant decrease of CML (Nε-carboxymethyl lysine) levels in serum and hippocampus byFgSE treatment in comparison with HFD group. Therefore, we deduced that FgSE prevents glycation-induced memory decline via entrapping the reactive carbonyl intermediates, formed during production of AGEs. Hence, as a promising functional food it slows down the harmful process of glycation and aging associated morbidities.
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Affiliation(s)
- Laila Anwar
- H.E.J. Research Institute of Chemistry, ICCBS, University of Karachi, Karachi, Pakistan
- Faculty of Pharmacy, Hamdard University, Karachi, Pakistan
| | - Syed Abid Ali
- H.E.J. Research Institute of Chemistry, ICCBS, University of Karachi, Karachi, Pakistan
| | - Sana Khan
- H.E.J. Research Institute of Chemistry, ICCBS, University of Karachi, Karachi, Pakistan
| | | | - Nazish Mustafa
- Dr. Panjwani Center for Molecular Medicine & Drug Research, ICCBS, University of Karachi, Karachi, Pakistan
| | | | | | - Huma Aslam Bhatti
- H.E.J. Research Institute of Chemistry, ICCBS, University of Karachi, Karachi, Pakistan
| | | | - Ghulam Abbas
- Department of Pharmacology, Faculty of Pharmacy, Ziauddin University, Karachi, Pakistan
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13
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Topal A, Mutlu AG, Alkan I, Korkmaz D, Yildiz H, Tikirdik M. The effects of metformın, acetylsalıcylıc acıd and ıbuprofen on telomerase enzyme actıvıty: ınhıbıtory effect of ıbuprofen. BRAZ J PHARM SCI 2023; 59. [DOI: 10.1590/s2175-97902022310233] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Affiliation(s)
| | | | - Irem Alkan
- Burdur Mehmet Akif Ersoy University, Turkey
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14
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Abstract
Age is the key risk factor for diseases and disabilities of the elderly. Efforts to tackle age-related diseases and increase healthspan have suggested targeting the ageing process itself to 'rejuvenate' physiological functioning. However, achieving this aim requires measures of biological age and rates of ageing at the molecular level. Spurred by recent advances in high-throughput omics technologies, a new generation of tools to measure biological ageing now enables the quantitative characterization of ageing at molecular resolution. Epigenomic, transcriptomic, proteomic and metabolomic data can be harnessed with machine learning to build 'ageing clocks' with demonstrated capacity to identify new biomarkers of biological ageing.
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Affiliation(s)
- Jarod Rutledge
- Department of Genetics, Stanford University, Stanford, CA, USA
- Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA
- Paul F. Glenn Center for the Biology of Ageing, Stanford University School of Medicine, Stanford, CA, USA
| | - Hamilton Oh
- Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA
- Paul F. Glenn Center for the Biology of Ageing, Stanford University School of Medicine, Stanford, CA, USA
- Graduate Program in Stem Cell and Regenerative Medicine, Stanford University, Stanford, CA, USA
| | - Tony Wyss-Coray
- Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
- Paul F. Glenn Center for the Biology of Ageing, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
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15
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Jinna N, Rida P, Su T, Gong Z, Yao S, LaBarge M, Natarajan R, Jovanovic-Talisman T, Ambrosone C, Seewaldt V. The DARC Side of Inflamm-Aging: Duffy Antigen Receptor for Chemokines (DARC/ACKR1) as a Potential Biomarker of Aging, Immunosenescence, and Breast Oncogenesis among High-Risk Subpopulations. Cells 2022; 11:cells11233818. [PMID: 36497078 PMCID: PMC9740232 DOI: 10.3390/cells11233818] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/09/2022] [Accepted: 11/23/2022] [Indexed: 11/30/2022] Open
Abstract
The proclivity of certain pre-malignant and pre-invasive breast lesions to progress while others do not continues to perplex clinicians. Clinicians remain at a crossroads with effectively managing the high-risk patient subpopulation owing to the paucity of biomarkers that can adequately risk-stratify and inform clinical decisions that circumvent unnecessary administration of cytotoxic and invasive treatments. The immune system mounts the most important line of defense against tumorigenesis and progression. Unfortunately, this defense declines or "ages" over time-a phenomenon known as immunosenescence. This results in "inflamm-aging" or the excessive infiltration of pro-inflammatory chemokines, which alters the leukocyte composition of the tissue microenvironment, and concomitant immunoediting of these leukocytes to diminish their antitumor immune functions. Collectively, these effects can foster the sequelae of neoplastic transformation and progression. The erythrocyte cell antigen, Duffy antigen receptor for chemokines(DARC/ACKR1), binds and internalizes chemokines to maintain homeostatic levels and modulate leukocyte trafficking. A negative DARC status is highly prevalent among subpopulations of West African genetic ancestry, who are at higher risk of developing breast cancer and disease progression at a younger age. However, the role of DARC in accelerated inflamm-aging and malignant transformation remains underexplored. Herein, we review compelling evidence suggesting that DARC may be protective against inflamm-aging and, therefore, reduce the risk of a high-risk lesion progressing to malignancy. We also discuss evidence supporting that immunotherapeutic intervention-based on DARC status-among high-risk subpopulations may evade malignant transformation and progression. A closer look into this unique role of DARC could glean deeper insight into the immune response profile of individual high-risk patients and their predisposition to progress as well as guide the administration of more "cyto-friendly" immunotherapeutic intervention to potentially "turn back the clock" on inflamm-aging-mediated oncogenesis and progression.
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Affiliation(s)
- Nikita Jinna
- Department of Population Science, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Padmashree Rida
- Department of Science, Rowland Hall, Salt Lake City, UT 84102, USA
| | - Tianyi Su
- Department of Science, Rowland Hall, Salt Lake City, UT 84102, USA
| | - Zhihong Gong
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Song Yao
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Mark LaBarge
- Department of Population Science, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Rama Natarajan
- Department of Diabetes Complications and Metabolism, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | | | - Christine Ambrosone
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Victoria Seewaldt
- Department of Population Science, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
- Correspondence:
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16
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Caponio D, Veverová K, Zhang SQ, Shi L, Wong G, Vyhnalek M, Fang EF. Compromised autophagy and mitophagy in brain ageing and Alzheimer's diseases. AGING BRAIN 2022; 2:100056. [PMID: 36908880 PMCID: PMC9997167 DOI: 10.1016/j.nbas.2022.100056] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 11/04/2022] [Accepted: 11/16/2022] [Indexed: 11/25/2022] Open
Abstract
Alzheimer's disease (AD) is one of the most persistent and devastating neurodegenerative disorders of old age, and is characterized clinically by an insidious onset and a gradual, progressive deterioration of cognitive abilities, ranging from loss of memory to impairment of judgement and reasoning. Despite years of research, an effective cure is still not available. Autophagy is the cellular 'garbage' clearance system which plays fundamental roles in neurogenesis, neuronal development and activity, and brain health, including memory and learning. A selective sub-type of autophagy is mitophagy which recognizes and degrades damaged or superfluous mitochondria to maintain a healthy and necessary cellular mitochondrial pool. However, emerging evidence from animal models and human samples suggests an age-dependent reduction of autophagy and mitophagy, which are also compromised in AD. Upregulation of autophagy/mitophagy slows down memory loss and ameliorates clinical features in animal models of AD. In this review, we give an overview of autophagy and mitophagy and their link to the progression of AD. We also summarize approaches to upregulate autophagy/mitophagy. We hypothesize that age-dependent compromised autophagy/mitophagy is a cause of brain ageing and a risk factor for AD, while restoration of autophagy/mitophagy to more youthful levels could return the brain to health.
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Affiliation(s)
- Domenica Caponio
- Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway
| | - Kateřina Veverová
- Memory Clinic, Department of Neurology, Charles University, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic
| | - Shi-qi Zhang
- Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway
| | - Liu Shi
- Department of Psychiatry, University of Oxford, Oxford, UK
- Novo Nordisk Research Centre Oxford (NNRCO)
| | - Garry Wong
- Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau, Macau 999078, China
| | - Martin Vyhnalek
- Memory Clinic, Department of Neurology, Charles University, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic
| | - Evandro F. Fang
- Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway
- The Norwegian Centre on Healthy Ageing (NO-Age), Oslo, Norway
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17
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Therapeutics That Can Potentially Replicate or Augment the Anti-Aging Effects of Physical Exercise. Int J Mol Sci 2022; 23:ijms23179957. [PMID: 36077358 PMCID: PMC9456478 DOI: 10.3390/ijms23179957] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 08/25/2022] [Accepted: 08/30/2022] [Indexed: 12/30/2022] Open
Abstract
Globally, better health care access and social conditions ensured a significant increase in the life expectancy of the population. There is, however, a clear increase in the incidence of age-related diseases which, besides affecting the social and economic sustainability of countries and regions around the globe, leads to a decrease in the individual’s quality of life. There is an urgent need for interventions that can reverse, or at least prevent and delay, the age-associated pathological deterioration. Within this line, this narrative review aims to assess updated evidence that explores the potential therapeutic targets that can mimic or complement the recognized anti-aging effects of physical exercise. We considered pertinent to review the anti-aging effects of the following drugs and supplements: Rapamycin and Rapamycin analogues (Rapalogs); Metformin; 2-deoxy-D-glucose; Somatostatin analogues; Pegvisomant; Trametinib; Spermidine; Fisetin; Quercetin; Navitoclax; TA-65; Resveratrol; Melatonin; Curcumin; Rhodiola rosea and Caffeine. The current scientific evidence on the anti-aging effect of these drugs and supplements is still scarce and no recommendation of their generalized use can be made at this stage. Further studies are warranted to determine which therapies display a geroprotective effect and are capable of emulating the benefits of physical exercise.
