|
1
|
Wang J, Shao F, Yu QX, Ye L, Wusiman D, Wu R, Tuo Z, Wang Z, Li D, Cho WC, Wei W, Feng D. The Common Hallmarks and Interconnected Pathways of Aging, Circadian Rhythms, and Cancer: Implications for Therapeutic Strategies. RESEARCH (WASHINGTON, D.C.) 2025; 8:0612. [PMID: 40046513 PMCID: PMC11880593 DOI: 10.34133/research.0612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 01/14/2025] [Accepted: 01/24/2025] [Indexed: 03/17/2025]
Abstract
The intricate relationship between cancer, circadian rhythms, and aging is increasingly recognized as a critical factor in understanding the mechanisms underlying tumorigenesis and cancer progression. Aging is a well-established primary risk factor for cancer, while disruptions in circadian rhythms are intricately associated with the tumorigenesis and progression of various tumors. Moreover, aging itself disrupts circadian rhythms, leading to physiological changes that may accelerate cancer development. Despite these connections, the specific interplay between these processes and their collective impact on cancer remains inadequately explored in the literature. In this review, we systematically explore the physiological mechanisms of circadian rhythms and their influence on cancer development. We discuss how core circadian genes impact tumor risk and prognosis, highlighting the shared hallmarks of cancer and aging such as genomic instability, cellular senescence, and chronic inflammation. Furthermore, we examine the interplay between circadian rhythms and aging, focusing on how this crosstalk contributes to tumorigenesis, tumor proliferation, and apoptosis, as well as the impact on cellular metabolism and genomic stability. By elucidating the common pathways linking aging, circadian rhythms, and cancer, this review provides new insights into the pathophysiology of cancer and identifies potential therapeutic strategies. We propose that targeting the circadian regulation of cancer hallmarks could pave the way for novel treatments, including chronotherapy and antiaging interventions, which may offer important benefits in the clinical management of cancer.
Collapse
Affiliation(s)
- Jie Wang
- Department of Urology, Institute of Urology, West China Hospital,
Sichuan University, Chengdu 610041, China
| | - Fanglin Shao
- Department of Rehabilitation,
The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Qing Xin Yu
- Department of Pathology,
Ningbo Clinical Pathology Diagnosis Center, Ningbo, Zhejiang 315211, China
- Department of Pathology,
Ningbo Medical Centre Lihuili Hospital, Ningbo, Zhejiang 315040, China
| | - Luxia Ye
- Department of Public Research Platform,
Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Dilinaer Wusiman
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA
- Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47906, USA
| | - Ruicheng Wu
- Department of Urology, Institute of Urology, West China Hospital,
Sichuan University, Chengdu 610041, China
| | - Zhouting Tuo
- Department of Urological Surgery, Daping Hospital, Army Medical Center of PLA,
Army Medical University, Chongqing, China
| | - Zhipeng Wang
- Department of Urology, Sichuan Provincial People’s Hospital,
University of Electronic Science and Technology of China, Chengdu, China
| | - Dengxiong Li
- Department of Urology, Institute of Urology, West China Hospital,
Sichuan University, Chengdu 610041, China
| | - William C. Cho
- Department of Clinical Oncology,
Queen Elizabeth Hospital, Hong Kong SAR, China
| | - Wuran Wei
- Department of Urology, Institute of Urology, West China Hospital,
Sichuan University, Chengdu 610041, China
| | - Dechao Feng
- Department of Urology, Institute of Urology, West China Hospital,
Sichuan University, Chengdu 610041, China
- Division of Surgery and Interventional Science,
University College London, London W1W 7TS, UK
| |
Collapse
|
|
2
|
Berk Ş, Cetin A, Özdemir ÖÜ, Pektaş AN, Yurtcu N, Dastan SD. The combination of metformin and high glucose increased longevity of Caenorhabditis elegans a DAF-16/FOXO-independent manner: cancer/diabetic model via C. elegans. Front Endocrinol (Lausanne) 2024; 15:1435098. [PMID: 39558974 PMCID: PMC11570278 DOI: 10.3389/fendo.2024.1435098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Accepted: 10/16/2024] [Indexed: 11/20/2024] Open
Abstract
Introduction Sedentary lifestyles and diets with high glycemic indexes are considered to be contributing factors to the development of obesity, type 2 diabetes in humans. Metformin, a biguanide medication commonly used to treat type 2 diabetes, has been observed to be associated with longevity; however, the molecular mechanisms underlying this observation are still unknown. Methods The effects of metformin and high glucose, which have important roles in aging-related disease such as diabetes and cancer, were studied in lin-35 worms because they are associated with cancer-associated pRb function in mammals and have a tumour suppressor property. Results and Discussion According to our results, the negative effect of high glucose on egg production of lin-35 worms was greater than that of N2 worms. High glucose shortened lifespan and increased body length and width in individuals of both strains. Metformin treatment alone extended the lifespan of N2 and lin-35 worms by reducing fertilization efficiency. However, when metformin was administered in the presence of high glucose, the lifespan of lin-35 worms was clearly longer compared to N2 worms. Additionally, we conclude that glucose and metformin in lin35 worms can extend life expectancy through a DAF-16/FOXO-independent mechanism. Furthermore, the results of this study will provide a new perspective on extending mammalian lifespan through the model organism C. elegans.
Collapse
Affiliation(s)
- Şeyda Berk
- Department of Molecular Biology and Genetics, Faculty of Science, Sivas Cumhuriyet University, Sivas, Türkiye
- Advanced Technology Research and Application Center (CUTAM), Sivas Cumhuriyet University, Sivas, Türkiye
| | - Ali Cetin
- Department of Obstetrics and Gynecology, Haseki Training and Research Hospital Affiliated with the University of Health Sciences, Istanbul, Türkiye
| | - Özgür Ülkü Özdemir
- Department of Molecular Biology and Genetics, Faculty of Science, Sivas Cumhuriyet University, Sivas, Türkiye
| | - Ayşe Nur Pektaş
- Advanced Technology Research and Application Center (CUTAM), Sivas Cumhuriyet University, Sivas, Türkiye
| | - Nazan Yurtcu
- Department of Obstetrics and Gynecology, Faculty of Medicine, Sivas Cumhuriyet University, Sivas, Türkiye
| | - Sevgi Durna Dastan
- Department of Biology, Faculty of Science, Sivas Cumhuriyet University, Sivas, Türkiye
| |
Collapse
|
|
3
|
Schmidt K, Thatcher A, Grobe A, Broussard P, Hicks L, Gu H, Ellies LG, Sears DD, Kalachev L, Kroll E. The combined treatment with ketogenic diet and metformin slows tumor growth in two mouse models of triple negative breast cancer. TRANSLATIONAL MEDICINE COMMUNICATIONS 2024; 9:21. [PMID: 39574543 PMCID: PMC11580796 DOI: 10.1186/s41231-024-00178-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 05/22/2024] [Indexed: 11/24/2024]
Abstract
Background Many tumors contain hypoxic microenvironments caused by inefficient tumor vascularization. Hypoxic tumors have been shown to resist conventional cancer therapies. Hypoxic cancer cells rely on glucose to meet their energetic and anabolic needs to fuel uncontrolled proliferation and metastasis. This glucose dependency is linked to a metabolic shift in response to hypoxic conditions. Methods To leverage the glucose dependency of hypoxic tumor cells, we assessed the effects of a mild reduction in systemic glucose by controlling both dietary carbohydrates with a ketogenic diet and endogenous glucose production by using metformin on two mouse models of triple-negative breast cancer (TNBC). Results Here, we showed that animals with TNBC treated with the combination regimen of ketogenic diet and metformin (a) had their tumor burden lowered by two-thirds, (b) displayed 38% slower tumor growth, and (c) showed 36% longer latency, compared to the animals treated with a ketogenic diet or metformin alone. As a result, lowering systemic glucose by this combined dietary and pharmacologic approach improved overall survival in our mouse TNBC models by 31 days, approximately equivalent to 3 years of life extension in human terms. Conclusion This preclinical study demonstrates that reducing systemic glucose by combining a ketogenic diet and metformin significantly inhibits tumor proliferation and increases overall survival. Our findings suggest a possible treatment for a broad range of hypoxic and glycolytic tumor types that can augment existing treatment options to improve patient outcomes.
Collapse
Affiliation(s)
- Karen Schmidt
- Division of Biological Sciences, University of Montana, Missoula, MT, USA
| | - Amber Thatcher
- Division of Biological Sciences, University of Montana, Missoula, MT, USA
| | - Albert Grobe
- Silverlake Research Corporation, Missoula, MT, USA
| | - Pamela Broussard
- College of Humanities and Sciences, University of Montana, Missoula, MT, USA
| | - Linda Hicks
- College of Humanities and Sciences, University of Montana, Missoula, MT, USA
| | - Haiwei Gu
- College of Health Solutions, Arizona State University, Phoenix, AZ, USA
| | - Lesley G Ellies
- Department of Pathology, University of California San Diego, San Diego, CA, USA
| | - Dorothy D. Sears
- College of Health Solutions, Arizona State University, Phoenix, AZ, USA
| | - Leonid Kalachev
- Department of Mathematical Sciences, University of Montana, Missoula, MT, USA
| | - Eugene Kroll
- Division of Biological Sciences, University of Montana, Missoula, MT, USA
- Present address: Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan
| |
Collapse
|
|
4
|
Schmidt K, Thatcher A, Grobe A, Hicks L, Gu H, Sears DD, Ellies LG, Kalachev L, Kroll E. The Combined Treatment with Ketogenic Diet and Metformin Slows Tumor Growth in Two Mouse Models of Triple Negative Breast Cancer. RESEARCH SQUARE 2023:rs.3.rs-3664129. [PMID: 38196628 PMCID: PMC10775859 DOI: 10.21203/rs.3.rs-3664129/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2024]
Abstract
BACKGROUND Many tumors contain hypoxic microenvironments caused by inefficient tumor vascularization. Hypoxic tumors have been shown to resist conventional cancer therapies. Hypoxic cancer cells rely on glucose to meet their energetic and anabolic needs to fuel uncontrolled proliferation and metastasis. This glucose dependency is linked to a metabolic shift in response to hypoxic conditions. METHODS To leverage the glucose dependency of hypoxic tumor cells, we assessed the effects of a controlled reduction in systemic glucose by combining dietary carbohydrate restriction, using a ketogenic diet, with gluconeogenesis inhibition, using metformin, on two mouse models of triple-negative breast cancer (TNBC). RESULTS We confirmed that MET - 1 breast cancer cells require abnormally high glucose concentrations to survive in a hypoxic environment in vitro. Then, we showed that, compared to a ketogenic diet or metformin alone, animals treated with the combination regimen showed significantly lower tumor burden, higher tumor latency and slower tumor growth. As a result, lowering systemic glucose by this combined dietary and pharmacologic approach improved overall survival in our mouse model by 31 days, which is approximately equivalent to 3 human years. CONCLUSION This is the first preclinical study to demonstrate that reducing systemic glucose by combining a ketogenic diet and metformin significantly inhibits tumor proliferation and increases overall survival. Our findings suggest a possible treatment for a broad range of hypoxic and glycolytic tumor types, one that can also augment existing treatment options to improve patient outcomes.
