Length, interelectrode spacing, electrode number and maximum depth below the modern topographic surface reached by each TM profile are listed.
\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"Milestone",originalUrl:"/media/original/124"}},components:[{type:"htmlEditorComponent",content:'
Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"10477",leadTitle:null,fullTitle:"Pheochromocytoma, Paraganglioma and Neuroblastoma",title:"Pheochromocytoma, Paraganglioma and Neuroblastoma",subtitle:null,reviewType:"peer-reviewed",abstract:"Pheochromocytoma, paraganglioma and neuroblastoma are the most common neural crest-derived tumors in adults and children, respectively. These neoplasms are associated with significant morbidity and mortality. Some international studies currently underway are researching and evaluating the presence of any similarities and differences between these tumors. Hopefully, future results will reveal several potential novel genes and pathways that might have major roles in the pathogenesis and progression of these neoplasms. This book discusses epidemiology, genetics, and treatment of these malignancies.",isbn:"978-1-83968-948-2",printIsbn:"978-1-83968-947-5",pdfIsbn:"978-1-83968-949-9",doi:"10.5772/intechopen.92492",price:119,priceEur:129,priceUsd:155,slug:"pheochromocytoma-paraganglioma-and-neuroblastoma",numberOfPages:130,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"ea4b534c4c57be0eaa9c5624c7e2b139",bookSignature:"Pasquale Cianci, Enrico Restini and Amit Agrawal",publishedDate:"August 18th 2021",coverURL:"https://cdn.intechopen.com/books/images_new/10477.jpg",numberOfDownloads:1664,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:0,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 30th 2020",dateEndSecondStepPublish:"December 9th 2020",dateEndThirdStepPublish:"February 7th 2021",dateEndFourthStepPublish:"April 28th 2021",dateEndFifthStepPublish:"June 27th 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"196218",title:"Dr.",name:"Pasquale",middleName:null,surname:"Cianci",slug:"pasquale-cianci",fullName:"Pasquale Cianci",profilePictureURL:"https://mts.intechopen.com/storage/users/196218/images/system/196218.png",biography:"General Surgeon at 'Lorenzo Bonomo” Hospital-Department of Surgery and Traumatology-ASL BAT-Andria-Puglia (Italy), and Ph.D. at the Department of Medical and Surgical Sciences, University of Foggia (Italy), Fellow of American College of Surgeons (FACS). Contract Professor in General and Emergency Surgery, Gastroenterology and Human Physiology, Faculty of Medicine - Nursing Science and Physiotherapy Courses. Professor in surgical anatomy at the specialty school in general surgery. Contract Professor of I Level Masters: Intestinal stoma care nurse, Operating room nurse and Emergency medicine and critical area. Member of some of the most important Italian Scientific Surgical Societies: EAES, SICE, ACOI, SPIGC, SIUCP, ACS. Author of 70 national and international scientific papers, books and book chapters which are well appreciated in the health community. Editorial Board member of Frontiers in Surgical Oncology, BMC Surgery, Annals of Medicine, WJSP, Asian Journal of Research and Reports in Endocrinology, IntechOpen Edition. Reviewer of major international scientific journals such as Medicina, the Turkish Journal of Gastroenterology, Medical Principles and Practice, IntechOpen Edition, World Journal of Surgical Procedures, Oxford Medical Case Reports, BMJ Case Reports, Austin Pancreat Disord, World Journal of Gastroenterology, Case Studies in Surgery, World Journal of Surgical Oncology, Journal of Cancer and Tumor International, Journal of Basic and Applied Research International, International Journal of Medical and Pharmaceutical Case Reports, British Journal of Medicine and Medical Research, Faculty and Speaker at numerous national and international Surgical Congresses. Special interest in laparoscopic surgery, robotic surgery, endocrine surgery and coloproctology.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"University of Foggia",institutionURL:null,country:{name:"Italy"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"302435",title:"Dr.",name:"Enrico",middleName:null,surname:"Restini",slug:"enrico-restini",fullName:"Enrico Restini",profilePictureURL:"https://mts.intechopen.com/storage/users/302435/images/system/302435.jpg",biography:"Enrico Restini, MD, is head of the Department of Surgery and Traumatology-Andria, Italy. He is a contract professor in Surgery and Health Management and an expert in advanced technologies and their impact on health organizations (HTA) (LUM University-BA). Since 2007, Dr. Restini has been honorary president of the Apulian section of Aistom. He is a member of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), the Italian Society of Endoscopic and Minimally Invasive Surgery (SICE), SICOB, SIC, Italian Society of Private Hospital Surgery, and Association of Italian Hospital Surgeons (ACOI). He is a founding member of ARTOI, and has been a SICE National Councilor since 2012. He has spoken at numerous national and international surgical congresses and authored fifty national and international scientific papers. His special interests include laparoscopic surgery, robotic surgery, endocrine surgery, and digestive surgery.",institutionString:"ASL BAT - Department of Surgery and Traumatology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:{id:"100142",title:"Prof.",name:"Amit",middleName:null,surname:"Agrawal",slug:"amit-agrawal",fullName:"Amit Agrawal",profilePictureURL:"https://mts.intechopen.com/storage/users/100142/images/system/100142.jfif",biography:"Dr. Agrawal completed his neurosurgery training at the National Institute of Mental Health and Neurosciences, Bangalore, India, in 2003. He is a self-motivated, enthusiastic, and results-oriented professional with more than eighteen years of experience in research and development, as well as teaching and mentoring in the field of neurosurgery. He is proficient in managing and leading teams for running successful process operations and has experience in developing procedures and service standards of excellence. He has attended and participated in many international and national symposiums and conferences and delivered lectures on vivid topics. Dr. Agrawal has published more than 750 scientific articles in various national and international journals. His expertise is in identifying training needs, designing training modules, and executing the same while working with limited resources. He has excellent communication, presentation, and interpersonal skills with proven abilities in teaching and training various academic and professional courses. Presently, he is working at the All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India.",institutionString:"All India Institute of Medical Sciences",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"8",institution:{name:"All India Institute of Medical Sciences",institutionURL:null,country:{name:"India"}}},coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"428",title:"Cancer Biology",slug:"biochemistry-genetics-and-molecular-biology-oncology-cancer-biology"}],chapters:[{id:"76248",title:"Introductory Chapter: Neural Crest Cell-Derived Tumors. An Introduction on Pheocromocytoma, Paraganglyoma and Neuroblastoma",doi:"10.5772/intechopen.97386",slug:"introductory-chapter-neural-crest-cell-derived-tumors-an-introduction-on-pheocromocytoma-paraganglyo",totalDownloads:166,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Pasquale Cianci, Giandomenico Sinisi and Sabino Capuzzolo",downloadPdfUrl:"/chapter/pdf-download/76248",previewPdfUrl:"/chapter/pdf-preview/76248",authors:[{id:"196218",title:"Dr.",name:"Pasquale",surname:"Cianci",slug:"pasquale-cianci",fullName:"Pasquale Cianci"},{id:"196220",title:"Dr.",name:"Sabino",surname:"Capuzzolo",slug:"sabino-capuzzolo",fullName:"Sabino Capuzzolo"},{id:"357493",title:"Dr.",name:"Giandomenico",surname:"Sinisi",slug:"giandomenico-sinisi",fullName:"Giandomenico Sinisi"}],corrections:null},{id:"74954",title:"Pheochromocytomas and Paragangliomas: Genotype-Phenotype Correlations",doi:"10.5772/intechopen.95888",slug:"pheochromocytomas-and-paragangliomas-genotype-phenotype-correlations",totalDownloads:236,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Pheochromocytomas and paragangliomas are rare neuroendocrine tumors, with genetic background in about 40% of cases, involving more than 30 susceptibility genes. The susceptibility genes can be divided into three main molecular clusters: pseudohypoxic, kinase signaling, and Wnt signaling. Biochemical characterization of these particular tumors should be integrated into the diagnostic algorithm because it can help apply personalized medicine principles and targeted therapy. These tumors can present with very different genotype-phenotype correlations, and their characterization can help the clinical practitioner make optimal clinical management decisions and prioritize genetic testing. This chapter summarizes the most important aspects of genetics and clinical characteristics, together with new genotype-phenotype correlation data.",signatures:"Diana Loreta Paun and Alexandra Mirica",downloadPdfUrl:"/chapter/pdf-download/74954",previewPdfUrl:"/chapter/pdf-preview/74954",authors:[{id:"190860",title:"Dr.",name:"Diana Loreta",surname:"Paun",slug:"diana-loreta-paun",fullName:"Diana Loreta Paun"},{id:"335620",title:"Dr.",name:"Alexandra",surname:"Mirica",slug:"alexandra-mirica",fullName:"Alexandra Mirica"}],corrections:null},{id:"75125",title:"Metastatic Paragangliomas and Pheochromocytomas: An Epigenetic