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18
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Moreno-Cabañas A, Ortega JF, Morales-Palomo F, Ramirez-Jimenez M, Alvarez-Jimenez L, Mora-Rodriguez R. One Bout of Resistance Training Does Not Enhance Metformin Actions in Prediabetic and Diabetic Individuals. Med Sci Sports Exerc 2022; 54:1043-1050. [PMID: 35142713 DOI: 10.1249/mss.0000000000002889] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
PURPOSE This study aimed to determine the separated and combined effects of metformin and resistance exercise on glycemic control, insulin sensitivity, and insulin-like growth factor 1 (IGF-1) in overweight/obese individuals with prediabetes and type 2 diabetes mellitus. METHODS Fourteen adults with a body mass index of 32.1 ± 4.1 kg·m-2, insulin resistance (HOMA-2 1.6 ± 0.6), and poor glycemic control (glycated hemoglobin, 6.9% ± 0.9%; 51.9 ± 10.7 mmol·mol-1) while taking metformin (1561 ± 470 g·d-1) were recruited. Participants underwent four 72-h long experimental trials in a randomized counterbalanced order, either 1) taking metformin (MET), 2) replacing metformin by placebo pills (PLAC), 3) taking placebo and undergoing a resistance training bout (RT + PLAC), and 4) taking metformin and undergoing the same RT bout (RT + MET). Interstitial fluid glucose concentration was frequently sampled to obtain 72-h glucose area under the curve (GAUC) and the percentage hyperglycemic glucose readings (>180 mg·dL-1; GPEAKS). Insulin sensitivity (i.e., HOMA-2) and IGF-1 were also assessed. RESULTS HOMA-2 was not affected by treatments. GAUC and GPEAKS were similarly reduced below PLAC during RT + MET and MET (all P < 0.05). In contrast, RT + PLAC did not affect glucose concentration. Metformin decreased serum IGF-1 concentrations (P = 0.006), and RT did not reverse this reduction. CONCLUSIONS A bout of full-body RT does not interfere or aid on metformin's blood glucose-lowering actions in individuals with prediabetes and type 2 diabetes mellitus.
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19
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Ke H, Li F, Deng W, Li Z, Wang S, Lv P, Chen Y. Metformin Exerts Anti-inflammatory and Mucus Barrier Protective Effects by Enriching Akkermansia muciniphila in Mice With Ulcerative Colitis. Front Pharmacol 2021; 12:726707. [PMID: 34658866 PMCID: PMC8514724 DOI: 10.3389/fphar.2021.726707] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 09/13/2021] [Indexed: 12/22/2022] Open
Abstract
The present study aimed to determine if metformin exerts anti-inflammatory and mucus-protective effects via the gut microbiota. Metformin has extensive benefits including anti-inflammatory effects. Previous studies showed that metformin changed the gut microbiota composition and increases the number of goblet cells. Intestinal dysbiosis and goblet cell depletion are important features of ulcerative colitis (UC). The underlying mechanism and whether metformin can improve the mucus barrier in UC remain unclear. Metformin (400 mg/kg/day) was administered to mice with dextran sulfate sodium (DSS)-induced UC for 2 wk to investigate the effects of metformin on the intestinal mucus barrier. The gut microbiota was depleted, using antibiotics, to explore its role in the mucus-protecting effects of metformin. Akkermansia muciniphila (A. muciniphila), which was enriched in metformin-treated mice, was administered to mice to investigate the effects of the bacteria on UC and the mucus barrier. Metformin attenuated DSS-induced UC in mice, as evidenced by the alleviation of diarrhea, hematochezia, and the decrease in body weight. The expression of mucin2, a prominent mucus barrier protein, was increased in the metformin-treated group compared to the DSS-treated group. Furthermore, fecal 16S rRNA analysis showed that metformin treatment changed the gut microbiota composition by increasing the relative abundance of Lactobacillus and Akkermansia species while decreasing Erysipelatoclostridium at the genus level. Antibiotic treatment partly abolished the anti-inflammatory and mucus-protecting effects of metformin. Administration of A. muciniphila alleviated the colonic inflammation and mucus barrier disruption. Metformin alleviated DSS-induced UC in mice and protected against cell damage via affecting the gut microbiota, thereby providing a new mechanism for the therapeutic effect of metformin in patients with UC. This study also provides evidence that A. muciniphila as a probiotic has potential benefits for UC.
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Affiliation(s)
- Haoran Ke
- Department of Gastroenterology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Fang Li
- Department of Gastroenterology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Hainan General Hospital, Haikou, China
| | - Wenlin Deng
- Department of Gastroenterology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pediatrics, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zitong Li
- Department of Gastroenterology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Siqi Wang
- Department of Gastroenterology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Pinjing Lv
- Department of Gastroenterology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ye Chen
- Department of Gastroenterology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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20
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Hurley DJ, Irnaten M, O’Brien C. Metformin and Glaucoma-Review of Anti-Fibrotic Processes and Bioenergetics. Cells 2021; 10:cells10082131. [PMID: 34440899 PMCID: PMC8394782 DOI: 10.3390/cells10082131] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/13/2021] [Accepted: 08/16/2021] [Indexed: 02/06/2023] Open
Abstract
Glaucoma is the leading cause of irreversible blindness globally. With an aging population, disease incidence will rise with an enormous societal and economic burden. The treatment strategy revolves around targeting intraocular pressure, the principle modifiable risk factor, to slow progression of disease. However, there is a clear unmet clinical need to find a novel therapeutic approach that targets and halts the retinal ganglion cell (RGC) degeneration that occurs with fibrosis. RGCs are highly sensitive to metabolic fluctuations as a result of multiple stressors and thus their viability depends on healthy mitochondrial functioning. Metformin, known for its use in type 2 diabetes, has come to the forefront of medical research in multiple organ systems. Its use was recently associated with a 25% reduced risk of glaucoma in a large population study. Here, we discuss its application to glaucoma therapy, highlighting its effect on fibrotic signalling pathways, mitochondrial bioenergetics and NAD oxidation.
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Affiliation(s)
- Daire J. Hurley
- Department of Ophthalmology, Mater Misericordiae University Hospital, Eccles Street, D07 R2WY Dublin, Ireland; (M.I.); (C.O.)
- School of Medicine, University College Dublin, Belfield, D04 V1W8 Dublin, Ireland
- Correspondence:
| | - Mustapha Irnaten
- Department of Ophthalmology, Mater Misericordiae University Hospital, Eccles Street, D07 R2WY Dublin, Ireland; (M.I.); (C.O.)
| | - Colm O’Brien
- Department of Ophthalmology, Mater Misericordiae University Hospital, Eccles Street, D07 R2WY Dublin, Ireland; (M.I.); (C.O.)
- School of Medicine, University College Dublin, Belfield, D04 V1W8 Dublin, Ireland
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21
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Biguanides drugs: Past success stories and promising future for drug discovery. Eur J Med Chem 2021; 224:113726. [PMID: 34364161 DOI: 10.1016/j.ejmech.2021.113726] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 07/27/2021] [Accepted: 07/27/2021] [Indexed: 12/13/2022]
Abstract
Biguanides have attracted much attention a century ago and showed resurgent interest in recent years after a long period of dormancy. They constitute an important class of therapeutic agents suitable for the treatment of a wide spectrum of diseases. Therapeutic indications of biguanides include antidiabetic, antimalarial, antiviral, antiplaque, and bactericidal applications. This review presents an extensive overview of the biological activity of biguanides and different mechanisms of action of currently marketed biguanide-containing drugs, as well as their pharmacological properties when applicable. We highlight the recent developments in research on biguanide compounds, with a primary focus on studies on metformin in the field of oncology. We aim to provide a critical overview of all main bioactive biguanide compounds and discuss future perspectives for the design of new drugs based on the biguanide fragment.
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22
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Smith DL, Orlandella RM, Allison DB, Norian LA. Diabetes medications as potential calorie restriction mimetics-a focus on the alpha-glucosidase inhibitor acarbose. GeroScience 2021. [PMID: 33006707 DOI: 10.1007/s11357-020-00278-x/figures/1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2023] Open
Abstract
The field of aging research has grown rapidly over the last half-century, with advancement of scientific technologies to interrogate mechanisms underlying the benefit of life-extending interventions like calorie restriction (CR). Coincident with this increase in knowledge has been the rise of obesity and type 2 diabetes (T2D), both associated with increased morbidity and mortality. Given the difficulty in practicing long-term CR, a search for compounds (CR mimetics) which could recapitulate the health and longevity benefits without requiring food intake reductions was proposed. Alpha-glucosidase inhibitors (AGIs) are compounds that function predominantly within the gastrointestinal tract to inhibit α-glucosidase and α-amylase enzymatic digestion of complex carbohydrates, delaying and decreasing monosaccharide uptake from the gut in the treatment of T2D. Acarbose, an AGI, has been shown in pre-clinical models to increase lifespan (greater longevity benefits in males), with decreased body weight gain independent of calorie intake reduction. The CR mimetic benefits of acarbose are further supported by clinical findings beyond T2D including the risk for other age-related diseases (e.g., cancer, cardiovascular). Open questions remain regarding the exclusivity of acarbose relative to other AGIs, potential off-target effects, and combination with other therapies for healthy aging and longevity extension. Given the promising results in pre-clinical models (even in the absence of T2D), a unique mechanism of action and multiple age-related reduced disease risks that have been reported with acarbose, support for clinical trials with acarbose focusing on aging-related outcomes and incorporating biological sex, age at treatment initiation, and T2D-dependence within the design is warranted.