Collapse
Affiliation(s)
- Karen Schmidt
- University of Montana Division of Biological Sciences
| | | | | | - Linda Hicks
- University of Montana Division of Biological Sciences
| | - Haiwei Gu
- Arizona State University School of Life Sciences
| | | | | | | | - Eugene Kroll
- University of Montana Missoula: University of Montana
| |
Collapse
|
|
5
|
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: 8] [Impact Index Per Article: 4.0] [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.
Collapse
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
| |
Collapse
|
|
6
|
Dutta S, Shah RB, Singhal S, Dutta SB, Bansal S, Sinha S, Haque M. Metformin: A Review of Potential Mechanism and Therapeutic Utility Beyond Diabetes. Drug Des Devel Ther 2023; 17:1907-1932. [PMID: 37397787 PMCID: PMC10312383 DOI: 10.2147/dddt.s409373] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 06/10/2023] [Indexed: 07/04/2023] Open
Abstract
Metformin has been designated as one of the most crucial first-line therapeutic agents in the management of type 2 diabetes mellitus. Primarily being an antihyperglycemic agent, metformin also has a plethora of pleiotropic effects on various systems and processes. It acts majorly by activating AMPK (Adenosine Monophosphate-Activated Protein Kinase) in the cells and reducing glucose output from the liver. It also decreases advanced glycation end products and reactive oxygen species production in the endothelium apart from regulating the glucose and lipid metabolism in the cardiomyocytes, hence minimizing the cardiovascular risks. Its anticancer, antiproliferative and apoptosis-inducing effects on malignant cells might prove instrumental in the malignancy of organs like the breast, kidney, brain, ovary, lung, and endometrium. Preclinical studies have also shown some evidence of metformin's neuroprotective role in Parkinson's disease, Alzheimer's disease, multiple sclerosis and Huntington's disease. Metformin exerts its pleiotropic effects through varied pathways of intracellular signalling and exact mechanism in the majority of them remains yet to be clearly defined. This article has extensively reviewed the therapeutic benefits of metformin and the details of its mechanism for a molecule of boon in various conditions like diabetes, prediabetes, obesity, polycystic ovarian disease, metabolic derangement in HIV, various cancers and aging.
Collapse
Affiliation(s)
- Siddhartha Dutta
- Department of Pharmacology, All India Institute of Medical Sciences, Rajkot, Gujarat, India
| | - Rima B Shah
- Department of Pharmacology, All India Institute of Medical Sciences, Rajkot, Gujarat, India
| | - Shubha Singhal
- Department of Pharmacology, All India Institute of Medical Sciences, Rajkot, Gujarat, India
| | - Sudeshna Banerjee Dutta
- Department of Medical Surgical Nursing, Shri Anand Institute of Nursing, Rajkot, Gujarat, 360005, India
| | - Sumit Bansal
- Department of Anaesthesiology, All India Institute of Medical Sciences, Rajkot, Gujarat, India
| | - Susmita Sinha
- Department of Physiology, Khulna City Medical College and Hospital, Khulna, Bangladesh
| | - Mainul Haque
- Unit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (National Defence University of Malaysia), Kuala Lumpur, 57000, Malaysia
| |
Collapse
|
|
7
|
Keshavarz M, Xie K, Bano D, Ehninger D. Aging - what it is and how to measure it. Mech Ageing Dev 2023:111837. [PMID: 37302556 DOI: 10.1016/j.mad.2023.111837] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/27/2023] [Accepted: 06/08/2023] [Indexed: 06/13/2023]
Abstract
The current understanding of the biology of aging is largely based on research aimed at identifying factors that influence lifespan. However, lifespan as a sole proxy measure of aging has limitations because it can be influenced by specific pathologies (not generalized physiological deterioration in old age). Hence, there is a great need to discuss and design experimental approaches that are well-suited for studies targeting the biology of aging, rather than the biology of specific pathologies that restrict the lifespan of a given species. For this purpose, we here review various perspectives on aging, discuss agreement and disagreement among researchers on the definition of aging, and show that while slightly different aspects are emphasized, a widely accepted feature, shared across many definitions, is that aging is accompanied by phenotypic changes that occur in a population over the course of an average lifespan. We then discuss experimental approaches that are in line with these considerations, including multidimensional analytical frameworks as well as designs that facilitate the proper assessment of intervention effects on aging rate. The proposed framework can guide discovery approaches to aging mechanisms in all key model organisms (e.g., mouse, fish models, D. melanogaster, C. elegans) as well as in humans.
Collapse
Affiliation(s)
- Maryam Keshavarz
- Translational Biogerontology Lab, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127 Bonn, Germany
| | - Kan Xie
- Translational Biogerontology Lab, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127 Bonn, Germany
| | - Daniele Bano
- Aging and Neurodegeneration Lab, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127 Bonn, Germany
| | - Dan Ehninger
- Translational Biogerontology Lab, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127 Bonn, Germany.
| |
Collapse
|
|
8
|
Targeting the "hallmarks of aging" to slow aging and treat age-related disease: fact or fiction? Mol Psychiatry 2023; 28:242-255. [PMID: 35840801 PMCID: PMC9812785 DOI: 10.1038/s41380-022-01680-x] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 06/20/2022] [Accepted: 06/27/2022] [Indexed: 01/09/2023]
Abstract
Aging is a major risk factor for a number of chronic diseases, including neurodegenerative and cerebrovascular disorders. Aging processes have therefore been discussed as potential targets for the development of novel and broadly effective preventatives or therapeutics for age-related diseases, including those affecting the brain. Mechanisms thought to contribute to aging have been summarized under the term the "hallmarks of aging" and include a loss of proteostasis, mitochondrial dysfunction, altered nutrient sensing, telomere attrition, genomic instability, cellular senescence, stem cell exhaustion, epigenetic alterations and altered intercellular communication. We here examine key claims about the "hallmarks of aging". Our analysis reveals important weaknesses that preclude strong and definitive conclusions concerning a possible role of these processes in shaping organismal aging rate. Significant ambiguity arises from the overreliance on lifespan as a proxy marker for aging, the use of models with unclear relevance for organismal aging, and the use of study designs that do not allow to properly estimate intervention effects on aging rate. We also discuss future research directions that should be taken to clarify if and to what extent putative aging regulators do in fact interact with aging. These include multidimensional analytical frameworks as well as designs that facilitate the proper assessment of intervention effects on aging rate.
Collapse
|
|
9
|
Xia J, Chen J, Vashisth MK, Ge Y, Dai Q, He S, Shi YL, Wang XB. Metformin ameliorates 5-fluorouracil-induced intestinal injury by inhibiting cellular senescence, inflammation, and oxidative stress. Int Immunopharmacol 2022; 113:109342. [DOI: 10.1016/j.intimp.2022.109342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 09/30/2022] [Accepted: 10/09/2022] [Indexed: 11/05/2022]
|
|
10
|
Therapeutic Antiaging Strategies. Biomedicines 2022; 10:biomedicines10102515. [PMID: 36289777 PMCID: PMC9599338 DOI: 10.3390/biomedicines10102515] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 09/21/2022] [Accepted: 09/24/2022] [Indexed: 11/17/2022] Open
Abstract
Aging constitutes progressive physiological changes in an organism. These changes alter the normal biological functions, such as the ability to manage metabolic stress, and eventually lead to cellular senescence. The process itself is characterized by nine hallmarks: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. These hallmarks are risk factors for pathologies, such as cardiovascular diseases, neurodegenerative diseases, and cancer. Emerging evidence has been focused on examining the genetic pathways and biological processes in organisms surrounding these nine hallmarks. From here, the therapeutic approaches can be addressed in hopes of slowing the progression of aging. In this review, data have been collected on the hallmarks and their relative contributions to aging and supplemented with in vitro and in vivo antiaging research experiments. It is the intention of this article to highlight the most important antiaging strategies that researchers have proposed, including preventive measures, systemic therapeutic agents, and invasive procedures, that will promote healthy aging and increase human life expectancy with decreased side effects.
Collapse
|
|
11
|
Nikitchenko YV, Klochkov VK, Kavok NS, Karpenko NA, Nikitchenko IV, Yefimova SL, Bozhkov AI. Comparative Studies of Orthovanadate Nanoparticles and Metformin on Life Quality and Survival of Senile Wistar Rats. Biol Trace Elem Res 2022; 200:1237-1247. [PMID: 33900529 DOI: 10.1007/s12011-021-02734-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 04/19/2021] [Indexed: 12/16/2022]
Abstract
Effect of prolong use of orthovanadate nanoparticles (GdVO4/Eu3+ NPs (8 × 25 nm)) on life quality and survival of male Wistar rats on the late stage of ontogenesis (from 23 months to the end of life) has been investigated. Multi-parametric assessment of orthovanadate NPs influences against metformin (Met) which is a well-known calorie restriction mimetic (CR-mimetic) has been completed. The quality of life was assessed by taking into account age-related hallmarks-phenotype and some physiological parameters (condition of the coat, body weight, concentration of thyroxine, rectal temperature) as well as indicators of the pro-oxidant/antioxidant balance of blood and liver (the content of lipid hydroperoxides; aconitase, glutathione peroxidase, glutathione reductase, glutaredoxin activity, and activity of NADP+-dehydrogenases (DG) (glucose-6-phosphate DG, malate DG, and isocitrate DG)) in aging animals. Kaplan-Meier curve and Gehan tests with Yates' correction were performed for the survival analysis. It has been found that long-term use of GdVO4/Eu3+ NPs (0.25-0.30 mg/kg/day), as well as Met (100-110 mg/kg/day) with drinking water led to reliable improvement of physiological parameters and normalization of the pro-oxidant/antioxidant balance in the liver and blood of experimental animals. A significant increase in the survival rate of aging rats was observed; the apparent median survival for control rats was 900 days, while for experimental rats, 1010 and 990 days for GdVO4/Eu3+ NPs and Met, respectively. In general, the data obtained demonstrate the ability of GdVO4/Eu3+ NPs and CR-mimetic-Met to improve the quality of life and increase the survival of an elderly organism.