View",doi:"10.5772/intechopen.96126",slug:"metastatic-paragangliomas-and-pheochromocytomas-an-epigenetic-view",totalDownloads:294,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Paragangliomas and pheochromocytoma (PPGLs) are hereditary tumors in about 40% of cases. Mutations in the genes encoding for components of the mitochondrial succinate dehydrogenase protein complex (SDHB, SDHD, SDHC) are among the most prevalent. Most PPGLs have a benign behavior, but patients with germline SDHB mutations may develop metastatic PPGLs in up to 30% of cases. This suggest that the SDH substrate, succinate, is key for the activation of the metastatic cascade. The last decade has witnessed significant advances in our understanding of how succinate may have oncogenic properties. It is now widely accepted that succinate is an oncometabolite that modifies the epigenetic landscape of SDH-deficient tumors via modulating the activities of DNA and histone modification enzymes. In this chapter, we summarize recent discoveries linking SDH-deficiency and metastasis in SDH-deficient PPGLs via inhibition of DNA methylcytosine dioxygenases, histone demethylases and modified expression of non-coding RNAs. We also highlight promising therapeutic avenues that may be used to counteract epigenetic deregulations.",signatures:"María-Dolores Chiara, Lucía Celada, Andrés San José Martinez, Tamara Cubiella, Enol Álvarez-González and Nuria Valdés",downloadPdfUrl:"/chapter/pdf-download/75125",previewPdfUrl:"/chapter/pdf-preview/75125",authors:[{id:"334857",title:"Prof.",name:"María-Dolores",surname:"Chiara",slug:"maria-dolores-chiara",fullName:"María-Dolores Chiara"},{id:"345989",title:"MSc.",name:"Andrés",surname:"San José Martinez",slug:"andres-san-jose-martinez",fullName:"Andrés San José Martinez"},{id:"345990",title:"MSc.",name:"Enol",surname:"Álvarez-González",slug:"enol-alvarez-gonzalez",fullName:"Enol Álvarez-González"},{id:"345991",title:"MSc.",name:"Tamara",surname:"Cubiella",slug:"tamara-cubiella",fullName:"Tamara Cubiella"},{id:"345992",title:"Ph.D. Student",name:"Lucía",surname:"Celada",slug:"lucia-celada",fullName:"Lucía Celada"},{id:"345994",title:"Dr.",name:"Nuria",surname:"Valdés",slug:"nuria-valdes",fullName:"Nuria Valdés"}],corrections:null},{id:"75164",title:"Surgical Approach in Pheochromocytoma",doi:"10.5772/intechopen.96066",slug:"surgical-approach-in-pheochromocytoma",totalDownloads:206,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Pheochromocytomas are tumors composed of chromaffin cells that can produce, secrete and metabolise catecholamines. The surgical excision procedure of these tumors may present the risk of significant variations in blood pressure, as well as the chance of cardiovascular complications in the perioperative period. During surgery, patients may be at risk for cardiovascular events such as major variations in blood pressure, pulmonary edema, stroke, myocardial infraction and a long period of intubation. The surgical approach to pheochromocytomas must always be preceded by accurate imaging evaluation, endocrine screening and identification of associated genetic mutations. In addition, the surgical technique of choice consists in using minimally invasive surgical methods, with a transabdominal or retroperitoneal approach.",signatures:"Radu Mihail Mirica and Sorin Paun",downloadPdfUrl:"/chapter/pdf-download/75164",previewPdfUrl:"/chapter/pdf-preview/75164",authors:[{id:"337478",title:"Dr.",name:"Sorin",surname:"Paun",slug:"sorin-paun",fullName:"Sorin Paun"},{id:"337479",title:"Dr.",name:"Radu Mihail",surname:"Mirica",slug:"radu-mihail-mirica",fullName:"Radu Mihail Mirica"}],corrections:null},{id:"77159",title:"Primary Central Nervous System Neuroblastoma: An Enigmatic Entity",doi:"10.5772/intechopen.98244",slug:"primary-central-nervous-system-neuroblastoma-an-enigmatic-entity",totalDownloads:261,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Neuroblastoma is one of the most common solid tumour in the paediatric age group. Central nervous system (CNS) involvement in neuroblastoma is commonly due to metastasis from the extracranial primary. Primary CNS Neuroblastoma (PCNS-NB) is a rare entity and highlights errors in development of neural crest cells and CNS. A lot has been published since the first description of PCNS-NB four decades ago. Over the years, neuroscientists, geneticists, and clinicians have improved the understanding of PCNS-NB. PCNS-NB is an enigmatic entity with variable presentation, epidemiology, clinical features and outcomes. Recent update in knowledge is seen in 2016 WHO classification of CNS tumours with reclassification of CNS neuroblastoma. It further subclassified different histological variants of PCNS-NB and its molecular correlates. Most common histological subtype of PCNS-NB is neuroblastoma followed by ganglioneuroblastoma. Studies support the view that younger age group, less number of lesions, ganglioneuroblastoma histology subtype and surgical management are good prognostic indicators. This chapter provides an updated overview of epidemiology, clinical features, histological and molecular diagnosis, and outcomes of PCNS-NB in addition to the role of adjuvant therapy.",signatures:"Rakesh Mishra and Amit Agrawal",downloadPdfUrl:"/chapter/pdf-download/77159",previewPdfUrl:"/chapter/pdf-preview/77159",authors:[{id:"100142",title:"Prof.",name:"Amit",surname:"Agrawal",slug:"amit-agrawal",fullName:"Amit Agrawal"},{id:"419056",title:"Dr.",name:"Rakesh",surname:"Mishra",slug:"rakesh-mishra",fullName:"Rakesh Mishra"}],corrections:null},{id:"75419",title:"The Scaffold Protein p140Cap as a Molecular Hub for Limiting Cancer Progression: A New Paradigm in Neuroblastoma",doi:"10.5772/intechopen.96383",slug:"the-scaffold-protein-p140cap-as-a-molecular-hub-for-limiting-cancer-progression-a-new-paradigm-in-ne",totalDownloads:236,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Neuroblastoma, the most common extra-cranial pediatric solid tumor, is responsible for 9–15% of all pediatric cancer deaths. Its intrinsic heterogeneity makes it difficult to successfully treat, resulting in overall survival of 50% for half of the patients. Here we analyze the role in neuroblastoma of the adaptor protein p140Cap, encoded by the SRCIN1 gene. RNA-Seq profiles of a large cohort of neuroblastoma patients show that SRCIN1 mRNA levels are an independent risk factor inversely correlated to disease aggressiveness. In high-risk patients, SRCIN1 was frequently altered by hemizygous deletion, copy-neutral loss of heterozygosity, or disruption. Functional assays demonstrated that p140Cap is causal in dampening both Src and Jak2 kinase activation and STAT3 phosphorylation. Moreover, p140Cap expression decreases in vitro migration and anchorage-independent cell growth, and impairs in vivo tumor progression, in terms of tumor volume and number of spontaneous lung metastasis. p140Cap also contributes to an increased sensitivity of neuroblastoma cells to chemotherapy drugs and to the combined usage of doxorubicin and etoposide with Src inhibitors. Overall, we provide the first evidence that SRCIN1/p140Cap is a new independent prognostic marker for patient outcome and treatment, with a causal role in curbing the aggressiveness of neuroblastoma. We highlight the potential clinical impact of SRCIN1/p140Cap expression in neuroblastoma tumors, in terms of reducing cytotoxic effects of chemotherapy, one of the main issues for pediatric tumor treatment.",signatures:"Giorgia Centonze, Jennifer Chapelle, Costanza Angelini, Dora Natalini, Davide Cangelosi, Vincenzo Salemme, Alessandro Morellato, Emilia Turco and Paola Defilippi",downloadPdfUrl:"/chapter/pdf-download/75419",previewPdfUrl:"/chapter/pdf-preview/75419",authors:[{id:"47942",title:"Prof.",name:"Paola",surname:"Defilippi",slug:"paola-defilippi",fullName:"Paola Defilippi"},{id:"60247",title:"Prof.",name:"Emilia",surname:"Turco",slug:"emilia-turco",fullName:"Emilia Turco"},{id:"346179",title:"Dr.",name:"Giorgia",surname:"Centonze",slug:"giorgia-centonze",fullName:"Giorgia Centonze"},{id:"346180",title:"Dr.",name:"Jennife",surname:"Chapelle",slug:"jennife-chapelle",fullName:"Jennife Chapelle"},{id:"346181",title:"Dr.",name:"Costanza",surname:"Angelini",slug:"costanza-angelini",fullName:"Costanza Angelini"},{id:"346182",title:"Dr.",name:"Dora",surname:"Natalini",slug:"dora-natalini",fullName:"Dora Natalini"},{id:"346183",title:"Dr.",name:"Davide",surname:"Cangelosi",slug:"davide-cangelosi",fullName:"Davide Cangelosi"},{id:"346184",title:"Dr.",name:"Vincenzo",surname:"Salemme",slug:"vincenzo-salemme",fullName:"Vincenzo Salemme"},{id:"346185",title:"Dr.",name:"Alessandro",surname:"Morellato",slug:"alessandro-morellato",fullName:"Alessandro Morellato"}],corrections:null},{id:"75151",title:"Targeting MYC and HDAC8 with a Combination of siRNAs Inhibits Neuroblastoma Cells Proliferation In Vitro and In Vivo Xenograft Tumor Growth",doi:"10.5772/intechopen.96021",slug:"targeting-myc-and-hdac8-with-a-combination-of-sirnas-inhibits-neuroblastoma-cells-proliferation-in-v",totalDownloads:267,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"HDAC8, c MYC and MYCN are involved in the tumorigenesis of neuroblastoma. A mouse Neuroblastoma (NB) tumor model was used to understand the role of miRNA, miR-665 in NB tumorigenesis and cellular differentiation. During cellular differentiation of NB cells there is an up regulated miRNA-665. We found that HDAC 8, c MYC and MYCN are the direct targets of mimic miR-665 which was validated by luciferase reporter plasmid with 3’ UTR and ELISA. Mimic miR-665 inhibited cell proliferation, arrested cells in G1 stage and decreased S Phase in cell cycle. miR-665 increased the acetylation of histones and activated Caspase 3. This is the first report to recognize miRNA 665 as