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Affiliation(s)
- Daniel L Smith
- Department of Nutrition Sciences, University of Alabama at Birmingham, 1720 2nd Avenue S, Webb 423, Birmingham, AL, 35294-3360, USA.
- Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL, USA.
- Integrative Center for Aging Research, University of Alabama at Birmingham, Birmingham, AL, USA.
- Nathan Shock Center of Excellence in the Biology of Aging, University of Alabama at Birmingham, Birmingham, AL, USA.
- Diabetes Research Center, University of Alabama at Birmingham, Birmingham, AL, USA.
| | - Rachael M Orlandella
- Graduate Biomedical Sciences, University of Alabama at Birmingham, Birmingham, AL, USA
| | - David B Allison
- School of Public Health, Indiana University - Bloomington, Bloomington, IN, USA
| | - Lyse A Norian
- Department of Nutrition Sciences, University of Alabama at Birmingham, 1720 2nd Avenue S, Webb 423, Birmingham, AL, 35294-3360, USA
- Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL, USA
- O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
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Smith DL, Orlandella RM, Allison DB, Norian LA. Diabetes medications as potential calorie restriction mimetics-a focus on the alpha-glucosidase inhibitor acarbose. GeroScience 2021; 43:1123-1133. [PMID: 33006707 PMCID: PMC8190416 DOI: 10.1007/s11357-020-00278-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 09/22/2020] [Indexed: 02/07/2023] Open
Abstract
The field of aging research has grown rapidly over the last half-century, with advancement of scientific technologies to interrogate mechanisms underlying the benefit of life-extending interventions like calorie restriction (CR). Coincident with this increase in knowledge has been the rise of obesity and type 2 diabetes (T2D), both associated with increased morbidity and mortality. Given the difficulty in practicing long-term CR, a search for compounds (CR mimetics) which could recapitulate the health and longevity benefits without requiring food intake reductions was proposed. Alpha-glucosidase inhibitors (AGIs) are compounds that function predominantly within the gastrointestinal tract to inhibit α-glucosidase and α-amylase enzymatic digestion of complex carbohydrates, delaying and decreasing monosaccharide uptake from the gut in the treatment of T2D. Acarbose, an AGI, has been shown in pre-clinical models to increase lifespan (greater longevity benefits in males), with decreased body weight gain independent of calorie intake reduction. The CR mimetic benefits of acarbose are further supported by clinical findings beyond T2D including the risk for other age-related diseases (e.g., cancer, cardiovascular). Open questions remain regarding the exclusivity of acarbose relative to other AGIs, potential off-target effects, and combination with other therapies for healthy aging and longevity extension. Given the promising results in pre-clinical models (even in the absence of T2D), a unique mechanism of action and multiple age-related reduced disease risks that have been reported with acarbose, support for clinical trials with acarbose focusing on aging-related outcomes and incorporating biological sex, age at treatment initiation, and T2D-dependence within the design is warranted.
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Affiliation(s)
- Daniel L Smith
- Department of Nutrition Sciences, University of Alabama at Birmingham, 1720 2nd Avenue S, Webb 423, Birmingham, AL, 35294-3360, USA.
- Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL, USA.
- Integrative Center for Aging Research, University of Alabama at Birmingham, Birmingham, AL, USA.
- Nathan Shock Center of Excellence in the Biology of Aging, University of Alabama at Birmingham, Birmingham, AL, USA.
- Diabetes Research Center, University of Alabama at Birmingham, Birmingham, AL, USA.
| | - Rachael M Orlandella
- Graduate Biomedical Sciences, University of Alabama at Birmingham, Birmingham, AL, USA
| | - David B Allison
- School of Public Health, Indiana University - Bloomington, Bloomington, IN, USA
| | - Lyse A Norian
- Department of Nutrition Sciences, University of Alabama at Birmingham, 1720 2nd Avenue S, Webb 423, Birmingham, AL, 35294-3360, USA
- Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL, USA
- O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
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24
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Kathuria D, Raul AD, Wanjari P, Bharatam PV. Biguanides: Species with versatile therapeutic applications. Eur J Med Chem 2021; 219:113378. [PMID: 33857729 DOI: 10.1016/j.ejmech.2021.113378] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 03/04/2021] [Accepted: 03/08/2021] [Indexed: 12/18/2022]
Abstract
Biguanides are compounds in which two guanidine moieties are fused to form a highly conjugated system. Biguanides are highly basic and hence they are available as salts mostly hydrochloride salts, these cationic species have been found to exhibit many therapeutic properties. This review covers the research and development carried out on biguanides and accounts the various therapeutic applications of drugs containing biguanide group-such as antimalarial, antidiabetic, antiviral, anticancer, antibacterial, antifungal, anti-tubercular, antifilarial, anti-HIV, as well as other biological activities. The aim of this review is to compile all the medicinal chemistry applications of this class of compounds so as to pave way for the accelerated efforts in finding the drug action mechanisms associated with this class of compounds. Importance has been given to the organic chemistry of these biguanide derivatives also.
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Affiliation(s)
- Deepika Kathuria
- University Center for Research and Development, Chandigarh University, Gharuan, Punjab, 140413, India
| | - Akshay D Raul
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, 160 062, Punjab, India
| | - Pravin Wanjari
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, 160 062, Punjab, India
| | - Prasad V Bharatam
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, 160 062, Punjab, India.
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25
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Balaguer F, Enrique M, Llopis S, Barrena M, Navarro V, Álvarez B, Chenoll E, Ramón D, Tortajada M, Martorell P. Lipoteichoic acid from Bifidobacterium animalis subsp. lactis BPL1: a novel postbiotic that reduces fat deposition via IGF-1 pathway. Microb Biotechnol 2021; 15:805-816. [PMID: 33620143 PMCID: PMC8913875 DOI: 10.1111/1751-7915.13769] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 01/26/2021] [Accepted: 01/27/2021] [Indexed: 02/06/2023] Open
Abstract
Obesity and its related metabolic disorders, such as diabetes and cardiovascular disease, are major risk factors for morbidity and mortality in the world population. In this context, supplementation with the probiotic strain Bifidobacterium animalis subsp. lactis BPL1 (CECT8145) has been shown to ameliorate obesity biomarkers. Analyzing the basis of this observation and using the pre-clinical model Caenorhabditis elegans, we have found that lipoteichoic acid (LTA) of BPL1 is responsible for its fat-reducing properties and that this attribute is preserved under hyperglycaemic conditions. This fat-reducing capacity of both BPL1 and LTA-BPL1 is abolished under glucose restriction, as a result of changes in LTA chemical composition. Moreover, we have demonstrated that LTA exerts this function through the IGF-1 pathway, as does BPL1 strain. These results open the possibility of using LTA as a novel postbiotic, whose beneficial properties can be applied therapeutically and/or preventively in metabolic syndrome and diabetes-related disorders.
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26
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Sunjaya AP, Sunjaya AF. Targeting ageing and preventing organ degeneration with metformin. DIABETES & METABOLISM 2021; 47:101203. [DOI: 10.1016/j.diabet.2020.09.009] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 08/29/2020] [Accepted: 09/28/2020] [Indexed: 12/14/2022]
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27
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Zhang B, Gladyshev VN. How can aging be reversed? Exploring rejuvenation from a damage-based perspective. ADVANCED GENETICS (HOBOKEN, N.J.) 2020; 1:e10025. [PMID: 36619246 PMCID: PMC9744548 DOI: 10.1002/ggn2.10025] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 03/13/2020] [Accepted: 03/17/2020] [Indexed: 01/11/2023]
Abstract
Advanced age is associated with accumulation of damage and other deleterious changes and a consequential systemic decline of function. This decline affects all organs and systems in an organism, leading to their inadaptability to the environment, and therefore is thought to be inevitable for humans and most animal species. However, in vitro and in vivo application of reprogramming strategies, which convert somatic cells to induced pluripotent stem cells, has demonstrated that the aged cells can be rejuvenated. Moreover, the data and theoretical considerations suggest that reversing the biological age of somatic cells (from old to young) and de-differentiating somatic cells into stem cells represent two distinct processes that take place during rejuvenation, and thus they may be differently targeted. We advance a stemness-function model to explain these data and discuss a possibility of rejuvenation from the perspective of damage accumulation. In turn, this suggests approaches to achieve rejuvenation of cells in vitro and in vivo.