Collapse
Affiliation(s)
- Yuri V Nikitchenko
- Karazin Kharkiv National University, 4 Svobody Sq., Kharkiv, 61022, Ukraine
| | - Vladimir K Klochkov
- Institute for Scintillation Materials, National Academy of Sciences of Ukraine, 60 Nauky Ave, Kharkiv, 61072, Ukraine
| | - Nataliya S Kavok
- Institute for Scintillation Materials, National Academy of Sciences of Ukraine, 60 Nauky Ave, Kharkiv, 61072, Ukraine.
| | - Nina A Karpenko
- Institute for Scintillation Materials, National Academy of Sciences of Ukraine, 60 Nauky Ave, Kharkiv, 61072, Ukraine
| | | | - Svetlana L Yefimova
- Institute for Scintillation Materials, National Academy of Sciences of Ukraine, 60 Nauky Ave, Kharkiv, 61072, Ukraine
| | - Anatoly I Bozhkov
- Karazin Kharkiv National University, 4 Svobody Sq., Kharkiv, 61022, Ukraine
| |
Collapse
|
|
12
|
Kim CK, Sachdev PS, Braidy N. Recent Neurotherapeutic Strategies to Promote Healthy Brain Aging: Are we there yet? Aging Dis 2022; 13:175-214. [PMID: 35111369 PMCID: PMC8782556 DOI: 10.14336/ad.2021.0705] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 07/05/2021] [Indexed: 12/21/2022] Open
Abstract
Owing to the global exponential increase in population ageing, there is an urgent unmet need to develop reliable strategies to slow down and delay the ageing process. Age-related neurodegenerative diseases are among the main causes of morbidity and mortality in our contemporary society and represent a major socio-economic burden. There are several controversial factors that are thought to play a causal role in brain ageing which are continuously being examined in experimental models. Among them are oxidative stress and brain inflammation which are empirical to brain ageing. Although some candidate drugs have been developed which reduce the ageing phenotype, their clinical translation is limited. There are several strategies currently in development to improve brain ageing. These include strategies such as caloric restriction, ketogenic diet, promotion of cellular nicotinamide adenine dinucleotide (NAD+) levels, removal of senescent cells, 'young blood' transfusions, enhancement of adult neurogenesis, stem cell therapy, vascular risk reduction, and non-pharmacological lifestyle strategies. Several studies have shown that these strategies can not only improve brain ageing by attenuating age-related neurodegenerative disease mechanisms, but also maintain cognitive function in a variety of pre-clinical experimental murine models. However, clinical evidence is limited and many of these strategies are awaiting findings from large-scale clinical trials which are nascent in the current literature. Further studies are needed to determine their long-term efficacy and lack of adverse effects in various tissues and organs to gain a greater understanding of their potential beneficial effects on brain ageing and health span in humans.
Collapse
Affiliation(s)
- Chul-Kyu Kim
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
| | - Perminder S Sachdev
- Neuropsychiatric Institute, Euroa Centre, Prince of Wales Hospital, Sydney, Australia
| | - Nady Braidy
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
| |
Collapse
|
|
13
|
Dołowy M, Jampilek J, Bober-Majnusz K. A Comparative Study of the Lipophilicity of Metformin and Phenformin. Molecules 2021; 26:molecules26216613. [PMID: 34771022 PMCID: PMC8588420 DOI: 10.3390/molecules26216613] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 11/16/2022] Open
Abstract
The results presented in this paper confirm the beneficial role of an easy-to-use and low-cost thin-layer chromatography (TLC) technique for describing the retention behavior and the experimental lipophilicity parameter of two biguanide derivatives, metformin and phenformin, in both normal-phase (NP) and reversed-phase (RP) TLC systems. The retention parameters (RF, RM) obtained under different chromatographic conditions, i.e., various stationary and mobile phases in the NP-TLC and RP-TLC systems, were used to determine the lipophilicity parameter (RMW) of metformin and phenformin. This study confirms the poor lipophilicity of both metformin and phenformin. It can be stated that the optimization of chromatographic conditions, i.e., the kind of stationary phase and the composition of mobile phase, was needed to obtain the reliable value of the chromatographic lipophilicity parameter (RMW) in this study. The fewer differences in the RMW values of both biguanide derivatives were ensured by the RP-TLC system composed of RP2, RP18, and RP18W plates and the mixture composed of methanol, propan-1-ol, and acetonitrile as an organic modifier compared to the NP-TLC analysis. The new calculation procedures for logP of drugs based on topological indices 0χν, 0χ, 1χν, M, and Mν may be a certain alternative to other algorithms as well as the TLC procedure performed under optimized chromatographic conditions. The knowledge of different lipophilicity parameters of the studied biguanides can be useful in the future design of novel and more therapeutically effective metformin and phenformin formulations for antidiabetic and possible anticancer treatment. Moreover, the topological indices presented in this work may be further used in the QSAR study of the examined biguanides.
Collapse
Affiliation(s)
- Małgorzata Dołowy
- Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Jagiellonska 4, 41-200 Sosnowiec, Poland;
- Correspondence: (M.D.); (J.J.)
| | - Josef Jampilek
- Department of Analytical Chemistry, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, 842 15 Bratislava, Slovakia
- Correspondence: (M.D.); (J.J.)
| | - Katarzyna Bober-Majnusz
- Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Jagiellonska 4, 41-200 Sosnowiec, Poland;
| |
Collapse
|
|
14
|
Talib WH, Mahmod AI, Abuarab SF, Hasen E, Munaim AA, Haif SK, Ayyash AM, Khater S, AL-Yasari IH, Kury LTA. Diabetes and Cancer: Metabolic Association, Therapeutic Challenges, and the Role of Natural Products. Molecules 2021; 26:2179. [PMID: 33920079 PMCID: PMC8070467 DOI: 10.3390/molecules26082179] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 04/02/2021] [Accepted: 04/06/2021] [Indexed: 02/06/2023] Open
Abstract
Cancer is considered the second leading cause of death worldwide and in 2018 it was responsible for approximately 9.6 million deaths. Globally, about one in six deaths are caused by cancer. A strong correlation was found between diabetes mellitus and carcinogenesis with the most evident correlation was with type 2 diabetes mellitus (T2DM). Research has proven that elevated blood glucose levels take part in cell proliferation and cancer cell progression. However, limited studies were conducted to evaluate the efficiency of conventional therapies in diabetic cancer patients. In this review, the correlation between cancer and diabetes will be discussed and the mechanisms by which the two diseases interact with each other, as well as the therapeutics challenges in treating patients with diabetes and cancer with possible solutions to overcome these challenges. Natural products targeting both diseases were discussed with detailed mechanisms of action. This review will provide a solid base for researchers and physicians to test natural products as adjuvant alternative therapies to treat cancer in diabetic patients.
Collapse
Affiliation(s)
- Wamidh H. Talib
- Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan; (A.I.M.); (S.F.A.); (E.H.); (A.A.M.); (S.K.H.); (A.M.A.); (S.K.)
| | - Asma Ismail Mahmod
- Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan; (A.I.M.); (S.F.A.); (E.H.); (A.A.M.); (S.K.H.); (A.M.A.); (S.K.)
| | - Sara Feras. Abuarab
- Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan; (A.I.M.); (S.F.A.); (E.H.); (A.A.M.); (S.K.H.); (A.M.A.); (S.K.)
| | - Eliza Hasen
- Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan; (A.I.M.); (S.F.A.); (E.H.); (A.A.M.); (S.K.H.); (A.M.A.); (S.K.)
| | - Amer A. Munaim
- Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan; (A.I.M.); (S.F.A.); (E.H.); (A.A.M.); (S.K.H.); (A.M.A.); (S.K.)
| | - Shatha Khaled Haif
- Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan; (A.I.M.); (S.F.A.); (E.H.); (A.A.M.); (S.K.H.); (A.M.A.); (S.K.)
| | - Amani Marwan Ayyash
- Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan; (A.I.M.); (S.F.A.); (E.H.); (A.A.M.); (S.K.H.); (A.M.A.); (S.K.)
| | - Samar Khater
- Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan; (A.I.M.); (S.F.A.); (E.H.); (A.A.M.); (S.K.H.); (A.M.A.); (S.K.)
| | - Intisar Hadi AL-Yasari
- Department of Genetic Engineering, College of Biotechnology, Al-Qasim Green University, Babylon 00964, Iraq;
| | - Lina T. Al Kury
- Department of Health Sciences, College of Natural and Health Sciences, Zayed University, Abu Dhabi 144534, United Arab Emirates;
| |
Collapse
|
|
15
|
Mehdi MM, Solanki P, Singh P. Oxidative stress, antioxidants, hormesis and calorie restriction: The current perspective in the biology of aging. Arch Gerontol Geriatr 2021; 95:104413. [PMID: 33845417 DOI: 10.1016/j.archger.2021.104413] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 02/25/2021] [Accepted: 03/30/2021] [Indexed: 12/12/2022]
Abstract
Aging, in a large measure, has long been defined as the resultant of oxidative stress acting on the cells. The cellular machinery eventually malfunctions at the basic level by the damage from the processes of oxidation and the system starts slowing down because of intrinsic eroding. To understand the initial destruction at the cellular level spreading outward to affect tissues, organs and the organism, the relationship between molecular damage and oxidative stress is required to understand. Retarding the aging process is a matter of cumulatively decreasing the rate of oxidative damage to the cellular machinery. Along with the genetic reasons, the decrease of oxidative stress is somehow a matter of lifestyle and importantly of diet. In the current review, the theories of aging and the understanding of various levels of molecular damage by oxidative stress have been emphasized. A broader understanding of mechanisms of aging have been elaborated in terms of effects of oxidative at molecular, mitochondrial, cellular and organ levels. The antioxidants supplementation, hormesis and calorie restriction as the prominent anti-aging strategies have also been discussed. The relevance and the efficacy of the antiaging strategies at system level have also been presented.
Collapse
Affiliation(s)
- Mohammad Murtaza Mehdi
- Department of Biochemistry, School of Bio-engineering and Biosciences, Lovely Professional University, Phagwara, 144411, Punjab, India.
| | - Preeti Solanki
- Multidisciplinary Research Unit, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, 124001, Haryana, India
| | - Prabhakar Singh
- Department of Biochemistry, Veer Bahadur Singh Purvanchal University, Jaunpur, 222003, Uttar Pradesh, India
| |
Collapse
|
|
16
|
Kosaisawe N, Sparta B, Pargett M, Teragawa CK, Albeck JG. Transient phases of OXPHOS inhibitor resistance reveal underlying metabolic heterogeneity in single cells. Cell Metab 2021; 33:649-665.e8. [PMID: 33561427 PMCID: PMC8005262 DOI: 10.1016/j.cmet.2021.01.014] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 10/13/2020] [Accepted: 01/13/2021] [Indexed: 12/16/2022]
Abstract
Cell-to-cell heterogeneity in metabolism plays an unknown role in physiology and pharmacology. To functionally characterize cellular variability in metabolism, we treated cells with inhibitors of oxidative phosphorylation (OXPHOS) and monitored their responses with live-cell reporters for ATP, ADP/ATP, or activity of the energy-sensing kinase AMPK. Across multiple OXPHOS inhibitors and cell types, we identified a subpopulation of cells resistant to activation of AMPK and reduction of ADP/ATP ratio. This resistant state persists transiently for at least several hours and can be inherited during cell divisions. OXPHOS inhibition suppresses the mTORC1 and ERK growth signaling pathways in sensitive cells, but not in resistant cells. Resistance is linked to a multi-factorial combination of increased glucose uptake, reduced protein biosynthesis, and G0/G1 cell-cycle status. Our results reveal dynamic fluctuations in cellular energetic balance and provide a basis for measuring and predicting the distribution of cellular responses to OXPHOS inhibition.