a suppressor miRNA of NB. The effects of miR-665 were confirmed with the transfection of siRNA for HDAC8 and siRNA for MYC. Individual siRNA- HDAC8 or siRNA-MYC inhibited 40–50% of cell proliferation in vitro, however, the treatment with the combination of both siRNA-MYC + siRNA- HDAC8 inhibited 86% of cell proliferation. Indicating that both the targets c MYC and HDAC 8 should be reduced to obtain a significant inhibition of cell proliferation. Intratumoral treatment of xenograft tumors in mice with the combination of siRNA-MYC + siRNA- HDAC8 reduced the levels of target c-MYC protein by 64% and target HDAC 8 protein by 85% and the average tumor growth reduced by 80% compared to control tumors treated with NC-siRNA. Our results suggest the potential therapeutic effect of suppressor miR-665 and the combination of siRNA-MYC + siRNA-HDAC8 for neuroblastoma treatment.",signatures:"Nagindra Prashad",downloadPdfUrl:"/chapter/pdf-download/75151",previewPdfUrl:"/chapter/pdf-preview/75151",authors:[{id:"338413",title:"Ph.D.",name:"Nagindra",surname:"Prashad",slug:"nagindra-prashad",fullName:"Nagindra Prashad"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"6591",title:"Proctological Diseases in Surgical Practice",subtitle:null,isOpenForSubmission:!1,hash:"df22314ee5125fe03618cc962080552f",slug:"proctological-diseases-in-surgical-practice",bookSignature:"Pasquale Cianci",coverURL:"https://cdn.intechopen.com/books/images_new/6591.jpg",editedByType:"Edited by",editors:[{id:"196218",title:"Dr.",name:"Pasquale",surname:"Cianci",slug:"pasquale-cianci",fullName:"Pasquale 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Pompeii, a famous ancient city in the Southern Italy, is located southeast of Naples in the Sarno Plain at the base of the Somma-Vesuvius volcano and about 2 km from the present Tyrrhenian coastline (Figure 1). The Sarno Plain is part of the Campania Plain, a wide Plio-Pleistocene tectonically depressed area (graben) bounded by Mesozoic and Cenozoic carbonate mountains. The graben is partially filled by alluvial, transitional, and marine deposits that are interbedded with pyroclastic deposits mainly from the eruption of the Somma-Vesuvius [1]. The geography and the development of land and population of the Campania Plain have all been conditioned by the volcanic activity [2–4]. The Late Pleistocene and Holocene volcanic activity of the Somma-Vesuvius is characterized by catastrophic Plinian and sub-Plinian eruptions, followed by inter-Plinian and quiescence phases [5–8]. During the settlement of Pompeii, the volcanic activity was weak or absent and the population ignored how danger was the area.
\nLocation map of the Campania Plain – Gulf of Naples. Pompeii, other population centers, and geographic features are showed.
Pompeii was founded at the end of the seventh century BC by the Oscans, a population from central Italy [9, 10]. The town was built on a lava flow or on a separate volcano [11] associated with eruptive events of the Somma-Vesuvius.
\nArchaeological area of Pompeii. The archaic part of the city and other archaeological features are showed and the position of archaeological excavations and of unexcavated areas is located. The numbers correspond to the topographic elevation.
Long before its major destruction by the well-documented earthquake in 62 AD [12, 13], and its final demise from the Plinian eruption in 79 AD (called the Pompeii eruption; e.g., [14–17]), Pompeii was damaged by two alluvial mass flows [18, 19]. These pre-79 AD volcaniclastic deposits had been emplaced by avalanches, slumps, and associated debris flows (secondary lahars) during volcanically quiescent phases of the Somma-Vesuvius volcano [20]. These deposits were transported and channelized along stream beds, some of which, extended to the immediate proximity of the northern wall of the city. Nowadays, there are no obvious rivers that would indicate how gravity flows would have reached into the walled city, but there is a stream, named Conte Sarno Canal, extending from the base of the Pizzo D’Alvano Mount (1133 m elevation; Figure 1) about 15 km to the northeast from Pompeii. On the northeastern side of the city, the stream shows a large bend (meander) due to the sudden change of the topographic relief occurred as a result of the barrier caused by the lava mound upon which Pompeii was built. The stream originally flowed from the Avella Mountains (Figure 1) and, during the Samnite occupation of the city (V–IV century BC), was associated with springs located at the base of the Pizzo D’Alvano ridge [21]. Borehole data collected northwest of the city indicate that a fluvial system reached Pompeii outside of Capua Gate (Figure 2). According to [18], the fluvial system was an artificial branch of the Conte Sarno Canal that was diverted toward west and had most likely been excavated to supply the city with water. It was constructed by Samnites as evidenced from the modifications performed along the path of Conte Sarno Canal discovered by [21].
\nThis chapter has two aims: the first is to show the characteristics and the path of the artificial canal discovered to the north of Pompeii, which provided water to the city; the second is to detail the flood units by new borehole data carried out in the south of the ancient city.
\nPreviously the historians studying Pompeii have long suggested that the city’s water needs were derived from the Sarnus River (modern Sarno River; Figure 1), the largest fluvial system in the area [22–24]. However, nowadays, the modern Sarno channel is positioned to the southeast and south of Pompeii, and the meandering course of the ancient Sarnus River and its delta, identified by analysis of the sediment collected in boreholes, was located at least 1 km south and southwest of the ancient city walls [18, 24–29]. Moreover, the elevation pattern within the city shows that Capua and Vesuvius gates are both positioned at highest elevations (Figure 2). Therefore, they occupy strategic points for distribution of the city’s water supply. It was from here that water of the artificial canal, entering into the city, discharged by gravity, was able to activate three water wheels (Figure 2) located at the edge of the archaic city [30, 31]. However, this artificial canal was also very dangerous because it had been the cause of two of three floods that led to extensive damage to the city. In fact, Senatore et al. [18] have identified, both within the city and outside it, three units referred to debris-flow deposits dated between the eighth and the second century BC. These mass flows are interpreted as having been triggered primarily by intense rains and channelized via the stream that once extended from high reliefs toward Pompeii and, then, through the artificial canal that reached the city. According to these authors, one of these events may have been partially responsible for urban decline during the fourth century BC. New data on the characteristics and distribution of the alluvial deposits related to the two more recent flood events will be analyzed. The interpretation of geological data will prove that a resource, the water, in some cases can turn out to be a geohazard.
\nThe aim of the researches, carried out in the Pompeii territory since 1995, has been the reconstruction of the paleo-landscape prior to the AD 79 Vesuvius eruption by means of geological stratigraphy and facies analysis. As the studied area is strongly urbanized, about 100 continuous drill-cores were carried out. The detailed stratigraphy of sediments in these drill-cores has been the base reference to re-interpret about 400 logs of older drill-cores. In this chapter, the results of analyses of several boreholes recovered to the northwest (C in Figure 3), south, and inside of the city (F in Figure 3) are detailed.
\nSeveral archeological excavations in the city were analyzed (Figure 2 and S in Figure 3). An electrical resistivity tomography (ERT) profile (TM1 in Table 1 and Figure 3) was recorded on the unexcavated front of a dig carried outside of Capua Gate (Figure 2) made by the Japan Institute of Paleontological Studies of Kyoto [32]. The dig brought to light an artificial canal and the TM1 ERT profile analyzed by [18] was made to obtain additional information on the subsurface stratigraphic architecture.
\nSince 2013, four more ERT profiles were carried out (Table 1 and Figure 3) to reconstruct the path of the artificial canal. The equipment included an MAE A3000E Georesistimeter. The electrical-resistivity measurements recorded were processed through the inversion software RES2DINV by GEOTOMO INTERNATIONAL. The Wenner-Schlumberger and dipole-dipole-array methods were employed as a measure of resistance distribution; Res3DInv software was used for data interpretation. Additional information on the geoelectric equipment and settings used are available in two internal reports [33, 34].
\nPosition of: (C) boreholes passing through the channel units; (F) boreholes passing through flood units; (S) excavations in the city; and (TM) electrical resistivity tomography (ERT) profiles. Section traces are also indicated.
Tomography | \nInterelectrode spacing | \nElectrode number | \nProfile length | \nTrending | \nMaximum depth reached | \n
---|---|---|---|---|---|
TM1 | \n5.0 m | \n24 | \n115 m | \nN 350° E | \n20.0 m | \n
TM2 | \n1.9 m | \n48 | \n89.3 m | \nN 344° E | \n17.0 m | \n
TM3 | \n2.5 m/5.0 m | \n72 | \n182.5 m | \nN 350° E | \n23.0 m | \n
TM4 | \n5.0 m | \n24 | \n115.0 m | \nN 340° E | \n22.5 m | \n
TM5 | \n2.5 m | \n48 | \n117.5 m | \nN 330° E | \n23.0 m | \n
Length, interelectrode spacing, electrode number and maximum depth below the modern topographic surface reached by each TM profile are listed.