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Affiliation(s)
- Bohan Zhang
- Division of Genetics, Department of Medicine, Brigham and Women's HospitalHarvard Medical SchoolBostonMassachusettsUSA
| | - Vadim N. Gladyshev
- Division of Genetics, Department of Medicine, Brigham and Women's HospitalHarvard Medical SchoolBostonMassachusettsUSA
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28
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Lian J, Yue Y, Yu W, Zhang Y. Immunosenescence: a key player in cancer development. J Hematol Oncol 2020; 13:151. [PMID: 33168037 PMCID: PMC7653700 DOI: 10.1186/s13045-020-00986-z] [Citation(s) in RCA: 275] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 10/28/2020] [Indexed: 12/11/2022] Open
Abstract
Immunosenescence is a process of immune dysfunction that occurs with age and includes remodeling of lymphoid organs, leading to changes in the immune function of the elderly, which is closely related to the development of infections, autoimmune diseases, and malignant tumors. T cell-output decline is an important feature of immunosenescence as well as the production of senescence-associated secretory phenotype, increased glycolysis, and reactive oxygen species. Senescent T cells exhibit abnormal phenotypes, including downregulation of CD27, CD28, and upregulation of CD57, killer cell lectin-like receptor subfamily G, Tim-3, Tight, and cytotoxic T-lymphocyte-associated protein 4, which are tightly related to malignant tumors. The role of immunosenescence in tumors is sophisticated: the many factors involved include cAMP, glucose competition, and oncogenic stress in the tumor microenvironment, which can induce the senescence of T cells, macrophages, natural killer cells, and dendritic cells. Accordingly, these senescent immune cells could also affect tumor progression. In addition, the effect of immunosenescence on the response to immune checkpoint blocking antibody therapy so far is ambiguous due to the low participation of elderly cancer patients in clinical trials. Furthermore, many other senescence-related interventions could be possible with genetic and pharmacological methods, including mTOR inhibition, interleukin-7 recombination, and NAD+ activation. Overall, this review aims to highlight the characteristics of immunosenescence and its impact on malignant tumors and immunotherapy, especially the future directions of tumor treatment through senescence-focused strategies.
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Affiliation(s)
- Jingyao Lian
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, 450052, Henan, China
| | - Ying Yue
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, 450052, Henan, China
- Clinical Laboratory, Henan Medical College Hospital Workers, Zhengzhou, 450000, Henan, China
| | - Weina Yu
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, 450052, Henan, China
| | - Yi Zhang
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China.
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, 450052, Henan, China.
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29
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Schneider A, Saccon TD, Garcia DN, Zanini BM, Isola JVV, Hense JD, Alvarado-Rincón JA, Cavalcante MB, Mason JB, Stout MB, Bartke A, Masternak MM. The Interconnections Between Somatic and Ovarian Aging in Murine Models. J Gerontol A Biol Sci Med Sci 2020; 76:1579-1586. [PMID: 33037434 DOI: 10.1093/gerona/glaa258] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Indexed: 12/12/2022] Open
Abstract
The mammalian female is born with a limited ovarian reserve of primordial follicles. These primordial follicles are slowly activated throughout the reproductive lifecycle, thereby determining lifecycle length. Once primordial follicles are exhausted, women undergo menopause, which is associated with several metabolic perturbations and a higher mortality risk. Long before exhaustion of the reserve, females experience severe declines in fertility and health. As such, significant efforts have been made to unravel the mechanisms that promote ovarian aging and insufficiency. In this review, we explain how long-living murine models can provide insights in the regulation of ovarian aging. There is now overwhelming evidence that most life-span-extending strategies, and long-living mutant models simultaneously delay ovarian aging. Therefore, it appears that the same mechanisms that regulate somatic aging may also be modulating ovarian aging and germ cell exhaustion. We explore several potential contributing mechanisms including insulin resistance, inflammation, and DNA damage-all of which are hallmarks of cellular aging throughout the body including the ovary. These findings are in alignment with the disposable soma theory of aging, which dictates a trade-off between growth, reproduction, and DNA repair. Therefore, delaying ovarian aging will not only increase the fertility window of middle age females, but may also actively prevent menopausal-related decline in systemic health parameters, compressing the period of morbidity in mid-to-late life in females.
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Affiliation(s)
- Augusto Schneider
- Departamento de Nutrição, Faculdade de Nutrição, Universidade Federal de Pelotas, Rio Grande do Sul, Brazil
| | - Tatiana D Saccon
- Departamento de Nutrição, Faculdade de Nutrição, Universidade Federal de Pelotas, Rio Grande do Sul, Brazil
| | - Driele N Garcia
- Departamento de Nutrição, Faculdade de Nutrição, Universidade Federal de Pelotas, Rio Grande do Sul, Brazil
| | - Bianka M Zanini
- Departamento de Nutrição, Faculdade de Nutrição, Universidade Federal de Pelotas, Rio Grande do Sul, Brazil
| | - José V V Isola
- Departamento de Nutrição, Faculdade de Nutrição, Universidade Federal de Pelotas, Rio Grande do Sul, Brazil
| | - Jéssica D Hense
- Departamento de Nutrição, Faculdade de Nutrição, Universidade Federal de Pelotas, Rio Grande do Sul, Brazil
| | - Joao A Alvarado-Rincón
- Departamento de Nutrição, Faculdade de Nutrição, Universidade Federal de Pelotas, Rio Grande do Sul, Brazil
| | | | - Jeffrey B Mason
- Department of Animal, Dairy and Veterinary Sciences, Center for Integrated BioSystems, School of Veterinary Medicine, Utah State University, Logan
| | - Michael B Stout
- Department of Nutritional Sciences, University of Oklahoma Health Sciences Center.,Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center
| | - Andrzej Bartke
- Departments of Internal Medicine and Physiology, Southern Illinois, University School of Medicine, Springfield
| | - Michal M Masternak
- College of Medicine, Burnett School of Biomedical Sciences, University of Central Florida, Orlando
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30
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Qin X, Du D, Chen Q, Wu M, Wu T, Wen J, Jin Y, Zhang J, Wang S. Metformin prevents murine ovarian aging. Aging (Albany NY) 2020; 11:3785-3794. [PMID: 31182682 PMCID: PMC6594816 DOI: 10.18632/aging.102016] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 05/31/2019] [Indexed: 02/07/2023]
Abstract
A number of studies have shown that metformin can delay aging process and extend healthy lifespan in animals. However, its role in female reproductive lifespan is unclear. This study was aimed to explore the potential anti-aging effect of metformin on the ovary and its possible mechanisms. Female C57BL/6 mice of 27-week old were divided into two groups, the control group (CON) and metformin-treated group (MET). CON mice were fed ad libitum, while MET mice were fed on chows supplied with 100mg/kg metformin for half a year. Ovarian reserve and function were assessed by ovarian follicle counts, estrous cycle and sex hormones levels. The expressions of oxidized metabolites, such as 8-hydroxy-2´-deoxyguanosine (8-OHdG), 4-hydroxynonenal (4-HNE), nitrotyrosine (NTY), and ovarian aging associated proteins P16, SIRT1, p-rpS6 and Bcl2 were examined. The MET mice exhibited increased level of serum E2 hormone and higher percentage of regular estrous cycles after 6 months' feeding, compared to the CON mice. The amount of primordial and primary follicles and the expression of SIRT1 were significantly increased, but the levels of P16, 8-OHdG, 4-HNE and p-rpS6 were decreased in the MET mice. These results indicate that metformin can delay ovarian aging process, probably by inducing the expression of SIRT1 and reducing the oxidative damage.
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Affiliation(s)
- Xian Qin
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.,Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Dingfu Du
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Qian Chen
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Meng Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Tong Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Jingyi Wen
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Yan Jin
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Jinjin Zhang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Shixuan Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
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31
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Almendáriz-Palacios C, Gillespie ZE, Janzen M, Martinez V, Bridger JM, Harkness TAA, Mousseau DD, Eskiw CH. The Nuclear Lamina: Protein Accumulation and Disease. Biomedicines 2020; 8:E188. [PMID: 32630170 PMCID: PMC7400325 DOI: 10.3390/biomedicines8070188] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/23/2020] [Accepted: 06/26/2020] [Indexed: 02/06/2023] Open
Abstract
Cellular health is reliant on proteostasis-the maintenance of protein levels regulated through multiple pathways modulating protein synthesis, degradation and clearance. Loss of proteostasis results in serious disease and is associated with aging. One proteinaceous structure underlying the nuclear envelope-the nuclear lamina-coordinates essential processes including DNA repair, genome organization and epigenetic and transcriptional regulation. Loss of proteostasis within the nuclear lamina results in the accumulation of proteins, disrupting these essential functions, either via direct interactions of protein aggregates within the lamina or by altering systems that maintain lamina structure. Here we discuss the links between proteostasis and disease of the nuclear lamina, as well as how manipulating specific proteostatic pathways involved in protein clearance could improve cellular health and prevent/reverse disease.