Collapse
Affiliation(s)
- Nont Kosaisawe
- Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616, USA
| | - Breanne Sparta
- Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616, USA
| | - Michael Pargett
- Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616, USA
| | - Carolyn K Teragawa
- Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616, USA
| | - John G Albeck
- Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616, USA.
| |
Collapse
|
|
17
|
Xu L, Ma F, Huang J, Frankie Leung KL, Qin C, Lu WW, Guo XE, Tang B. Metformin Hydrochloride Encapsulation by Alginate Strontium Hydrogel for Cartilage Regeneration by Reliving Cellular Senescence. Biomacromolecules 2021; 22:671-680. [PMID: 33486954 DOI: 10.1021/acs.biomac.0c01488] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Cartilage lesion is a common tissue defect and is challenging in clinical practice. Trauma-induced cellular senescence could decrease the chondrocyte capability of maintaining cartilage tissue regeneration. A previous investigation showed that, by controlling the cellular senescence, the cartilage regeneration can be significantly accelerated. Based on this finding, we design a novel hydrogel, Alg/MH-Sr, that combines metformin, an established drug for inhibiting senescence, and strontium, an effective anti-inflammatory material for cartilage tissue engineering. A RT-PCR test suggests the significant inhibitory effect of the hydrogel on senescent, apoptotic, oxidative, and inflammatory genes' expression. Histological examinations demonstrate that the Alg/MH-Sr hydrogel accelerated cartilage repairment, and chondrocyte senescence was significantly inhibited. Our study demonstrates that the Alg/MH-Sr hydrogel is effective for cartilage defect treatment and provides a new clue in accelerating tissue repairment by inhibiting the senescence of cells and tissues.
Collapse
Affiliation(s)
- Lei Xu
- Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen 518055, Guangdong, People's Republic of China.,Department of Orthopeadics and Traumatology, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong 999077, SAR, People's Republic of China.,Bone Bioengineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, 10027 New York, United States.,Department of Orthopeadics and Traumatology, Guangdong Second Provincial General Hospital, Guangzhou 510317, Guang Dong, People's Republic of China
| | - Fenbo Ma
- Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen 518055, Guangdong, People's Republic of China
| | - Jun Huang
- Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen 518055, Guangdong, People's Republic of China
| | - Ka Li Frankie Leung
- Department of Orthopeadics and Traumatology, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong 999077, SAR, People's Republic of China
| | - Chenghe Qin
- Department of Orthopeadics and Traumatology, Guangdong Second Provincial General Hospital, Guangzhou 510317, Guang Dong, People's Republic of China
| | - William Weijia Lu
- Department of Orthopeadics and Traumatology, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong 999077, SAR, People's Republic of China
| | - X Edward Guo
- Bone Bioengineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, 10027 New York, United States
| | - Bin Tang
- Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen 518055, Guangdong, People's Republic of China.,Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, SUSTech, Schenzhen, Guangdong, People's Republic of China.,Shenzhen Key Laboratory of Cell Microenvironment, SUSTech, Schenzhen, Guangdong, People's Republic of China
| |
Collapse
|
|
18
|
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.
Collapse
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
| |
Collapse
|
|
19
|
Piotrowska K, Zgutka K, Kupnicka P, Chlubek D, Pawlik A, Baranowska-Bosiacka I. Analysis of Bone Mineral Profile After Prolonged Every-Other-Day Feeding in C57BL/6J Male and Female Mice. Biol Trace Elem Res 2020; 194:177-183. [PMID: 31175634 PMCID: PMC6987084 DOI: 10.1007/s12011-019-01758-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 05/21/2019] [Indexed: 12/25/2022]
Abstract
Intermitted fasting or every-other-day feeding (EOD) has many positive effects in rodents and humans. Our goal was to describe how EOD influences bone mineral composition in female and male mice under prolonged EOD feeding. Male and female adult mice were fed EOD for 9 months. After this time, we used a direct method of measurement of mineral components in ashes of long bones (humerus and radius) to estimate the content of calcium (Ca), phosphorus (P), potassium (K), magnesium (Mg), and sodium (Na). We also performed histological analysis of sections of long bones. We found no significant changes in mineral composition between ad libitum and EOD fed males and females. We noted higher Ca and P contents in control males vs. females and lower content of Mg in control males vs. females. We observed the presence of marrow adipose tissue (MAT) in sections of EOD-fed females. EOD without supplementation during feeding days did not increase loss of mineral content of bones in C57BL/6J mice, but the presence of MAT only in EOD females indicates a gender-dependent response to EOD treatment in C57BL/6J mice.
Collapse
Affiliation(s)
- Katarzyna Piotrowska
- Department of Physiology, Pomeranian Medical University in Szczecin, al. Powstańców Wielkopolskich 72, 70-111, Szczecin, Poland.
| | - Katarzyna Zgutka
- Department of Physiology, Pomeranian Medical University in Szczecin, al. Powstańców Wielkopolskich 72, 70-111, Szczecin, Poland
| | - Patrycja Kupnicka
- Department of Biochemistry, Pomeranian Medical University in Szczecin, al. Powstańców Wielkopolskich 72, 70-111, Szczecin, Poland
| | - Dariusz Chlubek
- Department of Biochemistry, Pomeranian Medical University in Szczecin, al. Powstańców Wielkopolskich 72, 70-111, Szczecin, Poland
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University in Szczecin, al. Powstańców Wielkopolskich 72, 70-111, Szczecin, Poland
| | - Irena Baranowska-Bosiacka
- Department of Biochemistry, Pomeranian Medical University in Szczecin, al. Powstańców Wielkopolskich 72, 70-111, Szczecin, Poland
| |
Collapse
|
|
20
|
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.
Collapse
|
|
21
|
Golubev AG, Anisimov VN. Aging and cancer: Is glucose a mediator between them? Oncotarget 2019; 10:6758-6767. [PMID: 31827719 PMCID: PMC6887572 DOI: 10.18632/oncotarget.27344] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 11/07/2019] [Indexed: 02/07/2023] Open
Abstract
Aging can increase cancer incidence because of accumulated mutations that initiate cancer and via compromised body control of premalignant lesions development into cancer. Relative contributions of these two factors are debated. Recent evidence suggests that the latter is rate limiting. In particular, hyperglycemia caused by compromised body control of blood glucose may be a factor of selection of somatic mutation-bearing cells for the ability to use glucose for proliferation. High glucose utilization in aerobic glycolysis is a long known characteristic of cancer. The new evidence adds to the concepts that have been being developed starting from mid-1970ies to suggest that age-related shifts in glucose and lipid metabolism increase the risk of cancer and compromise prognoses for cancer patients and to propose antidiabetic biguanides, including metformin, for cancer prevention and as an adjuvant means of cancer treatment aimed at the metabolic rehabilitation of patients. The new evidence is consistent with several effects of glucose contributing to aging and acting synergistically to enhance carcinogenesis. Glucose can affect (i) separate cells (via promoting somatic mutagenesis and epigenetic instability), (ii) cell populations (via being a factor of selection of phenotypic variants in cell populations for higher glucose consumption and, ultimately, for high aerobic glycolysis); (iii) cell microenvironment (via modification of extracellular matrix proteins), and (iv) the systemic levels (via shifting the endocrine regulation of metabolism toward increasing blood lipids and body fat, which compromise immunological surveillance and promote inflammation). Thus, maintenance of youthful metabolic characteristics must be important for cancer prevention and treatment.
Collapse
Affiliation(s)
- Alexey G. Golubev
- Department of Carcinogenesis and Oncogerontology, N.N. Petrov National Medical Research Center of Oncology, Saint Petersburg 197758, Russia
| | - Vladimir N. Anisimov
- Department of Carcinogenesis and Oncogerontology, N.N. Petrov National Medical Research Center of Oncology, Saint Petersburg 197758, Russia
| |
Collapse
|
|
22
|
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.
Collapse
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
| |
Collapse
|
|
23
|
Fresques T, Zirbes A, Shalabi S, Samson S, Preto S, Stampfer MR, LaBarge MA. Breast Tissue Biology Expands the Possibilities for Prevention of Age-Related Breast Cancers. Front Cell Dev Biol 2019; 7:174. [PMID: 31555644 PMCID: PMC6722426 DOI: 10.3389/fcell.2019.00174] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 08/12/2019] [Indexed: 12/24/2022] Open
Abstract
Preventing breast cancer before it is able to form is an ideal way to stop breast cancer. However, there are limited existing options for prevention of breast cancer. Changes in the breast tissue resulting from the aging process contribute to breast cancer susceptibility and progression and may therefore provide promising targets for prevention. Here, we describe new potential targets, immortalization and inflammaging, that may be useful for prevention of age-related breast cancers. We also summarize existing studies of warfarin and metformin, current drugs used for non-cancerous diseases, that also may be repurposed for breast cancer prevention.
Collapse
Affiliation(s)
- Tara Fresques
- Department of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, United States
| | - Arrianna Zirbes
- Department of Population Sciences, Beckman Research Institute at City of Hope, Duarte, CA, United States.,Center for Cancer and Aging Research, Beckman Research Institute at City of Hope, Duarte, CA, United States
| | - Sundus Shalabi
- Department of Population Sciences, Beckman Research Institute at City of Hope, Duarte, CA, United States.,Center for Cancer and Aging Research, Beckman Research Institute at City of Hope, Duarte, CA, United States.,Medical Research Center, Al-Quds University, Jerusalem, Palestine
| | - Susan Samson
- Breast Science Advocacy Core, Breast Oncology Program, University of California, San Francisco, San Francisco, CA, United States
| | | | - Martha R Stampfer
- Department of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, United States
| | - Mark A LaBarge
- Department of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, United States.,Department of Population Sciences, Beckman Research Institute at City of Hope, Duarte, CA, United States.,Center for Cancer and Aging Research, Beckman Research Institute at City of Hope, Duarte, CA, United States
| |
Collapse
|
|
24
|
Haddadi NS, Shakiba S, Afshari K, Haj-Mirzaian A, Vesaghati S, Gharagozlou S, Foroumadi R, Shafaroodi H, Ostadhadi S, Dehpour A. Possible Involvement of Nitric Oxide in the Antipruritic Effect of Metformin on Chloroquine-Induced Scratching in Mice. Dermatology 2019; 236:151-159. [DOI: 10.1159/000501583] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 06/14/2019] [Indexed: 11/19/2022] Open
Abstract
Background: Metformin ameliorates non-histamine-mediated itch. We have recently reported that the nitric oxide (NO) pathway is involved in chloroquine (CQ)-induced scratching behavior. Here we investigated the involvement of the NO pathway in the antipruritic effect of metformin on CQ-induced itch. Methods: Metformin (5–200 mg/kg, given intraperitoneally [i.p.]) was injected 4 h before CQ (400 µg/site, given intradermally [i.d.]) or compound 48/80 (100 µg/site, i.d.). A nonspecific nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 1 and 10 mg/kg, i.p.), or an NO precursor, L-arginine (10 and 100 mg/kg, i.p.) was administered 30 min before injection of CQ. A neural NOS (nNOS) inhibitor, 7-nitroindazole (7-NI; 1 and 10 nmol/site, i.d.) was concurrently administered with CQ. The scratching behavior was recorded for 30 min following the injection of CQ. We studied the changes in skin and spinal nitrite levels after treatments. Results: Our results showed that metformin (100 and 200 mg/kg) significantly reduced the CQ-induced scratching behavior but not the compound 48/80-induced scratching behavior. L-Arginine inhibited the antipruritic effect of metformin, while L-NAME and 7-NI significantly potentiated the inhibitory effects of a subeffective dose of metformin on the CQ-induced scratching behavior. The skin but not the spinal nitrite level was significantly increased after CQ administration. The elevated cutaneous nitrite level was reversed by effective doses of either metformin or 7-NI, but not by the subeffective doses of metformin + 7-NI. Conclusion: Acute injection of metformin significantly inhibits CQ-induced scratching behavior. This effect is mediated through inhibition of the NO pathway, especially by inhibiting the dermal nNOS enzyme.