Drilling of the cores was performed without the use of circulation fluid to better preserve sedimentary structures, textures, and fabric. Macroscopic characters of the core sediment were defined by a caliper for granules and pebble-size clasts while the grain-size of sand was determined optically by using visual comparison charts. These also allowed to assess clast rounding, sphericity, and sediment sorting. The sediment color was determined by means of the Munsell Soil Color Charts [35], and the thickness of sediment units was defined according to [36]. Selected samples were also analyzed and statistical parameters were even calculated using standard methodologies [37, 38]. Graphic stratigraphic logs were plotted of each drill-core examined.
\nThe sediment cores and logs that constitute the geostratigraphic archive for the study area are stored at the Laboratory of Applied Researches of the Soprintendenza Archeologica at Pompeii.
\nThe AMS radiocarbon analysis reported by Senatore et al. [18] is used to insert the identified units in a chronostratigraphic framework. The base map of Figures 3 and 7 is an official georeferenced topographic map produced at 1:5000 scale.
\n\n\nThe geological interpretations were integrated with the available archeological information.
\nThe stratigraphic units, identified in the boreholes carried out northwest of Pompeii (Figure 3), are composed mostly of volcaniclastic deposits both in primary deposition (eruptive products) and secondary deposition (reworked deposits). Their thickness is from centimeters to several meters, with a highly variable lateral distribution.
\nSeven stratigraphic units have been identified in a section trending northeast-southwest (from A to B in Figure 3). From the topographic surface, they are (Figure 4):
\n- Uc1 represents the deposition following the AD 79 eruption and consists of volcaniclastic sand with brown clay matrix. Plant matter, especially roots, are present. In the upper unit, the sediments are mixed with material linked to the human activity, mainly fragments of brick and pottery. The thickness ranges from few centimeters to 3 m. The basal contact is always sharp.
\n- Uc2 represents part of the AD 79 eruption deposits and consists of two layers of pumice. The first one is composed of gray pumice, several centimeters in diameter in a volcaniclastic fine sand matrix. The second one is composed of white pumice, few centimeters in diameter. In some cases, the gray and white pumice are mixed to form a single layer. The thickness of the unit is from about 2 m to about 5 m.
\n- Uc3 represents the Roman and pre-Roman deposits and consists of brown coarse to fine well-rounded volcaniclastic sand. Rounded pumice (few centimeters in diameter) and lapilli clasts, and angular and subangular fragments of artifacts and of animal bones are found in this unit.\n\n
The character of the Uc3 deposits allows to define a fluvial channel and the Uc2 deposits as a channel fill while the Uc1 deposits cover the previous units hiding the preexisting morphologies.
\n\nCross section (A and B) showing the stratigraphic architecture of the units that constitute the northern Pompeii succession (position in
- Uc4 is constituted by dark gray, coarse to very fine volcaniclastic deposits with rounded centimetric pumice and lapilli clasts. These deposits are found in the C5 borehole, showing a thickness of about 5 m, and in the C4 borehole with a thickness of 12 m. They are typical of transitional environment and have been correlated to the well-known Bottaro ridge deposits [18], cropping out southwest to the archeological site. They represent an ancient shoreline with radiocarbon age of about 3600 yr/BP [39].\n
\n- Uc5 is composed of dark yellow, silty clay deposits with centimetric, rounded, gray pumice and lava clasts. They are found in the C4 borehole with a thickness of about 10 m. The character of the sediment, well known in other analyzed boreholes, allows the correlation to a marine environment linked of the Messigno ridge deposits [18, 23], cropping out southeast to the archeological site inland to the Bottaro ridge. Messigno ridge also represents an ancient shoreline with radiocarbon age of about 5600 yr/BP [39].\n
The Messigno and Bottaro ridge deposits are found at higher elevations than those with the same age studied in other tectonically stable areas. Significant Holocene ground movements at Somma-Vesuvius area are in fact recorded [40–42].
\n\n- Uc6 is constituted by very dark brown, silty clay deposits with weathered white pumice clasts, some millimeter in size, and some remains of roots. This layer is a paleosol and is present at the base of C4 borehole below the Messigno ridge deposits with a thickness of several centimeters, in the C1 borehole at the base of the Uc3 unit, and on the top of the Uc7 unit with a thickness of 2 m. This is lacking in the C2 and C3 boreholes, probably due to an artificial excavation.\n
\n- Uc7 is represented by the scoriaceous top of the lava layer that constitutes a morphological high on which the ancient city was built. This unit is found in the C1 borehole where, below the scoriaceous layer, the lava is present; while in the C2 borehole, the scoriaceous layer is just reached. The Uc7 unit is considered the base of the northwestern Pompeii succession.
\nFour electrical resistivity tomography (ERT) profiles were acquired to obtain additional information on the subsurface paleogeography based on the water content in the sediment referring to the resistivity values that are from about 10 ohms/m, indicating high humidity up to water presence in the sediment, to 2900 ohms/m, indicating complete absence of water.
\nThe profile trend is NNW-SSE (Figure 3). Table 1 shows the length, interelectrode spacing, electrode number and maximum depth below the modern topographic surface reached by each TM profile.
\nElectrical resistivity tomography (ERT profiles; location in
The TM1 profile shows two resistivity anomalies (AN1 and AN2), with resistivity values ranging between 222 ohms/m and 129 ohms/m (Figure 5). These anomalies are interpreted, respectively, as the levee and axis of an artificial canal since this profile was performed on the unexcavated dig-front of an archeological excavation outside of Capua Gate (Figure 2) and made to examine the subsurface beneath the 79 AD eruption deposits [18]. The archeological excavation has revealed the presence of an artificial canal, which is in the coincidence of the anomaly AN2 on TM1 of Figure 5, as there is a close match with regards to both its position relative to electrodes and its depth beneath the present topographic surface. The AN1 on TM1 represents the levee of the canal (see Figure 6 in [18]). Resistivity values ranging between 382 ohms/m and 659 ohms/m, recorded at the base of profile, are interpreted as the top of the lava layer on which the channel is excavated and Pompeii was built.
\n\n\nTwo other ERT anomalies are identified on TM1 (AN3 and AN4 in Figure 5) that have generally circular shapes, one of which (AN4) occurs in the archeological area that has not yet been excavated. Anomaly AN3, positioned near the wall, presents a series of concentric resistivity values, which range from 129 ohms/m at the periphery to 14.6 ohms/m at the center of the feature. These values suggest the presence of sediments characterized by high humidity or, possibly, water content. The characteristics of anomaly AN3, the base of which is at the same depth as that of the channel mapped in the excavation, have suggested an anthropogenic structure, probably linked to the water supply distribution to Pompeii [18]. Anomaly AN4, with circular profile and smaller size than AN3, has resistivity values at its center comparable to those of the channel (222 ohms/m and 129 ohms/m). This is interpreted as a smaller channeling feature such as a duct or conduit that was probably related to the city’s water distribution system as well [18].
\nThe other four ERT profiles were carried out to trace the path of the artificial canal excavated to carry water to the city, starting from the wide meander of the stream flowing from the inland mountains. In the TM2 profile (Figure 5), the canal is identified between electrodes 50 and 76 and between about 7 m and 14 m in depth while the resistivity ranges from 10 ohms/m to 114 ohms/m. In the TM3 profile, the canal is identified between electrodes 70 and 85, and at depth from 5 m to about 20 m. The resistivity ranges from about 50 ohms/m to 114 ohms/m. In these two profiles, the shape of the channel is unnatural, clearly artifact, to allow the flow of the water in the canal by gravity.
\nElectrical resistivity tomography (ERT profiles; location in
TM4 and TM5 profiles show the canal between electrodes 35–55 and 25–32, respectively, where the depth is from about 2 m to 10 m (Figure 6). The resistivity values are between 10 ohms/m and 114 ohms/m.
\n\nFigure 7 shows the path of the canal, which develops from Capua Gate, where, according to [18], a water basin and a conduit, supplied water to Pompeii. The water, entering the city, was then distributed utilizing the gravity. In fact, as stated before, the elevation is greater in this area, and it gradually decreases toward Stabia Gate and the archaic part of the city on the edge of which, the flowing water activated the water wheels (Figure 2). The channel path continues toward Vesuvius Gate, touching a farm (Villa Rustica Suburbana) with a foundry [43, 44] and then toward Villa of Mysteries.
\nReconstruction of the path of the artificial canal made by means of ERT profiles and sediments collected in the C boreholes.
The low-resistivity values recorded on the ERT profiles, in connection with the canal, indicate sediment characterized by high humidity up to contain water. They suggest that the canal incision, even today that it is filled by sediments, represents a preferential path for the water flow below the topographic surface.
\nThree flow units, termed Uf1, Uf2, and Uf3 (Figures 8 and 9), from the lava base of the succession upward, have been identified in the boreholes carried out the city and the surrounding area (Figure 3). Root structures at boundaries between the units indicate that some time has elapsed between the deposition of different mass-flow events.
\nCross sections: (1) through the flood units (F) to north of Pompeii; (2) through the flood units to south of (position in
- Uf1 is composed of massive volcaniclastic deposits with rounded volcanic clasts, rounded to angular fragments of animal bone and plant matter. The unit has a thickness from 1 to 5 m, and rests on the lava upon which Pompeii was built (F1 and F2 in Figure 8
The flood units cropping out in the archaeological excavation and laterally to the Guard Tower door (see text for details).