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Affiliation(s)
- Carla Almendáriz-Palacios
- Department of Food and Bioproduct Sciences, University of Saskatchewan, Saskatoon, SK S7N 5A8, Canada; (C.A.-P.); (V.M.)
| | - Zoe E. Gillespie
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5A8, Canada; (Z.E.G.); (M.J.); (T.A.A.H.)
| | - Matthew Janzen
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5A8, Canada; (Z.E.G.); (M.J.); (T.A.A.H.)
| | - Valeria Martinez
- Department of Food and Bioproduct Sciences, University of Saskatchewan, Saskatoon, SK S7N 5A8, Canada; (C.A.-P.); (V.M.)
| | - Joanna M. Bridger
- Centre for Genome Engineering and Maintenance, College of Health, Life and Medical Sciences, Brunel University London, Kingston Lane, Uxbridge UB8 3PH, UK;
| | - Troy A. A. Harkness
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5A8, Canada; (Z.E.G.); (M.J.); (T.A.A.H.)
| | - Darrell D. Mousseau
- Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, Saskatoon, SK S7N 5A5, Canada;
| | - Christopher H. Eskiw
- Department of Food and Bioproduct Sciences, University of Saskatchewan, Saskatoon, SK S7N 5A8, Canada; (C.A.-P.); (V.M.)
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5A8, Canada; (Z.E.G.); (M.J.); (T.A.A.H.)
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32
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Partridge L, Fuentealba M, Kennedy BK. The quest to slow ageing through drug discovery. Nat Rev Drug Discov 2020; 19:513-532. [DOI: 10.1038/s41573-020-0067-7] [Citation(s) in RCA: 280] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/16/2020] [Indexed: 02/07/2023]
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33
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Skulachev VP, Shilovsky GA, Putyatina TS, Popov NA, Markov AV, Skulachev MV, Sadovnichii VA. Perspectives of Homo sapiens lifespan extension: focus on external or internal resources? Aging (Albany NY) 2020; 12:5566-5584. [PMID: 32229707 PMCID: PMC7138562 DOI: 10.18632/aging.102981] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 03/24/2020] [Indexed: 01/01/2023]
Abstract
Homo sapiens and naked mole rats (Heterocephalus glaber) are vivid examples of social mammals that differ from their relatives in particular by an increased lifespan and a large number of neotenic features. An important fact for biogerontology is that the mortality rate of H. glaber (a maximal lifespan of more than 32 years, which is very large for such a small rodent) negligibly grows with age. The same is true for modern people in developed countries below the age of 60. It is important that the juvenilization of traits that separate humans from chimpanzees evolved over thousands of generations and millions of years. Rapid advances in technology resulted in a sharp increase in the life expectancy of human beings during the past 100 years. Currently, the human life expectancy has exceeded 80 years in developed countries. It cannot be excluded that the potential for increasing life expectancy by an improvement in living conditions will be exhausted after a certain period of time. New types of geroprotectors should be developed that protect not only from chronic phenoptosis gradual poisoning of the body with reactive oxygen species (ROS) but also from acute phenoptosis, where strong increase in the level of ROS immediately kills an already aged individual. Geroprotectors might be another anti-aging strategy along with neoteny (a natural physiological phenomenon) and technical progress.
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Affiliation(s)
- Vladimir P Skulachev
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119991, Russia
| | - Gregory A Shilovsky
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119991, Russia.,Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow 127051, Russia.,Faculty of Biology, Lomonosov Moscow State University, Moscow 119991, Russia
| | - Tatyana S Putyatina
- Faculty of Biology, Lomonosov Moscow State University, Moscow 119991, Russia
| | - Nikita A Popov
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow 119991, Russia
| | - Alexander V Markov
- Faculty of Biology, Lomonosov Moscow State University, Moscow 119991, Russia.,Paleontological Institute, Russian Academy of Sciences, Moscow 117997, Russia
| | - Maxim V Skulachev
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119991, Russia
| | - Victor A Sadovnichii
- Faculty of Mechanics and Mathematics, Lomonosov Moscow State University, Moscow 119991, Russia
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34
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Korean Red Ginseng Plays An Anti-Aging Role by Modulating Expression of Aging-Related Genes and Immune Cell Subsets. Molecules 2020; 25:molecules25071492. [PMID: 32218338 PMCID: PMC7181072 DOI: 10.3390/molecules25071492] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 03/20/2020] [Accepted: 03/25/2020] [Indexed: 12/23/2022] Open
Abstract
Despite previous reports of anti-aging effects of Korean red ginseng (KRG), the underlying mechanisms remain poorly understood. Therefore, this study investigated possible mechanisms of KRG-mediated anti-aging effects in aged mice. KRG significantly inhibited thymic involution in old mice. Interestingly, KRG only increased protein expression, but not mRNA expression, of aging-related genes Lin28a, GDF-11, Sirt1, IL-2, and IL-17 in the thymocytes of old mice. KRG also modulated the population of some types of immune cells in old mice. KRG increased the population of regulatory T cells and interferon-gamma (IFN-γ)-expressing natural killer (NK) cells in the spleen of old mice, but serum levels of regulatory T cell-specific cytokines IL-10 and TGF-β were unaffected. Finally, KRG recovered mRNA expression of Lin28a, GDF-11, and Sirt1 artificially decreased by concanavalin A (Con A) in both thymocytes and splenocytes of old mice without cytotoxicity. These results suggest that KRG exerts anti-aging effects by preventing thymic involution, as well as modulating the expression of aging-related genes and immune cell subsets.
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Drug synergy as a strategy for compression of morbidity in a Caenorhabditis elegans model of Alzheimer's disease. GeroScience 2020; 42:849-856. [PMID: 32088829 DOI: 10.1007/s11357-020-00169-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Accepted: 02/11/2020] [Indexed: 01/12/2023] Open
Abstract
Alzheimer's disease (AD) is the most common cause of dementia worldwide. AD is a multifactorial disease with simultaneous occurrence of several connected pathological processes including mitochondrial dysfunction and impaired proteostasis. Most of these are also implicated in organismal aging per se. The presence of separable pathological conditions poses the opportunity to try combination treatments that target these different processes separately. This approach may provide an effective strategy to target AD; therefore, we investigated whether a combination of metformin (targeting mitochondria and energy metabolism) and lithium (targeting proteostasis) could result in synergistic benefits. In this perspective paper, we looked for benefits in lifespan and healthspan using a transgenic nematode strain, GRU102, which expresses pan-neuronal human amyloid-beta (Aβ). Individually, metformin and lithium extended the lifespan of both non-transgenic GRU101 controls and GRU102. Combination treatment using metformin and lithium did not result in any synergistic increase in GRU102 lifespan, but this treatment did result in a significant compression of morbidity when compared with each individual drug, resulting in relative and absolute extension of healthspan. Despite over-expressing pathogenic human Aβ in their neurons, GRU102 worms treated with the combination treatment enjoyed longer lifespans and significantly compressed morbidity, even compared with untreated non-transgenic animals. These findings suggest combination treatment as a strategy to compress morbidity, and highlight the distinction between healthspan and lifespan.
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Blagosklonny MV. Disease or not, aging is easily treatable. Aging (Albany NY) 2019; 10:3067-3078. [PMID: 30448823 PMCID: PMC6286826 DOI: 10.18632/aging.101647] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Accepted: 11/02/2018] [Indexed: 12/14/2022]
Abstract
Is aging a disease? It does not matter because aging is already treated using a combination of several clinically-available drugs, including rapamycin. Whether aging is a disease depends on arbitrary definitions of both disease and aging. For treatment purposes, aging is a deadly disease (or more generally, pre-disease), despite being a normal continuation of normal organismal growth. It must and, importantly, can be successfully treated, thereby delaying classic age-related diseases such as cancer, cardiovascular and metabolic diseases, and neurodegeneration.
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Gupta V, Crudu A, Matsuoka Y, Ghosh S, Rozot R, Marat X, Jäger S, Kitano H, Breton L. Multi-dimensional computational pipeline for large-scale deep screening of compound effect assessment: an in silico case study on ageing-related compounds. NPJ Syst Biol Appl 2019; 5:42. [PMID: 31798962 PMCID: PMC6879499 DOI: 10.1038/s41540-019-0119-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 09/23/2019] [Indexed: 12/18/2022] Open
Abstract
Designing alternative approaches to efficiently screen chemicals on the efficacy landscape is a challenging yet indispensable task in the current compound profiling methods. Particularly, increasing regulatory restrictions underscore the need to develop advanced computational pipelines for efficacy assessment of chemical compounds as alternative means to reduce and/or replace in vivo experiments. Here, we present an innovative computational pipeline for large-scale assessment of chemical compounds by analysing and clustering chemical compounds on the basis of multiple dimensions-structural similarity, binding profiles and their network effects across pathways and molecular interaction maps-to generate testable hypotheses on the pharmacological landscapes as well as identify potential mechanisms of efficacy on phenomenological processes. Further, we elucidate the application of the pipeline on a screen of anti-ageing-related compounds to cluster the candidates based on their structure, docking profile and network effects on fundamental metabolic/molecular pathways associated with the cell vitality, highlighting emergent insights on compounds activities based on the multi-dimensional deep screen pipeline.