Collapse
|
|
25
|
Taheri A, Emami M, Asadipour E, Kasirzadeh S, Rouini MR, Najafi A, Heshmat R, Abdollahi M, Mojtahedzadeh M. A randomized controlled trial on the efficacy, safety, and pharmacokinetics of metformin in severe traumatic brain injury. J Neurol 2019; 266:1988-1997. [PMID: 31093755 DOI: 10.1007/s00415-019-09366-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Revised: 05/05/2019] [Accepted: 05/07/2019] [Indexed: 12/31/2022]
Abstract
OBJECTIVE Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide. Metformin is reported to have pleiotropic neuroprotective effects through anti-inflammatory, antioxidative, and anti-ischemic activity, and improvements in vascular hemodynamics and endothelial function. The aim of this study is to examine the efficacy and safety of metformin therapy in severe TBI patients. METHODS This single-blind, parallel-group, randomized controlled trial enrolled adult TBI patients. Of 158 trauma patients assessed, 30 met the eligibility criteria and were randomly allocated in a one-to-one ratio to receive 1 g metformin every 12 h for five consecutive days (intervention group) or to usual management only (control group). For efficacy analysis, temporal profiles of serum levels of S100b, neutrophil to lymphocyte ratio (NLR), and glial fibrillary acidic protein (GFAP) were assessed. For pharmacokinetic analysis, serum concentrations of metformin were evaluated in the intervention group. RESULTS The two study groups were similar in terms of demographics, baseline clinical characteristics, and on-admission biomarkers' serum levels. Longitudinal analysis of S100b and NLR levels showed statistically significant declines in values toward normal levels in the intervention group (p values of < 0.001 and 0.030, respectively), different from the profiles of the control group (p values of 0.074 and 0.645, respectively). Pharmacokinetic analysis demonstrated that metformin absorption is delayed in TBI patients. No events of hypoglycemia and lactic acidosis occurred. CONCLUSIONS Metformin could potentially be an effective and safe therapeutic intervention in patients with severe TBI. Large-scale, multicentre studies are needed to confirm our encouraging results.
Collapse
Affiliation(s)
- Ali Taheri
- Biopharmaceutics and Pharmacokinetics Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahdi Emami
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, 14155-6451, Tehran, Iran
| | - Erfan Asadipour
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, 14155-6451, Tehran, Iran
| | - Sara Kasirzadeh
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad-Reza Rouini
- Biopharmaceutics and Pharmacokinetics Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Atabak Najafi
- Department of Anesthesiology and Critical Care Medicine, Faculty of Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ramin Heshmat
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Abdollahi
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mojtaba Mojtahedzadeh
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, 14155-6451, Tehran, Iran.
| |
Collapse
|
|
26
|
Phenformin as an Anticancer Agent: Challenges and Prospects. Int J Mol Sci 2019; 20:ijms20133316. [PMID: 31284513 PMCID: PMC6651400 DOI: 10.3390/ijms20133316] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 06/28/2019] [Accepted: 07/03/2019] [Indexed: 12/13/2022] Open
Abstract
Currently, there is increasing evidence linking diabetes mellitus (especially type 2 diabetes mellitus) with carcinogenesis through various biological processes, such as fat-induced chronic inflammation, hyperglycemia, hyperinsulinemia, and angiogenesis. Chemotherapeutic agents are used in the treatment of cancer, but in most cases, patients develop resistance. Phenformin, an oral biguanide drug used to treat type 2 diabetes mellitus, was removed from the market due to a high risk of fatal lactic acidosis. However, it has been shown that phenformin is, with other biguanides, an authentic tumor disruptor, not only by the production of hypoglycemia due to caloric restriction through AMP-activated protein kinase with energy detection (AMPK) but also as a blocker of the mTOR regulatory complex. Moreover, the addition of phenformin eliminates resistance to antiangiogenic tyrosine kinase inhibitors (TKI), which prevent the uncontrolled metabolism of glucose in tumor cells. In this review, we evidence the great potential of phenformin as an anticancer agent. We thoroughly review its mechanism of action and clinical trial assays, specially focusing on current challenges and future perspectives of this promising drug.
Collapse
|
|
27
|
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.
Collapse
Affiliation(s)
- György Csaba
- 1 Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary
| |
Collapse
|
|
28
|
Vallet H, Fali T, Sauce D. Le vieillissement du système immunitaire : du fondamental à la clinique. Rev Med Interne 2019; 40:105-111. [DOI: 10.1016/j.revmed.2018.07.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 06/26/2018] [Accepted: 07/03/2018] [Indexed: 01/08/2023]
|
|
29
|
Metformin prevents cell tumorigenesis through autophagy-related cell death. Sci Rep 2019; 9:66. [PMID: 30635619 PMCID: PMC6329809 DOI: 10.1038/s41598-018-37247-6] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 12/03/2018] [Indexed: 11/15/2022] Open
Abstract
Autophagy is a cellular mechanism by which cells degrade intracellular components in lysosomes, maintaining cellular homeostasis. It has been hypothesized that autophagy could have a role in cancer prevention through the elimination of damaged proteins and organelles; this could explain epidemiological evidence showing the chemopreventive properties of the autophagy-inducer metformin. In this study, we analyzed the autophagy-related effect of metformin in both cancer initiation and progression in non-tumorigenic cells. We also analyzed the induction of tumorigenesis in autophagy-deficient cells, and its correlation with the ER stress. Our results showed that metformin induced massive cell death in preneoplastic JB6 Cl 41-5a cells treated with tumor promoter (phorbol) and in NIH/3T3 treated with H2O2. Inhibiting autophagy with wortmannin or ATG7 silencing, the effect of metformin decreased, indicating an autophagy-related cytotoxic activity under stress conditions. We also found an induction of tumorigenesis in ATG7-silenced NIH/3T3 cell clone (3T3-619C3 cells), but not in wild-type and in scrambled transfected cells, and an upregulation of unfolded protein response (UPR) markers in 3T3-619C3 cells treated with H2O2. These findings suggest that autophagic cell death could be considered as a new mechanism by which eliminate damaged cells, representing an attractive strategy to eliminate potential tumorigenic cells.
Collapse
|
|
30
|
Prattichizzo F, Giuliani A, Mensà E, Sabbatinelli J, De Nigris V, Rippo MR, La Sala L, Procopio AD, Olivieri F, Ceriello A. Pleiotropic effects of metformin: Shaping the microbiome to manage type 2 diabetes and postpone ageing. Ageing Res Rev 2018; 48:87-98. [PMID: 30336272 DOI: 10.1016/j.arr.2018.10.003] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 09/13/2018] [Accepted: 10/10/2018] [Indexed: 02/06/2023]
Abstract
Metformin is the first-choice therapy to lower glycaemia and manage type 2 diabetes. Continuously emerging epidemiological data and experimental models are showing additional protective effects of metformin against a number of age-related diseases (ARDs), e.g., cardiovascular diseases and cancer. This evidence has prompted the design of a specific trial, i.e., the Targeting Aging with Metformin (TAME) trial, to test metformin as an anti-ageing molecule. However, a unifying or prevailing mechanism of action of metformin is still debated. Here, we summarize the epidemiological data linking metformin to ARD prevention. Then, we dissect the deeply studied mechanisms of action explaining its antihyperglycemic effect and the putative mechanisms supporting its anti-ageing properties, focusing on studies using clinically pertinent doses. We hypothesize that the molecular observations obtained in different models with metformin could be indirectly mediated by its effect on gut flora. Novel evidence suggests that metformin reshapes the human microbiota, promoting the growth of beneficial bacterial species and counteracting the expansion of detrimental bacterial species. In turn, this action would influence the balance between pro- and anti-inflammatory circulating factors, thereby promoting glycaemic control and healthy ageing. This framework may reconcile diverse observations, providing information for designing further studies to elucidate the complex interplay between metformin and the metabiome harboured in mammalian body compartments, thereby paving the way for innovative, bacterial-based therapeutics to manage type 2 diabetes and foster a longer healthspan.
Collapse
Affiliation(s)
| | - Angelica Giuliani
- Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy
| | - Emanuela Mensà
- Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy
| | - Jacopo Sabbatinelli
- Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy
| | - Valeria De Nigris
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Maria Rita Rippo
- Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy
| | | | - Antonio Domenico Procopio
- Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy; Center of Clinical Pathology and Innovative Therapy, Italian National Research Centre on Aging, IRCCS INRCA, Ancona, Italy
| | - Fabiola Olivieri
- Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy; Center of Clinical Pathology and Innovative Therapy, Italian National Research Centre on Aging, IRCCS INRCA, Ancona, Italy
| | - Antonio Ceriello
- IRCCS MultiMedica, Milan, Italy; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
| |
Collapse
|
|
31
|
Lipid profiling of C. elegans strains administered pro-longevity drugs and drug combinations. Sci Data 2018; 5:180231. [PMID: 30351306 PMCID: PMC6198751 DOI: 10.1038/sdata.2018.231] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Accepted: 08/30/2018] [Indexed: 12/19/2022] Open
Abstract
We report the effect of four lifespan modifying drugs and of synergistic combinations of these drugs on lipid profile in Caenorhabditis elegans. We employ ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) to compare the abundance of lipid species in treated and control animals. Adult nematodes were treated with rapamycin, rifampicin, psora-4 and allantoin and combinations of these compounds and the resulting change in lipid profiles, specifically in those of triacylglycerol (TAG), phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were determined. We quantified changes resulting from treatment with the drug combinations relative to untreated controls and relative to animals treated with each constituent single drugs. We further determined the dependence of changes in lipid profiles on genes known to affect lipid metabolism using strains carrying mutations in these pathways. In particular, we determined lipid profiles in a genetic model of caloric restriction (eat-2), a strain lacking homolog of TGFβ (daf-7) and in a strain lacking the SREBP/sbp-1 transcription factor.