- Uf2 is identified within and outside city walls (Figure 8(1 and 2)), and is constituted of massive volcaniclastic deposits, mainly structureless, or with some thinner cross or planar lamination at the base unit. The matrix is prevalent, with clasts randomly oriented, or, some, may show imbricate structures. The clasts are represented by rounded volcanic clasts and calcareous pebbles, rounded to angular fragments of brick and ceramics, plaster, animal bone, and plant matter. This unit has an average thickness of ~2 m. In the archaic city, the Uf2, between two construction levels, incises Uf1 and covers an older building level (S2 in Figure 9). It can be reconstructed that the older dwelling, built upon Uf1, has been damaged by the Uf2 deposits. Subsequently, a new structure was built at a higher elevation upon the Uf2 and was used until its destruction by the 79 AD eruption.
\n\nGuard Tower (position in
- Uf3 is composed of matrix-prevalent volcaniclastic deposits with randomly distributed clasts that commonly comprise rounded volcanic clasts and rounded to angular fragments of pottery, plaster, animal bone, and plant matter. These deposits have an average thickness of ~1 m, occurring along the northern city wall (F1 and F2 in Figure 8(1)). In F3, Uf3 buries an ancient road trending from the city toward Villa of the Mysteries (Figures 3 and 8(1)). Section S1 (in Figure 9) is located laterally to the door of a Guard Tower (Figures 2 and 10) and shows the Uf3 character. The Guard Towers were added to the city wall during the second century BC [45]; the tower doors, openings at their base, nowadays, occur beneath the topographic surface of the AD 79 (Figure 10). They have been buried by Uf3 deposits and were used until the AD 79 eruption after the removal of the Uf3 material. The radiocarbon-dated animal bone gave a calibrated age of 170 years BC [18].
\nThe sediment characteristics of the three Uf units indicate that mass gravity mechanisms, especially debris flow, were the dominant processes responsible for their transport, and the two younger units had flooded Pompeii causing severe damage to the city. The volcaniclastic sediment with matrix-supported clasts likely originated as slope collapse and avalanche displacement from the flanks of calcareous terrains of mountains to the NE (Pizzo D’Alvano area; Figure 1). During landslides, slumped masses of unconsolidated material can be transformed to high-concentration debris flows as has been recorded in volcanic areas elsewhere [46]. Confined within downslope-trending depressions, such as channels, flows can travel considerable distances toward lowlands by expanding in volume during transport through a bulking mechanism that involves incorporation of additional sediment and water [47]. In the studied area, these deposits were released from hyperconcentrated slumps and debris flows that had incorporated sediment and water during the course of downslope transport in the fluvial channel. The first flood event, which had not occurred through the canal, took place in 764 BC, before the foundation of the city was built [18], and has affected a wide area of the Sarno Plain.
\nThe available data allow to reconstruct the hypothetical phenomena that can be occurred in a temporal sequence during the emplacement of the second and third flood events, linked both to the canal built by the Samnitic population for water supply [18]. Therefore, the flow, in the fluvial channel, reached the great bend to north of Pompeii. Hence it was channeled in the artificial canal and continued its course within it. In the proximity of the Capua Gate, the canal width being narrower than that of the fluvial channel, the flow overflowed its banks thus flooding the city. This event caused severe damage in the archaic city (S2 in Figure 9). According to [18], this flood could have occurred during the fourth century BC. The third flood event, which took place in 170 BC [18], whose sediments were found only in F1, F2, and F3 boreholes (Figure 8(1)) and in S1 section (Figure 9), seems to have caused severe damage only in the northern part of the city.
\nAt the Capua Gate inside the city walls, a duct was discovered under the first floor of a building [32]. This feature that was filled with sediment of the Uf3 unit may represent the extension of the duct highlighted by the anomaly AN4 in the TM1 ERT profile [18]. The sediment of the Uf3 unit was also piled against the entrance door of the building discovered at Capua Gate. According to [18], it is proven that at the time of the AD 79 eruption, the building and the duct below the floor were no longer used. It seems that after the mass-gravity flood event that had deposited the Uf3 unit, the water distribution system at the Capua Gate had to be abandoned due to its danger for the city. Hence, a new water supply system had to be organized. In fact, in 80 BC, a circular water basin was built close to the Vesuvius Gate and was connected to an aqueduct originating from the mountains northeast of the town named Avella (Avella Aqueduct [48]). The circular basin was afterwards covered (Castellum aquae, Figure 3) and was connected to the new Serino Aqueduct, in 20 BC [49–51]. This last water system was in use until the final demise of the city because of the Vesuvius eruption.
\nIn conclusion the geological data prove that the first system for water supply caused floods that, in turn, caused severe damage to the city. Hence, the water, usually as resource, in some cases can turn into geohazard.
Funding was provided by Ministero Università e Ricerca Scientifica (Pon Project 12232; MRS) and Università degli Studi del Sannio (FRA Projects; MRS). MRS is grateful to the staff of the Laboratory of Applied Researches of the Soprintendenza Archeologica di Pompei: Luigi Buffone, Antonio Stanpone, and Vincenzo Di Martino. In memory of Annamaria Ciarallo, the first director of the Laboratory of Applied Researches.
\nEverybody wants to live a long and healthy life. However, the universal laws of the Irreversible Thermodynamics drive changes in our bodies from the moment of birth, when a human baby has maximum information in his genes and minimum entropy in his body, through a series of consecutive changes to the last stage, when a human body has much less information left in the remaining old genes and maximum entropy in his body, which finally fails and the person dies.
We intentionally started our Chapter by mentioning the genetically predetermined stages of development of the human organism because, as it happened, the concept of ontogeny was somehow lost during the decades of research on mechanisms of aging and metabolic syndrome. As we will see, this approach gives completely different perspectives on the problems from the point of view of normal postembryonic ontogenesis.
The problems of aging and life longevity are not just medical problems, but are complex of fundamental biological problems, which comprise evolution, ontogenesis, genetics, epigenetics, and interactions with the environment. For this reasons, researchers studied aging and longevity starting from simple organisms like yeast and worms, then more complex laboratory animals, and even species like crocodiles and birds. Humans are, probably, much less studied in this respect than, say, mice and rats. To this day there are dozens of aging theories, which reflect the complexity of the problem. We mention only few of the relatively recent theories of aging: The heterochromatin loss model [1, 2]; adult stem cell and mesenchymal progenitor theory [3]; hormonal regulation of longevity in mammals [4]; telomere hypothesis of aging [5, 6]; epigenetic theory [7], and finally, currently the most popular and experimentally developed the free radical hypothesis of aging [8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21]. All theories of aging and longevity are interrelated, but so far, there is no generalizing theory. Therefore, we will start our discussions on human aging mechanisms from the currently most important theory of aging: the mitochondrial free radical theory.
Initially proposed by Harman [8], the “Free Radical Hypothesis of Aging” was later transformed to the “Mitochondrial Free Radical Theory of Aging” (MFRTA), because mitochondria were found to be the main source of free radicals [9, 10, 11, 12, 13, 14, 19, 22]. Collectively, the free radicals derived from oxygen were named “reactive oxygen species” (ROS).
In order to understand the logic of the worldwide research on aging development, it would be useful to look back on the intellectual and scientific background existing 40–50 years ago. After discovery that mitochondria generate oxygen radicals [23, 24], there was an excitement in finding the “universal mechanism” of all diseases. Therefore, for a long-time research on biological effects of ROS was titled “oxidative stress”, of which aging was only one of many damaging effects of ROS. For some time, it was not realized that organs and tissues age at different pace, and that environmental conditions, such as radiation, air contamination or industrial pollutants may contribute to the aging process.
Importantly, for a long time any clear-cut specific markers of systemic aging were not known, except mutations of mitochondrial DNA (mtDNA). There is a strong parallelism between production of ROS and mutations of mtDNA [13, 14, 25]. Until recently, this parallelism was explained by a belief that hundreds of “naked” circular mtDNA molecules lie in the mitochondrial matrix and thus mtDNA is an easy target for free radicals. The accumulation in cells of mtDNA damaged by ROS progressively inactivates the DNA templates necessary to repair damaged mitochondria. As a result, the accumulation of mtDNA mutations acts as the aging clock [25].
Understandably, mutations of mtDNA became one of the most important factors in explaining mechanisms of aging, age-associated diseases and practically most major human diseases [25, 26, 27, 28, 29]. Only recently it was discovered that mtDNA are protected by the proteinaceous “shield”, nucleoids, and that there is no proof for the free radical direct effects on mtDNA [30, 31, 32, 33].
Production of ROS occurs not only in organs and tissues, but also in blood cells where radicals evidently have functions different from those in parenchymal cells. The “respiratory burst” of phagocytic cells, when they come in contact with bacteria or immune complexes, is important source of superoxide radicals (O2•). Phagocytic cells include neutrophils, monocytes, macrophages and eosinophils known to produce large amounts of O2• [34].