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Affiliation(s)
| | - Alina Crudu
- L’Oréal Research and Innovation, Aulnay-sous-Bois, France
| | | | | | - Roger Rozot
- L’Oréal Research and Innovation, Aulnay-sous-Bois, France
| | - Xavier Marat
- L’Oréal Research and Innovation, Aulnay-sous-Bois, France
| | - Sibylle Jäger
- L’Oréal Research and Innovation, Aulnay-sous-Bois, France
| | - Hiroaki Kitano
- The Systems Biology Institute, Tokyo, Japan
- Okinawa Institute of Science and Technology, Okinawa, Japan
| | - Lionel Breton
- L’Oréal Research and Innovation, Aulnay-sous-Bois, France
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Khorraminejad-Shirazi M, Dorvash M, Estedlal A, Hoveidaei AH, Mazloomrezaei M, Mosaddeghi P. Aging: A cell source limiting factor in tissue engineering. World J Stem Cells 2019; 11:787-802. [PMID: 31692986 PMCID: PMC6828594 DOI: 10.4252/wjsc.v11.i10.787] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 05/03/2019] [Accepted: 09/05/2019] [Indexed: 02/06/2023] Open
Abstract
Tissue engineering has yet to reach its ideal goal, i.e. creating profitable off-the-shelf tissues and organs, designing scaffolds and three-dimensional tissue architectures that can maintain the blood supply, proper biomaterial selection, and identifying the most efficient cell source for use in cell therapy and tissue engineering. These are still the major challenges in this field. Regarding the identification of the most appropriate cell source, aging as a factor that affects both somatic and stem cells and limits their function and applications is a preventable and, at least to some extents, a reversible phenomenon. Here, we reviewed different stem cell types, namely embryonic stem cells, adult stem cells, induced pluripotent stem cells, and genetically modified stem cells, as well as their sources, i.e. autologous, allogeneic, and xenogeneic sources. Afterward, we approached aging by discussing the functional decline of aged stem cells and different intrinsic and extrinsic factors that are involved in stem cell aging including replicative senescence and Hayflick limit, autophagy, epigenetic changes, miRNAs, mTOR and AMPK pathways, and the role of mitochondria in stem cell senescence. Finally, various interventions for rejuvenation and geroprotection of stem cells are discussed. These interventions can be applied in cell therapy and tissue engineering methods to conquer aging as a limiting factor, both in original cell source and in the in vitro proliferated cells.
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Affiliation(s)
- Mohammadhossein Khorraminejad-Shirazi
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran
- Cell and Molecular Medicine Student Research Group, School of Medicine, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran
| | - Mohammadreza Dorvash
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran
- Cell and Molecular Medicine Student Research Group, School of Medicine, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz 7134814336, Iran
| | - Alireza Estedlal
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran
- Cell and Molecular Medicine Student Research Group, School of Medicine, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran
| | - Amir Human Hoveidaei
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran
| | - Mohsen Mazloomrezaei
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran
- Cell and Molecular Medicine Student Research Group, School of Medicine, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran
| | - Pouria Mosaddeghi
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran
- Cell and Molecular Medicine Student Research Group, School of Medicine, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz 7134814336, Iran
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Piccirillo F, Carpenito M, Verolino G, Chello C, Nusca A, Lusini M, Spadaccio C, Nappi F, Di Sciascio G, Nenna A. Changes of the coronary arteries and cardiac microvasculature with aging: Implications for translational research and clinical practice. Mech Ageing Dev 2019; 184:111161. [PMID: 31647940 DOI: 10.1016/j.mad.2019.111161] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 10/09/2019] [Accepted: 10/14/2019] [Indexed: 12/28/2022]
Abstract
Aging results in functional and structural changes in the cardiovascular system, translating into a progressive increase of mechanical vessel stiffness, due to a combination of changes in micro-RNA expression patterns, autophagy, arterial calcification, smooth muscle cell migration and proliferation. The two pivotal mechanisms of aging-related endothelial dysfunction are oxidative stress and inflammation, even in the absence of clinical disease. A comprehensive understanding of the aging process is emerging as a primary concern in literature, as vascular aging has recently become a target for prevention and treatment of cardiovascular disease. Change of life-style, diet, antioxidant regimens, anti-inflammatory treatments, senolytic drugs counteract the pro-aging pathways or target senescent cells modulating their detrimental effects. Such therapies aim to reduce the ineluctable burden of age and contrast aging-associated cardiovascular dysfunction. This narrative review intends to summarize the macrovascular and microvascular changes related with aging, as a better understanding of the pathways leading to arterial aging may contribute to design new mechanism-based therapeutic approaches to attenuate the features of vascular senescence and its clinical impact on the cardiovascular system.
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Affiliation(s)
| | | | | | - Camilla Chello
- Dermatology, Università "La Sapienza" di Roma, Rome, Italy
| | | | - Mario Lusini
- Cardiovascular surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | | | - Francesco Nappi
- Cardiac surgery, Centre Cardiologique du Nord de Saint Denis, Paris, France
| | | | - Antonio Nenna
- Cardiovascular surgery, Università Campus Bio-Medico di Roma, Rome, Italy.
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Blagosklonny MV. Rapamycin for longevity: opinion article. Aging (Albany NY) 2019; 11:8048-8067. [PMID: 31586989 PMCID: PMC6814615 DOI: 10.18632/aging.102355] [Citation(s) in RCA: 133] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 10/03/2019] [Indexed: 12/31/2022]
Abstract
From the dawn of civilization, humanity has dreamed of immortality. So why didn't the discovery of the anti-aging properties of mTOR inhibitors change the world forever? I will discuss several reasons, including fear of the actual and fictional side effects of rapamycin, everolimus and other clinically-approved drugs, arguing that no real side effects preclude their use as anti-aging drugs today. Furthermore, the alternative to the reversible (and avoidable) side effects of rapamycin/everolimus are the irreversible (and inevitable) effects of aging: cancer, stroke, infarction, blindness and premature death. I will also discuss why it is more dangerous not to use anti-aging drugs than to use them and how rapamycin-based drug combinations have already been implemented for potential life extension in humans. If you read this article from the very beginning to its end, you may realize that the time is now.
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Zhao X, Zeng Z, Gaur U, Fang J, Peng T, Li S, Zheng W. Metformin protects PC12 cells and hippocampal neurons from H 2 O 2 -induced oxidative damage through activation of AMPK pathway. J Cell Physiol 2019; 234:16619-16629. [PMID: 30784077 DOI: 10.1002/jcp.28337] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 12/20/2018] [Accepted: 02/01/2019] [Indexed: 01/24/2023]
Abstract
Metformin, a first line anti type 2 diabetes drug, has recently been shown to extend lifespan in various species, and therefore, became the first antiaging drug in clinical trial. Oxidative stress due to excess reactive oxygen species (ROS) is considered to be an important factor in aging and related disease, such as Alzheimer's disease (AD). However, the antioxidative effects of metformin and its underlying mechanisms in neuronal cells is not known. In the present study, we showed that metformin, in clinically relevant concentrations, protected neuronal PC12 cells from H2 O2 -induced cell death. Metformin significantly ameliorated cell death due to H2 O2 insult by restoring abnormal changes in nuclear morphology, intracellular ROS, lactate dehydrogenase, and mitochondrial membrane potential induced by H2 O2 . Hoechst staining assay and flow cytometry analysis revealed that metformin significantly reduced the apoptosis in PC12 cells exposed to H2 O2 . Western blot analysis further demonstrated that metformin stimulated the phosphorylation and activation of AMP-activated protein kinase (AMPK) in PC12 cells, while application of AMPK inhibitor compound C, or knockdown of the expression of AMPK by specific small interfering RNA or short hairpin RNA blocked the protective effect of metformin. Similar results were obtained in primary cultured hippocampal neurons. Taken together, these results indicated that metformin is able to protect neuronal cells from oxidative injury, at least in part, via the activation of AMPK. As metformin is comparatively cheaper with much less side effects in clinic, our findings support its potential to be a drug for prevention and treatment of aging and aging-related diseases.
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Affiliation(s)
- Xia Zhao
- Center of Reproduction, Development & Aging, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Zhiwen Zeng
- Center of Reproduction, Development & Aging, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Uma Gaur
- Center of Reproduction, Development & Aging, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Jiankang Fang
- Center of Reproduction, Development & Aging, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Tangming Peng
- Center of Reproduction, Development & Aging, Faculty of Health Sciences, University of Macau, Taipa, Macau, China.,Department of Neurosurgery, Affiliated Hospital of Southwest Medical University, China
| | - Shuai Li
- Center of Reproduction, Development & Aging, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Wenhua Zheng
- Center of Reproduction, Development & Aging, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
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Zakeri M, Fatemi I, Kaeidi A, Zakeri MA, Hakimizadeh E, Hassanipour M, Rahmani M, Hassanshahi J, Ayoobi F, Allahtavakoli M. Pro-neurocognitive and anti-sarcopenic benefits of one-year metformin therapy in ovariectomized aged mice. Clin Exp Pharmacol Physiol 2019; 46:1133-1140. [PMID: 31357227 DOI: 10.1111/1440-1681.13149] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Revised: 07/18/2019] [Accepted: 07/24/2019] [Indexed: 01/14/2023]
Abstract
Health promotion and healthy nutrition significantly increased life expectancy around the world. Aging is associated with an increase in age-related diseases. The use of metformin (Met) as an anti-aging drug has recently been proposed based on its widespread use in clinical practice. Reports have shown that Met acts as an anti-aging agent. In this study, the effects of long-term, 1 year, Met administration on aging-related behaviors and longevity in ovariectomized mice was studied. Met (1 and 10 mg/kg, daily) was administered orally in ovariectomized mice. The anxiety-like behavior, working memory, and physical strength were measured through elevated plus maze, Y-maze, vertical grid holding, and the obligatory swimming capacity tests. Brains were harvested to measure brain-derived neurotrophic factor (BDNF) level. Also, the Kaplan-Meier survival curves were used to show differences and similarities in survival patterns. Met (10 mg/kg) decreased anxiety-like behaviors as well as increased muscle strength and working memory in the ovariectomized mice. Moreover, Met increased the physical strength and longevity as well as the level of BDNF in the ovariectomized mice. Our results indicate that Met administration can be an effective strategy for having a healthy aging in the absence of female gonadal hormones and reverses deleterious effects of ovariectomy-induced aging possibly through BDNF.