Collapse
|
|
32
|
Metformin treatment prevents gallstone formation but mimics porcelain gallbladder in C57Bl/6 mice. Eur J Pharmacol 2018; 833:165-172. [DOI: 10.1016/j.ejphar.2018.06.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Revised: 06/03/2018] [Accepted: 06/04/2018] [Indexed: 11/15/2022]
|
|
33
|
Impact of stress on aged immune system compartments: Overview from fundamental to clinical data. Exp Gerontol 2018; 105:19-26. [DOI: 10.1016/j.exger.2018.02.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 02/03/2018] [Accepted: 02/05/2018] [Indexed: 12/12/2022]
|
|
34
|
Xu Z, Feng W, Shen Q, Yu N, Yu K, Wang S, Chen Z, Shioda S, Guo Y. Rhizoma Coptidis and Berberine as a Natural Drug to Combat Aging and Aging-Related Diseases via Anti-Oxidation and AMPK Activation. Aging Dis 2017; 8:760-777. [PMID: 29344415 PMCID: PMC5758350 DOI: 10.14336/ad.2016.0620] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2016] [Accepted: 06/20/2017] [Indexed: 12/25/2022] Open
Abstract
Aging is the greatest risk factor for human diseases, as it results in cellular growth arrest, impaired tissue function and metabolism, ultimately impacting life span. Two different mechanisms are thought to be primary causes of aging. One is cumulative DNA damage induced by a perpetuating cycle of oxidative stress; the other is nutrient-sensing adenosine monophosphate-activated protein kinase (AMPK) and rapamycin (mTOR)/ ribosomal protein S6 (rpS6) pathways. As the main bioactive component of natural Chinese medicine rhizoma coptidis (RC), berberine has recently been reported to expand life span in Drosophila melanogaster, and attenuate premature cellular senescence. Most components of RC including berberine, coptisine, palmatine, and jatrorrhizine have been found to have beneficial effects on hyperlipidemia, hyperglycemia and hypertension aging-related diseases. The mechanism of these effects involves multiple cellular kinase and signaling pathways, including anti-oxidation, activation of AMPK signaling and its downstream targets, including mTOR/rpS6, Sirtuin1/ forkhead box transcription factor O3 (FOXO3), nuclear factor erythroid-2 related factor-2 (Nrf2), nicotinamide adenine dinucleotide (NAD+) and nuclear factor-κB (NF-κB) pathways. Most of these mechanisms converge on AMPK regulation on mitochondrial oxidative stress. Therefore, such evidence supports the possibility that rhizoma coptidis, in particular berberine, is a promising anti-aging natural product, and has pharmaceutical potential in combating aging-related diseases via anti-oxidation and AMPK cellular kinase activation.
Collapse
Affiliation(s)
- Zhifang Xu
- 1Acu-moxibustion and Tuina Department, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.,2Acupuncture Research Center, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Wei Feng
- 3South Branch of Guang'anmen Hospital, China Academy of Chinese Medical Science, Beijing 102618, China
| | - Qian Shen
- 4Dongfang hospital, Beijing University of Chinese Medicine, Beijing 100078, China
| | - Nannan Yu
- 1Acu-moxibustion and Tuina Department, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Kun Yu
- 1Acu-moxibustion and Tuina Department, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Shenjun Wang
- 1Acu-moxibustion and Tuina Department, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.,2Acupuncture Research Center, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Zhigang Chen
- 4Dongfang hospital, Beijing University of Chinese Medicine, Beijing 100078, China
| | - Seiji Shioda
- 5Peptide Drug Innovation, Global Research Center for Innovative Life Science, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa, Tokyo 142-8501, Japan
| | - Yi Guo
- 1Acu-moxibustion and Tuina Department, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.,2Acupuncture Research Center, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| |
Collapse
|
|
35
|
Aliper A, Jellen L, Cortese F, Artemov A, Karpinsky-Semper D, Moskalev A, Swick AG, Zhavoronkov A. Towards natural mimetics of metformin and rapamycin. Aging (Albany NY) 2017; 9:2245-2268. [PMID: 29165314 PMCID: PMC5723685 DOI: 10.18632/aging.101319] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 11/02/2017] [Indexed: 12/14/2022]
Abstract
Aging is now at the forefront of major challenges faced globally, creating an immediate need for safe, widescale interventions to reduce the burden of chronic disease and extend human healthspan. Metformin and rapamycin are two FDA-approved mTOR inhibitors proposed for this purpose, exhibiting significant anti-cancer and anti-aging properties beyond their current clinical applications. However, each faces issues with approval for off-label, prophylactic use due to adverse effects. Here, we initiate an effort to identify nutraceuticals-safer, naturally-occurring compounds-that mimic the anti-aging effects of metformin and rapamycin without adverse effects. We applied several bioinformatic approaches and deep learning methods to the Library of Integrated Network-based Cellular Signatures (LINCS) dataset to map the gene- and pathway-level signatures of metformin and rapamycin and screen for matches among over 800 natural compounds. We then predicted the safety of each compound with an ensemble of deep neural network classifiers. The analysis revealed many novel candidate metformin and rapamycin mimetics, including allantoin and ginsenoside (metformin), epigallocatechin gallate and isoliquiritigenin (rapamycin), and withaferin A (both). Four relatively unexplored compounds also scored well with rapamycin. This work revealed promising candidates for future experimental validation while demonstrating the applications of powerful screening methods for this and similar endeavors.
Collapse
Affiliation(s)
- Alexander Aliper
- Insilico Medicine, Inc, Research Department, Baltimore, MD 21218, USA
| | - Leslie Jellen
- Insilico Medicine, Inc, Research Department, Baltimore, MD 21218, USA
| | - Franco Cortese
- Biogerontology Research Foundation, Research Department, Oxford, United Kingdom
- Department of Biomedical and Molecular Science, Queen's University School of Medicine, Queen's University, Kingston, ON K7L 3N6, Canada
| | - Artem Artemov
- Insilico Medicine, Inc, Research Department, Baltimore, MD 21218, USA
| | | | - Alexey Moskalev
- Laboratory of Molecular Radiobiology and Gerontology, Institute of Biology of Komi Science Center of Ural Branch of Russian Academy of Sciences, Syktyvkar, 167982, Russia
| | | | - Alex Zhavoronkov
- Insilico Medicine, Inc, Research Department, Baltimore, MD 21218, USA
- Biogerontology Research Foundation, Research Department, Oxford, United Kingdom
| |
Collapse
|
|
36
|
Heiss C, Spyridopoulos I, Haendeler J. Interventions to slow cardiovascular aging: Dietary restriction, drugs and novel molecules. Exp Gerontol 2017; 109:108-118. [PMID: 28658611 DOI: 10.1016/j.exger.2017.06.015] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2017] [Revised: 06/16/2017] [Accepted: 06/21/2017] [Indexed: 02/05/2023]
Abstract
Cardiovascular aging is a highly dynamic process. Despite the fact that cardiovascular function and structure change with age, they can still be modulated even in aged humans. The most prominent approaches to improve age-dependent vascular changes include dietary restriction and pharmacologic agents interacting with signaling pathways implicated in this context. These include inhibition of TOR, glycolysis, and GH/IGF-1, activation of sirtuins, and AMPK, as well as modulators of inflammation, epigenetic pathways, and telomeres. Promising nutritional approaches include Mediterranean diet and novel dietary bioactives including flavanols, anthocyanins, and lignins. Many plant bioactives improve cardiovascular parameters implied in vascular healthy aging including endothelial function, arterial stiffness, blood pressure, cholesterol, and glycemic control. However, the mechanism of action of most bioactives is not established and it remains to be elucidated whether they act as dietary restriction mimetics or via other modes of action. Even more importantly, whether these interventions can slow or even reverses components of cardiovascular aging itself and can increase healthspan or longevity in humans needs to be determined.
Collapse
Affiliation(s)
- Christian Heiss
- Division of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.
| | - Ioakim Spyridopoulos
- Institute of Genetic Medicine, Medical Faculty, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
| | - Judith Haendeler
- Central Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty, University of Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany; IUF-Leibniz Research Institute for Environmental Medicine, Auf'm Hennekamp 50, 40225 Duesseldorf, Germany.
| |
Collapse
|
|
37
|
Marti N, Bouchoucha N, Sauter KS, Flück CE. Resveratrol inhibits androgen production of human adrenocortical H295R cells by lowering CYP17 and CYP21 expression and activities. PLoS One 2017; 12:e0174224. [PMID: 28323907 PMCID: PMC5360261 DOI: 10.1371/journal.pone.0174224] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 03/05/2017] [Indexed: 12/22/2022] Open
Abstract
Resveratrol, a natural compound found in grapes, became very popular for its suggested protective effects against aging. It was reported to have similar positive effects on the human metabolism as caloric restriction. Recently, positive effects of resveratrol on steroid biosynthesis in cell systems and in humans suffering from polycystic ovary syndrome have also been reported, but the exact mechanism of this action remains unknown. Sirtuins seem targeted by resveratrol to mediate its action on energy homeostasis. In this study, we investigated the mechanisms of action of resveratrol on steroidogenesis in human adrenal H295R cells. Resveratrol was found to inhibit protein expression and enzyme activities of CYP17 and CYP21. It did not alter CYP17 and CYP21 mRNA expression, nor protein degradation. Only SIRT3 mRNA expression was found to be altered by resveratrol, but SIRT1, 3 and 5 overexpression did not result in a change in the steroid profile of H295R cells, indicating that resveratrol may not engage sirtuins to modulate steroid production. Previous studies showed that starvation leads to a hyperandrogenic steroid profile in H295R cells through inhibition of PKB/Akt signaling, and that resveratrol inhibits steroidogenesis of rat ovarian theca cells via the PKB/Akt pathway. Therefore, the effect of resveratrol on PKB/Akt signaling was tested in H295R cells and was found to be decreased under starvation growth conditions, but not under normal growth conditions. Overall, these properties of action together with recent clinical findings make resveratrol a candidate for the treatment of hyperandrogenic disorders such as PCOS.