In some cells, particularly in hepatocytes, the major source of ROS may be of extramitochondrial origin [35]. In the liver, both O2• and H2O2 are produced during metabolism of xenobiotics by the microsomal P-450-monoxygenases [36], and in the course of catabolism of purine nucleotides and nucleosides by xanthine oxidoreductase [37]. Liver peroxisomes also produce large amounts of hydrogen peroxide during catabolism of very long chain fatty acids and polyunsaturated fatty acids [38]. However, in the liver both mitochondria and peroxisomes possess high catalase activity, which neutralizes hydrogen peroxide [38, 39]. In addition to catalase and superoxide dismutase (isoforms 1 and 2) high activities, liver has high activities of glutathione S-transferase (GST) and glutathione peroxidase [40, 41], and Prohibitin-1 [42], which enhance the liver’s antioxidant system. For this reason, liver is relatively protected from deleterious effects of ROS, has high regenerative capacity [43] and, therefore, the rate of aging of this organ is much slower, as compared with other organs [44, 45]. Kidneys also rarely create problems for elderly people because they work constantly at a relatively even pace. In the actively working organs production of ROS is minimal [21]. The fastest rates of aging occur in those organs, which have a wide range of workloads, such as skeletal muscles, brain and heart. These organs have very high capacities in respiratory activity and ATP production to satisfy the organ’s energy demands at high workloads. These organs usually have increased ROS production at lower workloads or at rest [21].
Thus, aging is not an evenly distributed over the body process. In addition, mechanisms of aging are distinct in different organs and tissues, and the causing aging oxidants in various organs and tissues can also be different. In order to clarify the last statement and for the sake of the following discussion on the shortcuts of the current paradigm of the MFRTA, we give a brief description of the major biological and environmental radicals and biologically active molecules.
Superoxide radical (O2•) and hydrogen peroxide (H2O2) are quantitatively the main species of ROS that are produced constantly by the mitochondrial respiratory chain [21, 22]. Superoxide radicals serve also as a source for other ROS: hydroperoxyl radical, peroxynitrite, lipid radicals. The proportion of H2O2, produced at the sites of the respiratory chain is small [21], but the superoxide in many tissues rapidly dismutate to hydrogen peroxide by very high activities of superoxide dismutases in the cytosol (Cu,Zn-SOD1) and mitochondrial matrix (Mn-SOD2) [22, 46]. At the beginning of the mitochondrial free radical theory, superoxide radical was regarded as very dangerous [34]. However, soon it was realized that after O2• leaves the membrane’s lipid phase, small and negatively charged superoxide anion instantly acquires the hydration shell and thus loses most of its chemical activity [47]. In addition, due to the high activities of SOD1 and SOD2, present at micromolar concentrations, the superoxide radical half-life is very short (milliseconds) [22]. For this reason attention was shifted to other radicals, which can be formed from the superoxide and hydrogen peroxide. Nevertheless, O2• can directly damage enzymes, which contain 4Fe-4S clusters by knocking out one Fe2+ atom and turning the 4Fe-4S cluster to inactive 3Fe-4S. A typical enzyme is aconitase, which is sensitive to inhibition by superoxide.
Hydrogen peroxide (H2O2), which by itself is a rather harmless chemical, in the presence of transition metal ions Fe2+ and Cu1+ produces highly aggressive hydroxyl radical (•OH) [34]. However, •OH is so active that it instantly reacts with any molecule it encounters (except water). For this reason •OH half-life is only 10−9 sec [48] and under normal conditions it is not as harmful as initially believed. This radical is dangerous when formed in very large quantities, such as after exposure to radiation, or high concentration of H2O2 and transition metal poisoning. The latter situation is often observed in the experiments
Tissues, such as blood vessels endothelium, neurons and others, which possess tissue-specific nitric oxide synthases (eNOS), produce a free radical nitric oxide (•NO), an important cellular signaling molecule involved in many physiological and pathological processes. Formation of one molecule of •NO requires two molecules of O2, and since the •NO half-life
At this point, we have not discussed the protonated form of superoxide radical (O2•), namely hydroperoxyl radical (•HO2) because it will be done in conjunctions with the description of polyunsaturated fatty acids (PUFA) autoxidation, named “Isoprostane Pathway of Lipid Peroxidation” (IPLP), which we propose as the main mechanism of aging in people with Metabolic syndrome.
Unlike the above described ROS, which are formed in the body and relatively well-studied, the biological effects of sun radiation and air pollutants involving singlet oxygen and ozone are less known. However, they are the major causes of accelerated aging of skin and lung epithelium. For this reason, we provide a brief description of toxic effects of these ROS.
Singlet oxygen is the common name for the two metastable states of molecular oxygen, but the singlet O21Δg is the most active in biological systems. It has no unpaired electrons and therefore is not a radical, but upon excitation, one of the O2 electrons shifts to a higher and unstable orbit, which makes it chemically more active than regular triplet O2.
Ozone (O3) is an allotrope of oxygen and is much less stable than normal O2. It forms under the influence of ultraviolet light and during atmospheric electrical discharges (lightning). Even at low concentrations ozone causes damages to respiratory tracts of experimental animals and organic materials, such as latex and various types of plastic. The ozone’s half-life depends on temperature, humidity and air circulation. In a closed room with running fan, ozone’s half-life is about 24 hours [53]. That is, in a laboratory room, an instrument, like spectrophotometer or spectrophluorometer without special device for burning ozone (for example, instruments from Perkin Elmer), after several hours of work may create a concentration of ozone high enough to cause a headache and errors in experimental results due to accumulation of peroxides in water solutions.
For the human’s health it is important that in industrial areas with chemical factories and coal power stations the air may be polluted with nitrogen dioxide that may damage skin and respiratory organs. •NO2 induces oxidation, as well as cell’s membrane proteins nitration. Nitrated biological products, for example, tyrosine-containing proteins and nitrolipids are often found in the body. It is likely, that •NO2 has been involved in the formation of these products [54].
Nitrogen dioxide quickly reacts with other radicals. This is one of nitrotyrosines formation important mechanisms. During reaction •NO2 + O2• → O2NOO• very rapidly forms peroxynitrate: It contributes to skin and lung damage mechanisms during their contact with air polluted with nitrogen dioxide [54].
From the described above different free radicals and environmental pollutants, we see that all of them have the potential ability to cause damages to cellular and mitochondrial functions, although by different mechanisms. Some of the biologically active molecules and radicals show clear tissue and organ specificities. For example, singlet oxygen damages predominantly skin and eyes; ozone and nitrogen dioxide - lung epithelium, nitric oxide and peroxynitrite - vascular endothelium and neuronal cells. However, none of the above ROS is directly related, with the exception of the superoxide radical, to the inevitable aging mechanism [55].
After decades of research a vast amount of accumulated knowledge revealed serious inconsistencies between the data obtained and the MFRTA, which call into question the correctness of the free radical theory in its current paradigms. We refer the reader to excellent reviews on this topic [16, 18, 56, 57, 58]. Taking into consideration the controversies regarding various species, in this Chapter we will focus only on those inconsistencies that directly relate to the topic of humans and mammalians aging mechanism. Animals are often used for modeling of aging mechanisms [59, 60, 61, 62]. We shall discuss the following most important for MFRTA facts, which undermine this theory.
Recently, it has been established that neither of the above listed ROS and biologically active molecules are capable to cause directly mutations of mtDNA, which was and still is for many researchers the main hallmark of the aging process and it is considered as the main pathogenic mechanism of many diseases [30, 31, 32, 33]. From the beginning of free radical theory of aging, mutations of mtDNA were the only reliable markers of oxidative stress. As a matter of fact, the MFRTA itself arose on the basis that changes in the production of ROS were always accompanied by parallel changes in the number of mtDNA mutations [13, 14, 25]. Recently, however, it was concluded that there was no reliable evidence for the direct involvement of ROS in mtDNA mutations [31, 57]. There are two main reasons for this conclusion. First, the commonly studied radicals are not active enough to cause mutations [55]. Secondly, mtDNA are encased into a protein coating of nucleoid, which prevents direct contact of mtDNA and radicals [31].
Antioxidant supplementation interventions do not increase longevity, as would be predicted by the MFRTA. This Antioxidant Paradox is considered as the strongest evidence against the MFRTA; it comes from studies that manipulate antioxidant levels. Many studies have shown that administration of low-molecular weight antioxidants failed to extend longevity [reviewed in 16, 56, 57, 63]. Barja (2014) suggested that the lack of antioxidants to exert effects on longevity could be explained by the spatial separation: a free radical, which causes aging, acts in the lipid phase of membranes, while antioxidants exerts their effects mostly in the water phase of cells [16]. Barja (2014) also summarized the numerous studies of life longevities on various species: “Only two parameters currently correlate with species longevity in the right sense: the mitochondrial rate of reactive oxygen species (mitoROS) production and the degree of fatty acid unsaturation of tissue membranes” [16]. As we will see, these are very correct suggestions.
Muller (2000) has stressed that SOD activity interspecies variation is not correlated with the maximal life span (MLSP) in mammals and the activity of other antioxidant enzymes negatively correlates with MLSP. However, there is a strong negative correlation between longevity and the O2• and H2O2 production rates by isolated mitochondria from diverse mammalian species. The longevity depends not on the amount of superoxide in a cell, but on the rate of its production [18]. To explain this unexpected observation, Muller suggested that a significant fraction (between 10% and 50%) of O2• is not produced as aqueous O2• but instead is produced as lipid-phase HO2• in the inner mitochondrial membrane. In other words, Muller has proposed that it is not the O2• in the water phase, but its protonated form - hydroperoxyl radical (HO2•) in the membrane lipid phase exerts damaging effects on longevity, where the radical cannot be affected by a superoxide dismutase. Muller suggested that hydroperoxyl radical may initiate lipid peroxidation and the formation of peroxynitrous acid [18]. Unfortunately, the proposal that the hydroperoxyl radical is the aging main cause remained unnoticed for the next two decades, as well as the earlier similar attempts of other researchers before Muller [48, 63].