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Affiliation(s)
- Maryam Zakeri
- Student Research Committee, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Iman Fatemi
- Research Center for Tropical and Infectious Diseases, Kerman University of Medical Sciences, Kerman, Iran
| | - Ayat Kaeidi
- Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.,Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mohammad Ali Zakeri
- Student Research Committee, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Elham Hakimizadeh
- Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.,Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mahsa Hassanipour
- Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.,Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mohammadreza Rahmani
- Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.,Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Jalal Hassanshahi
- Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.,Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Fatemeh Ayoobi
- Non-Communicable Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mohammad Allahtavakoli
- Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.,Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
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de Diego I, Peleg S, Fuchs B. The role of lipids in aging-related metabolic changes. Chem Phys Lipids 2019; 222:59-69. [DOI: 10.1016/j.chemphyslip.2019.05.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 05/22/2019] [Accepted: 05/28/2019] [Indexed: 12/30/2022]
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Routy JP, Isnard S, Mehraj V, Ostrowski M, Chomont N, Ancuta P, Ponte R, Planas D, Dupuy FP, Angel JB. Effect of metformin on the size of the HIV reservoir in non-diabetic ART-treated individuals: single-arm non-randomised Lilac pilot study protocol. BMJ Open 2019; 9:e028444. [PMID: 31005944 PMCID: PMC6500211 DOI: 10.1136/bmjopen-2018-028444] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
INTRODUCTION People living with HIV (PLWH) on antiretroviral therapy (ART) do not progress to AIDS. However, they still suffer from an increased risk of inflammation-associated complications. HIV persists in long-lived CD4+ T cells, which form the major viral reservoir. The persistence of this reservoir despite long-term ART is the major hurdle to curing HIV. Importantly, the size of the HIV reservoir is larger in individuals who start ART late in the course of infection and have a low CD4+/CD8+ ratio. HIV reservoir size is also linked to the levels of persistent inflammation on ART. Thus, novel strategies to reduce immune inflammation and improve the host response to control the HIV reservoir would be a valuable addition to current ART. Among the different strategies under investigation is metformin, a widely used antidiabetic drug that was recently shown to modulate T-cell activation and inflammation. Treatment of non-diabetic individuals with metformin controls inflammation by improving glucose metabolism and by regulating intracellular immunometabolic checkpoints such as the adenosin 5 monophosphate activated protein kinase and mammalian target of rapamycin, in association with microbiota modification. METHODS AND ANALYSIS 22 PLWH on ART for more than 3 years, at high risk of inflammation or the development of non-AIDS events (low CD4+/CD8+ ratio) will be recruited in a clinical single-arm pilot study. We will test whether supplementing ART with metformin in non-diabetic HIV-infected individuals can reduce the size of the HIV reservoir as determined by various virological assays. The expected outcome of this study is a reduction in both the size of the HIV reservoir and inflammation following the addition of metformin to ART, thus paving the way towards HIV eradication. ETHICS AND DISSEMINATION Ethical approval: McGill university Health Centre committee number MP-37-2016-2456. Canadian Canadian Institutes of Health Research/Canadian HIV Trials Network (CTN) protocol CTNPT027. Results will be made available through publication in peer-reviewed journals and through the CTN website. TRIAL REGISTRATION NUMBER NCT02659306.
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Affiliation(s)
- Jean-Pierre Routy
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, Quebec, Canada
- Division of Hematology, Department of Medicine, McGill University Health Centre, Montréal, Quebec, Canada
| | - Stéphane Isnard
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, Quebec, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, Quebec, Canada
| | - Vikram Mehraj
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, Quebec, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, Quebec, Canada
| | - Mario Ostrowski
- Immunology, University of Toronto, Toronto, Ontario, Canada
- St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Nicolas Chomont
- Centre de Recherche du CHUM and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada
| | - Petronela Ancuta
- Centre de Recherche du CHUM and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada
| | - Rosalie Ponte
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, Quebec, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, Quebec, Canada
| | - Delphine Planas
- Centre de Recherche du CHUM and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada
| | - Franck P Dupuy
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, Quebec, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, Quebec, Canada
| | - Jonathan B Angel
- The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada
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Abstract
The role of immune system is to protect the organism from the not built-in program-like alterations inside and against the agents penetrating from outside (bacteria, viruses, and protozoa). These functions were developed and formed during the evolution. Considering these functions, the immune system promotes the lengthening of lifespan and helps longevity. However, some immune functions have been conveyed by men to medical tools (e.g., pharmaceuticals, antibiotics, and prevention), especially in our modern age, which help the struggle against microbes, but evolutionarily weaken the immune system. Aging is a gradual slow attrition by autoimmunity, directed by the thymus and regulated by the central nervous system and pineal gland. Considering this, thymus could be a pacemaker of aging. The remodeling of the immune system, which can be observed in elderly people and centenarians, is probably not a cause of aging, but a consequence of it, which helps to suit immunity to the requirements. Oxidative stress also helps the attrition of the immune cells and antioxidants help to prolong lifespan. There are gender differences in the aging of the immune system as well as in the longevity. There is an advantage for women in both cases. This can be explained by hormonal differences (estrogens positively influences both processes); however, social factors are also not excluded. The endocrine disruptor chemicals act similar to estrogens, like stimulating or suppressing immunity and provoking autoimmunity; however, their role in longevity is controversial. There are some drugs (rapamycin, metformin, and selegiline) and antioxidants (as vitamins C and E) that prolong lifespan and also improve immunity. It is difficult to declare that longevity is exclusively dependent on the state of the immune system; however, there is a parallelism between the state of immune system and lifespan. It seems likely that there is not a real decline of immunity during aging, but there is a remodeling of the system according to the claims of senescence. This is manifested in the remaining (sometimes stronger) function of memory cells in contrast to the production and number of the new antigen-reactive naive T-cells.
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Affiliation(s)
- György Csaba
- 1 Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary
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Geagea AG, Rizzo M, Jurjus A, Cappello F, Leone A, Tomasello G, Gracia C, Al Kattar S, Massaad-Massade L, Eid A. A novel therapeutic approach to colorectal cancer in diabetes: role of metformin and rapamycin. Oncotarget 2019; 10:1284-1305. [PMID: 30863490 PMCID: PMC6407684 DOI: 10.18632/oncotarget.26641] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 01/14/2019] [Indexed: 12/28/2022] Open
Abstract
The link between colorectal cancer (CRC), diabetes mellitus (DM) and inflammation is well established, and polytherapy, including rapamycin, has been adopted. This study is a novel approach that aimed at assessing the effect of a combination therapy of metformin and rapamycin on the control or prevention of CRC in diabetic animals, in presence or absence of probiotics. Fifty NOD/SCIDs male mice developed xenograft by inoculating HCT116 cells. They were equally divided into diabetics (induced by Streptozotocin) and non-diabetics. Metformin was given in drinking water, whereas rapamycin was administered via intra-peritoneal injections. Probiotics were added to the double therapy two weeks before the sacrifice. Assessment was performed by clinical observation, histological analysis, Reactive oxygen species (ROS) activities and molecular analysis of Interleukin 3 and 6, Tumor Necrosis Factor alpha, AMP-activated protein Kinase and the mammalian target of rapamycin. Decreases in the level of tumorigenesis resulted, to various extents, with the different treatment regimens. The combination of rapamycin and metformin had no significant result, however, after adding probiotics to the combination, there was a marked delay in tumor formation and reduction of its size, suppression of ROS and a decrease in inflammatory cytokines as well as an inhibition of phosphorylated mTOR. Existing evidence clearly supports the use of rapamycin and metformin especially in the presence of probiotics. It also highlighted the possible mechanism of action of the 2 drugs through AMPK and mTOR signaling pathways and offered preliminary data on the significant role of probiotics in the combination. Further investigation to clarify the exact role of probiotics and decipher in more details the involved pathways is needed.