Collapse
Affiliation(s)
- Nesa Marti
- Division of Pediatric Endocrinology, Department of Pediatrics and Department of Clinical Research, University of Bern, Bern, Switzerland
- Graduate School of Bern, University of Bern, Bern, Switzerland
| | - Nadia Bouchoucha
- Division of Pediatric Endocrinology, Department of Pediatrics and Department of Clinical Research, University of Bern, Bern, Switzerland
| | - Kay-Sara Sauter
- Division of Pediatric Endocrinology, Department of Pediatrics and Department of Clinical Research, University of Bern, Bern, Switzerland
| | - Christa E. Flück
- Division of Pediatric Endocrinology, Department of Pediatrics and Department of Clinical Research, University of Bern, Bern, Switzerland
- * E-mail:
| |
Collapse
|
|
38
|
Raffaghello L, Longo V. Metabolic Alterations at the Crossroad of Aging and Oncogenesis. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2017; 332:1-42. [PMID: 28526131 DOI: 10.1016/bs.ircmb.2017.01.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Aging represents the major risk factor for cancer. Cancer and aging are characterized by a similar dysregulated metabolism consisting in upregulation of glycolysis and downmodulation of oxidative phosphorylation. In this respect, metabolic interventions can be viewed as promising strategies to promote longevity and to prevent or delay age-related disorders including cancer. In this review, we discuss the most promising metabolic approaches including chronic calorie restriction, periodic fasting/fasting-mimicking diets, and pharmacological interventions mimicking calorie restriction. Metabolic interventions can also be viewed as adjuvant anticancer strategies to be combined to standard cancer therapy (chemotherapeutic agents, ionizing radiation, and drugs with specific molecular target), whose major limiting factors are represented by toxicity against healthy cells but also limited efficacy easily circumvented by tumor cells. In fact, conventional cancer therapy is unable to distinguish normal and cancerous cells and thus causes toxic side effects including secondary malignancies, cardiovascular and respiratory complications, endocrinopathies, and other chronic conditions, that resemble and, in some cases, accelerate the age-related disorders and profoundly affect the quality of life. In this scenario, geroscience contributes to the understanding of the mechanisms of protection of normal cells against a cytotoxic agent and finding strategies focused on the preserving healthy cells while enhancing the efficacy of the treatment against malignant cells.
Collapse
Affiliation(s)
- L Raffaghello
- Laboratory of Oncology, Istituto Giannina Gaslini, Genova, Italy
| | - V Longo
- Longevity Institute, Davis School of Gerontology, University of Southern California, Los Angeles, CA, United States; IFOM, FIRC Institute of Molecular Oncology, Milano, Italy.
| |
Collapse
|
|
39
|
Honoki K. Preventing aging with stem cell rejuvenation: Feasible or infeasible? World J Stem Cells 2017; 9:1-8. [PMID: 28154735 PMCID: PMC5253185 DOI: 10.4252/wjsc.v9.i1.1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 08/22/2016] [Accepted: 10/09/2016] [Indexed: 02/06/2023] Open
Abstract
Characterized by dysfunction of tissues, organs, organ systems and the whole organism, aging results from the reduced function of effective stem cell populations. Recent advances in aging research have demonstrated that old tissue stem cells can be rejuvenated for the purpose of maintaining the old-organ function by youthful re-calibration of the environment where stem cells reside. Biochemical cues regulating tissue stem cell function include molecular signaling pathways that interact between stem cells themselves and their niches. Historically, plasma fractions have been shown to contain factors capable of controlling age phenotypes; subsequently, signaling pathways involved in the aging process have been identified. Consequently, modulation of signaling pathways such as Notch/Delta, Wnt, transforming growth factor-β, JAK/STAT, mammalian target of rapamycin and p38 mitogen-activated protein kinase has demonstrated potential to rejuvenate stem cell function leading to organismic rejuvenation. Several synthetic agents and natural sources, such as phytochemicals and flavonoids, have been proposed to rejuvenate old stem cells by targeting these pathways. However, several concerns still remain to achieve effective organismic rejuvenation in clinical settings, such as possible carcinogenic actions; thus, further research is still required.
Collapse
|
|
40
|
Wang Y, Chang J, Liu X, Zhang X, Zhang S, Zhang X, Zhou D, Zheng G. Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. Aging (Albany NY) 2016; 8:2915-2926. [PMID: 27913811 PMCID: PMC5191878 DOI: 10.18632/aging.101100] [Citation(s) in RCA: 177] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Accepted: 11/04/2016] [Indexed: 04/16/2023]
Abstract
Accumulating evidence indicates that senescent cells play an important role in many age-associated diseases. The pharmacological depletion of senescent cells (SCs) with a "senolytic agent", a small molecule that selectively kills SCs, is a potential novel therapeutic approach for these diseases. Recently, we discovered ABT-263, a potent and highly selective senolytic agent, by screening a library of rationally-selected compounds. With this screening approach, we also identified a second senolytic agent called piperlongumine (PL). PL is a natural product that is reported to have many pharmacological effects, including anti-tumor activity. We show here that PL preferentially killed senescent human WI-38 fibroblasts when senescence was induced by ionizing radiation, replicative exhaustion, or ectopic expression of the oncogene Ras. PL killed SCs by inducing apoptosis, and this process did not require the induction of reactive oxygen species. In addition, we found that PL synergistically killed SCs in combination with ABT-263, and initial structural modifications to PL identified analogs with improved potency and/or selectivity in inducing SC death. Overall, our studies demonstrate that PL is a novel lead for developing senolytic agents.
Collapse
Affiliation(s)
- Yingying Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Jianhui Chang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Xingui Liu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Xuan Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Suping Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Xin Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Daohong Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Guangrong Zheng
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| |
Collapse
|
|
41
|
Cuyàs E, Fernández-Arroyo S, Joven J, Menendez JA. Metformin targets histone acetylation in cancer-prone epithelial cells. Cell Cycle 2016; 15:3355-3361. [PMID: 27792453 DOI: 10.1080/15384101.2016.1249547] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The usage of metabolic intermediates as substrates for chromatin-modifying enzymes provides a direct link between the metabolic state of the cell and epigenetics. Because this metabolism-epigenetics axis can regulate not only normal but also diseased states, it is reasonable to suggest that manipulating the epigenome via metabolic interventions may improve the clinical manifestation of age-related diseases including cancer. Using a model of BRCA1 haploinsufficiency-driven accelerated geroncogenesis, we recently tested the hypothesis that: 1.) metabolic rewiring of the mitochondrial biosynthetic nodes that overproduce epigenetic metabolites such as acetyl-CoA should promote cancer-related acetylation of histone H3 marks; 2.) metformin-induced restriction of mitochondrial biosynthetic capacity should manifest in the epigenetic regulation of histone acetylation. We now provide one of the first examples of how metformin-driven metabolic shifts such as reduction of the 2-carbon epigenetic substrate acetyl-CoA is sufficient to correct specific histone H3 acetylation marks in cancer-prone human epithelial cells. The ability of metformin to regulate mitonuclear communication and modulate the epigenetic landscape in genomically unstable pre-cancerous cells might guide the development of new metabolo-epigenetic strategies for cancer prevention and therapy.
Collapse
Affiliation(s)
- Elisabet Cuyàs
- a ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism & Cancer Group, Catalan Institute of Oncology , Girona , Catalonia , Spain.,b Girona Biomedical Research Institute (IDIBGI) , Girona , Catalonia , Spain
| | - Salvador Fernández-Arroyo
- c Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Reus, Spain, The Campus of International Excellence Southern Catalonia , Tarragona , Spain
| | - Jorge Joven
- c Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Reus, Spain, The Campus of International Excellence Southern Catalonia , Tarragona , Spain
| | - Javier A Menendez
- a ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism & Cancer Group, Catalan Institute of Oncology , Girona , Catalonia , Spain.,b Girona Biomedical Research Institute (IDIBGI) , Girona , Catalonia , Spain
| |
Collapse
|
|
42
|
Evangelisti C, Cenni V, Lattanzi G. Potential therapeutic effects of the MTOR inhibitors for preventing ageing and progeria-related disorders. Br J Clin Pharmacol 2016; 82:1229-1244. [PMID: 26952863 PMCID: PMC5061804 DOI: 10.1111/bcp.12928] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Revised: 03/02/2016] [Accepted: 03/02/2016] [Indexed: 12/25/2022] Open
Abstract
The mammalian target of rapamycin (mTOR) pathway is an highly conserved signal transduction axis involved in many cellular processes, such as cell growth, survival, transcription, translation, apoptosis, metabolism, motility and autophagy. Recently, this signalling pathway has come to the attention of the scientific community owing to the unexpected finding that inhibition of mTOR by rapamycin, an antibiotic with immunosuppressant and chemotherapeutic properties, extends lifespan in diverse animal models. Moreover, rapamycin has been reported to rescue the cellular phenotype in a progeroid syndrome [Hutchinson–Gilford Progeria syndrome (HGPS)] that recapitulates most of the traits of physiological ageing. The promising perspectives raised by these results warrant a better understanding of mTOR signalling and the potential applications of mTOR inhibitors to counteract ageing‐associated diseases and increase longevity. This review is focused on these issues.
Collapse
Affiliation(s)
- Camilla Evangelisti
- CNR Institute for Molecular Genetics, Unit of Bologna, Bologna, Italy.,Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, Bologna, Italy
| | - Vittoria Cenni
- CNR Institute for Molecular Genetics, Unit of Bologna, Bologna, Italy.,Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, Bologna, Italy
| | - Giovanna Lattanzi
- CNR Institute for Molecular Genetics, Unit of Bologna, Bologna, Italy. .,Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, Bologna, Italy.
| |
Collapse
|
|
43
|
Gender Differences in Response to Prolonged Every-Other-Day Feeding on the Proliferation and Apoptosis of Hepatocytes in Mice. Nutrients 2016; 8:176. [PMID: 27007393 PMCID: PMC4808902 DOI: 10.3390/nu8030176] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Accepted: 03/07/2016] [Indexed: 02/07/2023] Open
Abstract
Intermittent fasting decreases glucose and insulin levels and increases insulin sensitivity and lifespan. Decreased food intake influences the liver. Previous studies have shown gender differences in response to various types of caloric restriction, including every-other-day (EOD) feeding, in humans and rodents. Our goal was to show the influence of prolonged EOD feeding on the morphology, proliferation and apoptosis of livers from male and female mice. After nine months of an EOD diet, the livers from male and female mice were collected. We examined their morphology on histological slides using the Hematoxilin and Eosine (H_E) method and Hoechst staining of cell nuclei to evaluate the nuclear area of hepatocytes. We also evaluated the expression of mRNA for proto-oncogens, pro-survival proteins and apoptotic markers using Real Time Polimerase Chain Reaction (PCR). We noted increased lipid content in the livers of EOD fed female mice. EOD feeding lead to a decrease of proliferation and apoptosis in the livers of female and male mice, which suggest that tissue maintenance occurred during EOD feeding. Our experiment revealed sex-specific expression of mRNA for proto-oncogenes and pro-survival and pro-apoptotic genes in mice as well as sex-specific responses to the EOD treatment.