Here we present in brief our current views on the mechanisms of the hydroperoxyl radical formation and its damaging effects, which we consider as the systemic aging main mechanism. The details of the mechanism are presented in recent publications [55, 64, 65, 66, 67].
Lipid phase of the mitochondrial membrane has 4–5 fold higher concentration of oxygen than the cells’ water in the cytosol. When O2 acquires an electron from the respiratory chain and becomes O2•, it must quickly leave the lipid phase of the membrane. However, before O2• riches the bulk of the matrix or cytosol, it crosses the thing layer of the structured water near the charged surfaces of the membrane. The inner leaflet of the inner mitochondrial membrane contains approximately 80–90% of total cardiolipin (CL), which, together with phosphatidylethanolamine (PEA), accommodate respiratory complexes and ATP-synthase into the mitochondrial cristae sharp curves [67]. Since CL bears strong negative charge, at some arears of the inner membrane aggregates of CL form areas with strong negative charge, called antennae, which attract protons [reviewed in 66, 68]. For this reason, the thin layer of structured water near the charged surfaces of the inner mitochondrial membrane has up to three units more acid pH than the bulk of a compartment. This is a very important issue, because 1000 times higher concentration of H+ increases the probability of the hydroperoxyl radical formation in the O2• + H+ ↔ •HО2 reversible reaction (pKα of the reaction is 4.8) [68]. Highly hydrophobic •HО2 returns back into the membrane’s lipid phase. The described mechanism explains why the aging process depends only on the rate of superoxide formation, but not on the concentration of O2• and the activities of SODs. Hydroperoxyl radical is a much stronger oxidizing agent than superoxide radical, and has a specific propensity to abstract H atoms from α-tocopherol and, particularly, from the polyunsaturated fatty acids, such as arachidonic acid (C20:4 n6) and docosahexaenoic acid (C22:6 n3) [69].
For unknown reason, the perhydroxyl radical for a long time was almost completely excluded from the oxidative stress literature [61, 70]. Mitchell (2000) proposed perhydroxyl radical damaging mechanism through formation of peroxynitrite radical in the membrane [18]. This possible situation has been discussed by Gebicki and Bielski [69]. These authors indicated that although both •NO and •HО2 аre hydrophobic radicals, the radicals are spatially separated since •NO is normally present in the blood vessel endothelium, and thus the mitochondrial hydroperoxyl radicals have little chance to meet nitric oxide, and even if this might happen, the negatively charged ONOO− hardly could be a systemic damaging factor because it is immediately excluded from the membrane’s lipid phase [69]. Bielski et al. (1983) studied reactions of •HО2 with linoleic (C18:2), linolenic (C18:3) and arachidonic acids (C20:4) in water/ethanol solutions [68]. The obtained kinetic parameters of the reactions indicate that •HО2 reacts with the double allyl hydrogens of polyunsaturated fatty acids, and the more double bonds was present in a PUFA, the more active was the reaction. The abstraction of H atoms by •HО2 was exothermic, which indicates that it is irreversible and highly probable, when •HО2 encounters a PUFA. Since the reactions were performed in the water/ethanol solution, H2O2 formed cleaved heterolytically (2H2O2 → H2O + O2), and the final products of the fatty acids with •HО2 reactions were stable hydroperoxides without much variation in their structure [68].
When •HО2 reacts inside the lipid phase of the membrane with a PUFA, which is still part of a phospholipid, the products are a racemic mixture of a very large number of various stereo- and positional isomers [71]. Many of these products are similar to enzymatically produced prostaglandins, and were named Isoprostanes (IsoPs). For this reason, this type of PUFA autoxidation was named the Isoprostane Pathway of Lipid Peroxidation (IPLP) [71, 72, 73]. IsoPs possess potent biological activity and thus may convey abnormal cellular signaling and inflammation [71, 74]. Furthermore, many products of IPLP are very toxic, such as γ-ketoaldehydes. They form adducts with primary amines of the lysine-containing proteins and phosphatidylethanolamine (PEA). The most active among γ-ketoaldehydes are isolevuglandins (IsoLG) produced from arachidonic acid can be only detected as adducts with proteins or ethanolamine of PEA [74]. In addition to arachidonic acid the most common PUFA among phospholipids, other PUFA such as eicosapentaenoic acid (20:5 n3) and docosahexaenoic acid (22:6 n3), have been found as substrates for the IPLP [75]. Because docosahexaenoic acid (DHA) is present in a larger quantity in neurons, the products of IPLP were correspondingly named neuroprostanes and neuroketals. From arachidonic acid, which has four double bonds, the racemic mixture may contain up to eight hundreds of different products, whereas the products number from the containing 6 double bonds docosahexaenoic acid may be more than one thousand [71, 72, 73].
IsoPs and the cyclooxygenase derived prostaglandins (PGs) have a number of distinctions in their origin and properties, which have been discussed in a number of publications [65, 71, 76, 77]. Here we briefly list the most important distinctions: 1) The side chains of normal PGs are almost always oriented
Figure 1A very schematically presents the pathways of arachidonic acid oxidation, and Figure 1B illustrates the suggested mechanism of AA oxidation by •HО2 [65]. The key event after abstraction of the first H atom is that H2O2 formed under hydrophobic condition undergoes homolytic cleavage with formation of two molecules of the hydroxyl radicals H2O2 → 2 •OH, which instantly subtract another two H atoms from the same PUFA with formation of two molecules of H2O. The remaining molecule of the AA has completely disarranged double bonds, becomes extremely unstable and quickly attaches randomly two O2 molecules, and undergoes intramolecular transitions with formation of one out of many possible positional and stereoisomers. Thus •HO2 converts into 2 H2O and AA loses two out of 4 double bonds, and becomes one of hundreds isoprostanes. The differences between IPLP and the “classical” lipid peroxidation have been discussed in [65, 79].
Autoxidation of arachidonic acid with transformation of the molecule into various ring structures. (A) this part of the figure was adapted from the article [
It has been demonstrated by researchers from the Vanderbilt University that IsoPs are the most early and reliable markers of lipid peroxidation
The different toxic products of the IPLP evidently cause numerous and different lesions to mitochondria gradually causing wear and tear of mitochondrial and cellular functions. We distinguish two types of direct lesions to mitochondria: one dysfunctions type is caused by oxidation of CL and PEA, which result in structural changes of respirosomes and ATP-synthase complexes. The second dysfunctions type is caused by direct damages by toxic products, like isolevuglandins, which directly form adducts with PEA and lysine of proteins. This type of damages may explain mtDNA replication damages [33, 34, 83]. Anderson et al. [83] have shown that mtDNA replicase
Mammalian tissues mitochondria generate superoxide and hydrogen peroxide (ROS) from 11 different sites depending on substrates used and the redox state of the electron transport chain [21]. All mitochondrial ROS production sites have distinct properties [21, 84]. They can be divided into two groups: six sites operate at the redox potential of the NADH/NAD+ isopotential pool, about −280 mV, and five sites operate at the redox potential of the ubiquinol/ubiquinone (QH2/Q) isopotential pool, about +20 mV [21, 84].
Much of the published literature on contribution of separate respiratory complexes in generation of ROS have potential problems for several reasons: first, the authors often used inhibitors of the respiratory chain, which is far from situation
It has been recently shown that active oxidation of palmitoyl-carnitine by mitochondria in all metabolic states absolutely requires the simultaneous presence of any of the other mitochondrial metabolites such as: pyruvate, succinate, malate or glutamate, which were designated as “fatty acid oxidation supporting substrates” [87, 88]. In the presence of supporting substrates, fatty acids are actively oxidized not only by the isolated heart mitochondria [88], but also by the brain synaptic mitochondria [87], which breaks the old myth that the brain’s energy metabolism is supported almost exclusively by glucose [reviewed in 87].
Most importantly, active oxidation of fatty acids in the presence of supporting substrates results in a manifold increase in ROS production in resting mitochondria (Figure 2). Earlier, we have proposed that oxidative damages and thus accelerated aging, are more common for organs, which have a wide range of physiological activities, such as heart, skeletal muscles and brain [65, 88]. When these organs are at low workloads or at rest, the very efficient oxidation of fatty acids may redirect excessive electrons to generation of ROS.
Production of superoxide radicals by rat heart mitochondria oxidizing palmitoyl-carnitine. Designations: 1. Supporting substrate only; 2. Palmitoyl-carnitine only, and 3. Palmitoyl-carnitine + supporting substrate. Substrates:
In the sections above, we presented evidence that in spite of complications of the MFRTA based on old paradigms, the latest discoveries clearly support the essence of this theory, and the introduction of the perhydroxyl radical as a new mediator of oxidative stress resolve most of the contradictions. However, MFRTA still requires further consideration and we have to find answers to simple questions: what is aging and when the aging begins?