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Affiliation(s)
- Alice Gerges Geagea
- Department of Internal Medicine, University of Palermo, Palermo, Italy
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Manfredi Rizzo
- Department of Internal Medicine, University of Palermo, Palermo, Italy
| | - Abdo Jurjus
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Francesco Cappello
- Department of Biomedicine, Neurosciences and Advanced Diagnosis, School Of Medicine of Palermo, Palermo, Italy
| | - Angelo Leone
- Department of Biomedicine, Neurosciences and Advanced Diagnosis, School Of Medicine of Palermo, Palermo, Italy
| | - Giovanni Tomasello
- Department of Biomedicine, Neurosciences and Advanced Diagnosis, School Of Medicine of Palermo, Palermo, Italy
| | - Céline Gracia
- Equipe Nouvelles Thérapies Anticancéreuses, UMR8203 CNRS, Gustave Roussy, Villejuif, France
| | - Sahar Al Kattar
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | | | - Assaad Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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Solymár M, Ivic I, Pótó L, Hegyi P, Garami A, Hartmann P, Pétervári E, Czopf L, Hussain A, Gyöngyi Z, Sarlós P, Simon M, Mátrai P, Bérczi B, Balaskó M. Metformin induces significant reduction of body weight, total cholesterol and LDL levels in the elderly - A meta-analysis. PLoS One 2018; 13:e0207947. [PMID: 30475888 PMCID: PMC6258123 DOI: 10.1371/journal.pone.0207947] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 11/08/2018] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Metformin is the first-choice drug for patients with Type 2 diabetes, and this therapy is characterized by being weight neutral. However, in the elderly an additional unintentional weight loss could be considered as an adverse effect of the treatment. OBJECTIVES We aimed to perform a meta-analysis of placebo-controlled studies investigating the body weight changes upon metformin treatment in participants older than 60 years. MATERIALS AND METHODS PubMed, EMBASE and the Cochrane Library were searched. We included at least 12 week-long studies with placebo control where the mean age of the metformin-treated patients was 60 years or older and the body weight changes of the patients were reported. We registered our protocol on PROSPERO (CRD42017055287). RESULTS From the 971 articles identified by the search, 6 randomized placebo-controlled studies (RCTs) were included in the meta-analysis (n = 1541 participants). A raw difference of -2.23 kg (95% CI: -2.84 --1.62 kg) body weight change was detected in the metformin-treated groups as compared with that of the placebo groups (p<0.001). Both total cholesterol (-0.184 mmol/L, p<0.001) and LDL cholesterol levels (-0.182 mmol/L, p<0.001) decreased upon metformin-treatment. CONCLUSIONS Our meta-analysis of RCTs showed a small reduction of body weight together with slight improvement of the blood lipid profile in patients over 60 years. With regard to the risk of unintentional weight loss, metformin seems to be a safe agent in the population of over 60 years. Our results also suggest that metformin treatment may reduce the risk of major coronary events (-4-5%) and all-cause mortality (-2%) in elderly diabetic populations.
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Affiliation(s)
- Margit Solymár
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Ivan Ivic
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - László Pótó
- Institute of Bioanalysis, Medical School, University of Pécs, Pécs, Hungary
| | - Péter Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Hungarian Academy of Sciences—University of Szeged, Momentum Gastroenterology Multidisciplinary Research Group, Szeged, Hungary
- Department of Translational Medicine, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - András Garami
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Petra Hartmann
- Institute of Surgical Research, University of Szeged, Szeged, Hungary
| | - Erika Pétervári
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - László Czopf
- Department of Cardiology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Alizadeh Hussain
- Department of Haematology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Zoltán Gyöngyi
- Department of Public Health Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Patrícia Sarlós
- Department of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Mária Simon
- Department of Psychiatry and Psychotherapy, Medical School, University of Pécs, Pécs, Hungary
| | - Péter Mátrai
- Institute of Bioanalysis, Medical School, University of Pécs, Pécs, Hungary
| | - Bálint Bérczi
- Department of Public Health Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Márta Balaskó
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
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Ren J, Zhang Y. Targeting Autophagy in Aging and Aging-Related Cardiovascular Diseases. Trends Pharmacol Sci 2018; 39:1064-1076. [PMID: 30458935 DOI: 10.1016/j.tips.2018.10.005] [Citation(s) in RCA: 195] [Impact Index Per Article: 27.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2018] [Revised: 09/19/2018] [Accepted: 10/04/2018] [Indexed: 01/19/2023]
Abstract
Aging, an irreversible biological process, serves as an independent risk factor for chronic disease including cancer, pulmonary, neurodegenerative, and cardiovascular diseases. In particular, high morbidity and mortality have been associated with cardiovascular aging, but effective clinical therapeutic remedies are suboptimal for the ever-rising aging population. Recent evidence suggests a unique role for aberrant aggregate clearance and the protein quality control machinery - the process of autophagy - in shortened lifespan, compromised healthspan, and the onset and development of aging-associated cardiovascular diseases. Autophagy degrades and removes long-lived or damaged cellular organelles and proteins, the functions of which decline with advanced aging. Induction of autophagy using rapamycin, resveratrol, nicotinamide derivatives, metformin, urolithin A, or spermidine delays aging, prolongs lifespan, and improves cardiovascular function in aging. Given the ever-rising human lifespan and aging population as well as the prevalence of cardiovascular disease provoked by increased age, it is pertinent to understand the contribution and underlying mechanisms of autophagy and organelle-selective autophagy (e.g., mitophagy) in the regulation of lifespan, healthspan, and cardiovascular aging. Here we dissect the mechanism of action for autophagy failure in aging and discuss the potential rationale of targeting autophagy using pharmacological agents as new avenues in the combating of biological and cardiovascular aging.
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Affiliation(s)
- Jun Ren
- Department of Cardiology, Fudan University Zhongshan Hospital, Shanghai 200032, China; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
| | - Yingmei Zhang
- Department of Cardiology, Fudan University Zhongshan Hospital, Shanghai 200032, China; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
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49
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Metformin: An Old Drug with New Applications. Int J Mol Sci 2018; 19:ijms19102863. [PMID: 30241400 PMCID: PMC6213209 DOI: 10.3390/ijms19102863] [Citation(s) in RCA: 161] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 09/11/2018] [Accepted: 09/17/2018] [Indexed: 12/12/2022] Open
Abstract
Metformin is a biguanide drug that has been used to treat type 2 diabetes mellitus for more than 60 years. The United Kingdom Prospective Diabetic Study (UKPDS) has shown metformin to improve mortality rates in diabetes patients, and recent studies suggest metformin has additional effects in treating cancer, obesity, nonalcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and metabolic syndrome. Metformin has also been shown to alleviate weight gain associated with antipsychotic medication. Metformin has recently been extensively studied and emerging evidence suggests metformin decreases hepatocyte triglyceride accumulation in NAFLD and prevents liver tumorigenesis. Interestingly, studies have also shown metformin reduces visceral fat, suppresses white-adipose-tissue (WAT) extracellular matrix remodeling, and inhibits obesity-induced inflammation. However, clinical evidence for using metformin to treat NAFLD, cancer, metabolic syndrome, or to prevent hepatocellular carcinoma in NAFLD patients is lacking. This review therefore addresses the potential beneficial effects of metformin on NAFLD, its role in protecting against cardiac ischemia–reperfusion (I/R) injury, atherosclerosis, glucotoxicity, and lipotoxicity induced oxidative and ER stress in pancreatic β-cell dysfunction, as well as its underlying molecular mechanisms of action.
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50
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Liu W, Zhang L, Xuan K, Hu C, Liu S, Liao L, Li B, Jin F, Shi S, Jin Y. Alpl prevents bone ageing sensitivity by specifically regulating senescence and differentiation in mesenchymal stem cells. Bone Res 2018; 6:27. [PMID: 30210899 PMCID: PMC6131243 DOI: 10.1038/s41413-018-0029-4] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 06/16/2018] [Accepted: 07/09/2018] [Indexed: 12/21/2022] Open
Abstract
Mutations in the liver/bone/kidney alkaline phosphatase (Alpl) gene cause hypophosphatasia (HPP) and early-onset bone dysplasia, suggesting that this gene is a key factor in human bone development. However, how and where Alpl acts in bone ageing is largely unknown. Here, we determined that ablation of Alpl induces prototypical premature bone ageing characteristics, including bone mass loss and marrow fat gain coupled with elevated expression of p16INK4A (p16) and p53 due to senescence and impaired differentiation in mesenchymal stem cells (MSCs). Mechanistically, Alpl deficiency in MSCs enhances ATP release and reduces ATP hydrolysis. Then, the excessive extracellular ATP is, in turn, internalized by MSCs and causes an elevation in the intracellular ATP level, which consequently inactivates the AMPKα pathway and contributes to the cell fate switch of MSCs. Reactivating AMPKα by metformin treatment successfully prevents premature bone ageing in Alpl+/- mice by improving the function of endogenous MSCs. These results identify a previously unknown role of Alpl in the regulation of ATP-mediated AMPKα alterations that maintain MSC stemness and prevent bone ageing and show that metformin offers a potential therapeutic option.
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Affiliation(s)
- Wenjia Liu
- MS-State Key Laboratory & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi’an, China
- Xi’an Institute of Tissue Engineering and Regenerative Medicine, Xi’an, China
| | - Liqiang Zhang
- MS-State Key Laboratory & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi’an, China
- Xi’an Institute of Tissue Engineering and Regenerative Medicine, Xi’an, China
| | - Kun Xuan
- MS-State Key Laboratory & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi’an, China
| | - Chenghu Hu
- Xi’an Institute of Tissue Engineering and Regenerative Medicine, Xi’an, China
| | - Shiyu Liu
- MS-State Key Laboratory & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi’an, China
| | - Li Liao
- Xi’an Institute of Tissue Engineering and Regenerative Medicine, Xi’an, China
| | - Bei Li
- MS-State Key Laboratory & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi’an, China
| | - Fang Jin
- MS-State Key Laboratory & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi’an, China
| | - Songtao Shi
- Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA USA
| | - Yan Jin
- MS-State Key Laboratory & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi’an, China
- Xi’an Institute of Tissue Engineering and Regenerative Medicine, Xi’an, China
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