Collapse
|
|
44
|
Anisimov VN. Metformin for cancer and aging prevention: is it a time to make the long story short? Oncotarget 2015; 6:39398-407. [PMID: 26583576 PMCID: PMC4741834 DOI: 10.18632/oncotarget.6347] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 11/17/2015] [Indexed: 12/30/2022] Open
Abstract
During the last decade, the burst of interest is observed to antidiabetic biguanide metformin as candidate drug for cancer chemoprevention. The analysis of the available data have shown that the efficacy of cancer preventive effect of metformin (MF) and another biguanides, buformin (BF) and phenformin (PF), has been studied in relation to total tumor incidence and to 17 target organs, in 21 various strains of mice, 4 strains of rats and 1 strain of hamsters (inbred, outbred, transgenic, mutant), spontaneous (non- exposed to any carcinogenic agent) or induced by 16 chemical carcinogens of different classes (polycycIic aromatic hydrocarbons, nitroso compounds, estrogen, etc.), direct or indirect (need metabolic transformation into proximal carcinogen), by total body X-rays and γ- irradiation, viruses, genetic modifications or special high fat diet, using one stage and two-stage protocols of carcinogenesis, 5 routes of the administration of antidiabetic biguanides (oral gavage, intraperitoneal or subcutaneous injections, with drinking water or with diet) in a wide ranks of doses and treatment regimens. In the majority of cases (86%) the treatment with biguanides leads to inhibition of carcinogenesis. In 14% of the cases inhibitory effect of the drugs was not observed. Very important that there was no any case of stimulation of carcinogenesis by antidiabetic biguanides. It was conclude that there is sufficient experimental evidence of anti-carcinogenic effect of antidiabetic biguanides.
Collapse
Affiliation(s)
- Vladimir N. Anisimov
- Department of Carcinogenesis and Oncogerontology, N.N.Petrov Research Institute of Oncology, St.Petersburg, Russian Federation
| |
Collapse
|
|
45
|
Anisimov VN, Popovich IG, Zabezhinski MA, Egormin PA, Yurova MN, Semenchenko AV, Tyndyk ML, Panchenko AV, Trashkov AP, Vasiliev AG, Khaitsev NV. Sex differences in aging, life span and spontaneous tumorigenesis in 129/Sv mice neonatally exposed to metformin. Cell Cycle 2015; 14:46-55. [PMID: 25483062 DOI: 10.4161/15384101.2014.973308] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The perinatal (prenatal and early neonatal) period is a critical stage for hypothalamic programming of sexual differentiation as well as for the development of energy and metabolic homeostasis. We hypothesized that neonatal treatment with antidiabetic drug biguanide metformin would positively modify regulation of growth hormone--IGF-1--insulin signaling pathway slowing down aging and improving cancer preventive patterns in rodents. To test this hypothesis male and female 129/Sv mice were s.c. injected with metformin (100 mg/kg) at the 3rd, 5th and 7th days after birth. Metformin-treated males consumed less food and water and their body weight was decreased as compared with control mice practically over their entire lifespan. There were no significant differences in age-related dynamics of food and water consumption in females and they were heavier than controls. The fraction of mice with regular estrous cycles decreased with age and demonstrated a tendency to decrease in the females neonatally treated with metformin. Neonatal exposure to metformin practically failed to change the extent of hormonal and metabolic parameters in blood serum of male and female mice. In males, neonatal metformin treatment significantly increased the mean life span (+20%, P < 0.05) and slightly increased the maximum life span (+3.5%). In females, the mean life span and median in metformin-treated groups were slightly decreased (-9.1% and -13.8% respectively, P > 0.05) in comparison to controls, whereas mean life span of last 10% survivors and maximum life span were the same as in controls. Almost half (45%) of control male mice and 71.8% male mice neonatally exposed to metformin survived up to 800 d of age, the same age was achieved by 54.3% of mice in control female group and 30% of metformin-treated females (P < 0.03). Thus, neonatal metformin exposure slows down aging and prolongs lifespan in male but not in female mice.
Collapse
|
|
46
|
Hindupur SK, González A, Hall MN. The opposing actions of target of rapamycin and AMP-activated protein kinase in cell growth control. Cold Spring Harb Perspect Biol 2015; 7:a019141. [PMID: 26238356 DOI: 10.1101/cshperspect.a019141] [Citation(s) in RCA: 103] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cell growth is a highly regulated, plastic process. Its control involves balancing positive regulation of anabolic processes with negative regulation of catabolic processes. Although target of rapamycin (TOR) is a major promoter of growth in response to nutrients and growth factors, AMP-activated protein kinase (AMPK) suppresses anabolic processes in response to energy stress. Both TOR and AMPK are conserved throughout eukaryotic evolution. Here, we review the fundamentally important roles of these two kinases in the regulation of cell growth with particular emphasis on their mutually antagonistic signaling.
Collapse
Affiliation(s)
| | - Asier González
- Biozentrum, University of Basel, CH4056 Basel, Switzerland
| | - Michael N Hall
- Biozentrum, University of Basel, CH4056 Basel, Switzerland
| |
Collapse
|
|
47
|
Longo VD, Antebi A, Bartke A, Barzilai N, Brown‐Borg HM, Caruso C, Curiel TJ, Cabo R, Franceschi C, Gems D, Ingram DK, Johnson TE, Kennedy BK, Kenyon C, Klein S, Kopchick JJ, Lepperdinger G, Madeo F, Mirisola MG, Mitchell JR, Passarino G, Rudolph KL, Sedivy JM, Shadel GS, Sinclair DA, Spindler SR, Suh Y, Vijg J, Vinciguerra M, Fontana L. Interventions to Slow Aging in Humans: Are We Ready? Aging Cell 2015; 14:497-510. [PMID: 25902704 PMCID: PMC4531065 DOI: 10.1111/acel.12338] [Citation(s) in RCA: 382] [Impact Index Per Article: 38.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/11/2015] [Indexed: 12/17/2022] Open
Abstract
The workshop entitled ‘Interventions to Slow Aging in Humans: Are We Ready?’ was held in Erice, Italy, on October 8–13, 2013, to bring together leading experts in the biology and genetics of aging and obtain a consensus related to the discovery and development of safe interventions to slow aging and increase healthy lifespan in humans. There was consensus that there is sufficient evidence that aging interventions will delay and prevent disease onset for many chronic conditions of adult and old age. Essential pathways have been identified, and behavioral, dietary, and pharmacologic approaches have emerged. Although many gene targets and drugs were discussed and there was not complete consensus about all interventions, the participants selected a subset of the most promising strategies that could be tested in humans for their effects on healthspan. These were: (i) dietary interventions mimicking chronic dietary restriction (periodic fasting mimicking diets, protein restriction, etc.); (ii) drugs that inhibit the growth hormone/IGF-I axis; (iii) drugs that inhibit the mTOR–S6K pathway; or (iv) drugs that activate AMPK or specific sirtuins. These choices were based in part on consistent evidence for the pro-longevity effects and ability of these interventions to prevent or delay multiple age-related diseases and improve healthspan in simple model organisms and rodents and their potential to be safe and effective in extending human healthspan. The authors of this manuscript were speakers and discussants invited to the workshop. The following summary highlights the major points addressed and the conclusions of the meeting.
Collapse
|
|
48
|
Leontieva OV, Paszkiewicz GM, Blagosklonny MV. Comparison of rapamycin schedules in mice on high-fat diet. Cell Cycle 2015; 13:3350-6. [PMID: 25485580 DOI: 10.4161/15384101.2014.970491] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
At a wide range of doses, rapamycin extends life span in mice. It was shown that intraperitoneal injections (i.p.) of rapamycin prevent weight gain in mice on high-fat diet (HFD). We further investigated the effect of rapamycin on weight gain in female C57BL/6 mice on HFD started at the age of 7.5 months. By the age of 16 and 23 months, mice on HFD weighed significantly more (52 vs 33 g; p = 0.0001 and 70 vs 38 g; p < 0.0001, respectively) than mice on low fat diet (LFD). The i.p. administration of 1.5 mg/kg rapamycin, 3 times a week every other week, completely prevented weight gain, whereas administration of rapamycin by oral gavash did not. Rapamycin given in the drinking water slightly decreased weight gain by the age of 23 months. In addition, metabolic parameters were evaluated at the age of 16 and 23 months, 6 and 13 days after last rapamycin administration, respectively. Plasma leptin levels strongly correlated with body weight, (P < 0.0001, r=0.86), suggesting that the difference in weight was due to fat tissue mass. Levels of insulin, glucose, triglycerides and IGF1 were not statistically different in all groups, indicating that these courses of rapamycin treatment did not impair metabolic parameters at least after rapamycin discontinuation. Despite rapamycin discontinuation, cardiac levels of phospho-S6 and pAKT(S473) were low in the i.p.-treated group. This continuous effect of rapamycin can be explained by prevention of obesity in the i.p. group. We conclude that intermittent i.p. administration of rapamycin prevents weight gain without causing gross metabolic abnormalities. Intermittent gavash administration minimally affected weight gain. Potential clinical applications are discussed.
Collapse
Affiliation(s)
- Olga V Leontieva
- a Cell Stress Biology; Roswell Park Cancer Institute ; Buffalo , NY USA
| | | | | |
Collapse
|
|
49
|
Schosserer M, Grubeck-Loebenstein B, Grillari J. [Principles of biological aging]. Z Gerontol Geriatr 2015; 48:285-94. [PMID: 25700994 DOI: 10.1007/s00391-015-0857-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 01/12/2015] [Indexed: 12/01/2022]
Abstract
The aging process is the substrate on which aging-associated diseases develop; therefore, the scientific discipline of gerontology aims at understanding this biological aging process, which refers to the progressive increase in the risk of death caused by a loss of body functions. Studies in simple model organisms demonstrate that pharmacological substances, genetic interventions and dietary restriction can slow down the process of aging. The cell culture model of cellular senescence gives researchers the opportunity to conduct studies in a system more closely related to the human organism; therefore, cells from different human tissues are cultured in vitro until they stop proliferating. This permanent growth arrest is called cellular senescence. Recent studies have demonstrated that senescent cells also accumulate in many tissues in vivo and contribute to age-related pathologies.
Collapse
Affiliation(s)
- M Schosserer
- Department für Biotechnologie, BOKU - Universität für Bodenkultur Wien, Muthgasse 18, 1190, Wien, Österreich
| | | | | |
Collapse
|
|
50
|
Piano A, Titorenko VI. The Intricate Interplay between Mechanisms Underlying Aging and Cancer. Aging Dis 2015; 6:56-75. [PMID: 25657853 PMCID: PMC4306474 DOI: 10.14336/ad.2014.0209] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 01/30/2014] [Accepted: 02/09/2014] [Indexed: 12/15/2022] Open
Abstract
Age is the major risk factor in the incidence of cancer, a hyperplastic disease associated with aging. Here, we discuss the complex interplay between mechanisms underlying aging and cancer as a reciprocal relationship. This relationship progresses with organismal age, follows the history of cell proliferation and senescence, is driven by common or antagonistic causes underlying aging and cancer in an age-dependent fashion, and is maintained via age-related convergent and divergent mechanisms. We summarize our knowledge of these mechanisms, outline the most important unanswered questions and suggest directions for future research.
Collapse
Affiliation(s)
- Amanda Piano
- Department of Biology, Concordia University, Montreal, Quebec, Canada
| | | |
Collapse
|