From the beginning, researchers working on MFRTA held the point of view that aging is a pathological process caused by oxidative stress that affects our health, and over time, we succumb to a myriad of age-related pathologies and eventually die [12, 58]. But is aging simply the process of errors accumulation? The Dictionary of Science and Technology designates aging as “the process of growing older or changing over time” [90]. In other words, a person after birth goes through a series of genetically controlled transitions, which are called postembryonic ontogenesis [91]. From the point of view of a human ontogeny, we can roughly divide a person’s individual life into five periods: infancy, childhood, adolescence, reproductive period and post-reproductive, or aging period. For several reasons, we hardly expect that during infancy, childhood and adolescence “a myriad of age-related pathologies” might be accumulated [58]. We will consider the last two periods: “reproductive”, which comprises the ages from 20 to 50, and the “aging period”, which begins after the age of 50 [92].
Among recent definitions of aging there were few in more general terms: “Aging is characterized by a gradual decline in various health parameters across multiple biochemical, physiological and behavioral systems” [93]. Correspondingly, some researchers started looking for a subset of aging individuals with lack of resilience within these general physiological systems, a condition termed frailty. Frailty has been defined in broad terms as an age-associated syndrome characterized by increased vulnerability to external influences, a diminished capacity to respond correctly to stressors and as an overall loss of fitness. In general, frail individuals are at a greater risk of falls, dependency, disability, institutionalization, hospitalization and mortality [94]. Frailty can be measured in relation to the accumulation of deficits using a frailty index. A frailty index can be developed from most aging databases [95, 96].
In another parallel world of Science, a large group of researchers study the metabolic syndrome, a nosological entity established at the end of 80s of the last century. The metabolic syndrome (MetS) was defined as a condition of simultaneous existence of several risk factors, including obesity, insulin resistance, atherogenic dyslipidemia and hypertension, which are interrelated, age-dependent, and share underlying mediators and metabolic pathways [97]. Undoubtedly, both concepts of frailty and metabolic syndrome are important from a medical perspective, but apparently did little for understanding the mechanisms of aging. Due to intensive research on both concepts, however, there has been made a great discovery: the rates of aging and energy metabolism are sex-specific. In our opinion, these discoveries are crucial for understanding the mechanisms of aging as the process of transition of an individual from the reproduction period to the last stage of ontogeny – aging.
Most animals and plants are sexual, in spite of the reproductive advantages experienced by asexual variants. Evidently there where selective forces that gave an advantage to sexuality and genetic recombination at either the population or individual level. The effect of sex and recombination increases the efficiency of natural selection, which is a major factor favoring evolution [98, 99]. It has been experimentally shown that sex increases the rate of adaptation to a new harsh environment, but has no measurable effect on fitness in a new benign environment where there is little selection [100]. Nonetheless, we are still far from a definitive answer to the question of why sexual reproduction is so common [99]. Recently, the hypothesis has been put forward that the internal production of ROS 2 billion years ago started the eukaryotic sex (re)evolution [101]. It has also been stressed that earlier theoretical works on sexual reproduction ignored important complexities that face natural populations, such as genetic drift and the spatial structure of populations [102].
The data accumulated show that in many species, including humans, females have slower rate of aging and longer life span than males [99, 103, 104, 105]. We suggest that this observation has important general biological goals for a female: bearing and raising a new generation despite any external difficulties and metabolic restrictions. These goals demand that females have to be efficient enough, but not superefficient from the metabolic (thermodynamic) point of view, resilient to harsh environmental conditions, and, in accord with the MFRTA, have lower rate of oxidative stress. Numerous studies of various species showed that in general females have slower production of ROS than males [99]. As always, there are some exclusions from the general rule, but again they hold the same conclusion: the longer living gender produces less ROS [106].
In the next sections we will discuss possible mechanisms underlying the slower aging and slower rates of ROS production in the longer living females.
Laboratory animals are indispensable part of biomedical research and widely used for modeling physiological and pathological situations in humans [107]. For ethical and technical restrictions, it is impossible to study many biomedical problems on humans, whereas animal research provides a degree of experimental control and precision not usually feasible in studies using human subjects [108]. Meanwhile, the animals used in most experiments were males, because researchers usually avoid using females for the reason of their reproductive cycles and hormone fluctuations that may affect the results of their studies [109]. For these reasons research on sex differences has begun relatively recently, but today the related literature is enormous. Human studies on metabolic differences between men and women were stimulated largely due to the progress of the sport medicine. Here, we will discuss only those works, which have direct relation to our subject under discussion: what sex metabolic differences underlie the fact that females live longer than males in many species, including humans [108].
Evidently, the sex differences in the body structure and metabolism depend on the stage of a person’s ontogeny. Vijay et al. (2015) studied sexual differences in the expression of mitochondria-related genes in rat heart at different ages that correspond to different stages of the rat’s reproductive capacities [110]. The authors studied the whole genome expression profiling in the hearts of young (8-week), adult (21-week), and old (78-week) male and female Fischer 344 rats, and the expression of 670 unique genes related to various mitochondrial functions was analyzed. A significant (p < 0.05) sexual dimorphism in expression was observed in young animals for 46, adult for 114 and old rats for 41 genes, respectively [110]. Importantly, in young and adult hearts, sexual dimorphism was not noted in genes encoding oxidative phosphorylation. Adult males showed higher expression of genes associated with the pyruvate dehydrogenase complex as compared to females. In old rats a majority of genes involved in oxidative phosphorylation had higher expression in females. This clearly shows that sexual dimorphism largely depends on the stage of ontogeny. Other studies demonstrated better preservation of myocardial mass and a greater cardiac contractility in women than men during aging [111]. The better heart health in aged women might be the result of either genetically predetermined factors or less oxidative damages and slower aging as compared to men.
It is a well-known observation that women generally have a higher amount of body fat than men. Distribution of fat is also different: women store more fat in the gluteal-femoral region, whereas men have more body fat in the abdominal (visceral) region [112, 113]. Importantly, that visceral fat accumulation is accompanied with multiple endocrine perturbations, including elevated cortisol and androgens in women, as well as low growth hormone and, in men, testosterone secretion. The consequences of the hormones effects will be more expressed in visceral than subcutaneous adipose tissues, because omental fat has higher cellularity, innervation and blood flow. Furthermore, the density of cortisol and androgen receptors seems to be higher in visceral fat than in other regions of adipose tissue [114]. In addition, there are epidemiological and metabolic associations between centralized (visceral) fat accumulation and disease [114]. This is an important fact because visceral obesity is a common symptom for men and women with metabolic syndrome.
Physiological experiments with oral administration of triglycerides, labeled with a small amount of oleic acid, revealed the following regional differences in the order of lipid uptake: omental = retroperitoneal > subcutaneous abdominal > subcutaneous femoral adipose tissues in men, with a similar rank order for half-life of the triglyceride, indicating also a turn-over of triglycerides in that order. Testosterone amplifies these differences in men. In premenopausal women, the visceral fat accumulation is smaller than in men, and subcutaneous abdominal has a higher turnover than femoral adipose tissue [114]. Among regional gender differences of fat metabolism, there is an interesting evidence that
These experiments
As regards protein metabolism, no gender differences in the basal level net muscle protein balance have been found [115]. In general, testosterone increases muscle protein synthesis and net muscle protein balance, resulting in increased muscle mass. At young age, boys and girls have similar amounts of testosterone. At puberty testosterone levels increase much more dramatically in males, as does muscle mass. Furthermore, although no evidence exists in humans, the in-vitro and rat data suggest that ovarian hormones inhibit muscle protein synthesis [115].
The indirect effect of the sex hormones on fat metabolism is supported by the data on sexual dimorphism in utilization of fatty acids during physical activities, which demonstrate that the proportion of energy derived from fat during exercise is higher in women than in men [112, 116]. Carter et al. (2001) investigated the effect of endurance training on whole body substrate, glucose, and glycerol utilization during 90 min of exercise in males and females [116]. First, during submaximal physical loads females show a lower respiratory exchange ratio (RER) than males, which indicates on a proportionately lower carbohydrate and higher fat oxidation [116, 117]. In comparison with females, exercising males had a greater increase in leucine oxidation but not lysine levels, which indicated that during intensive physical activity males increase their need for amino acids to fuel energy needs. Under the same conditions, females responded by increased mobilization of fat, thereby requiring less alternative fuels such as carbohydrate and amino acids [116, 117, 118]. The overall conclusion of these experiments was that females oxidize a greater proportion of fat and less carbohydrates and amino acids as compared with males. Thus physiologists support our finding that fatty acids oxidation requires simultaneous presence of other mitochondrial metabolites derived from carbohydrates or proteins [88]. Because women have lesser consumption of supporting substrates, the rate of fatty acids oxidation should be also diminished. This might explain why, in general, women demonstrate lower levels of physical performance during endurance sports and produce less ROS [119, 120, 121].
Knowing the fact that mitochondria oxidize fatty acids only in the presence of supporting substrates [87, 88], the data presented above suggest that females require less or different supporting substrates for effective oxidation of fatty acids. We can, therefore, predict that the isolated skeletal muscle or heart mitochondria from females must be different from males in terms of the type and requirement of supporting substrates, and also produce ROS at a slower rate. Unfortunately, until now we have been the only ones who have studied the oxidation of fatty acids in the presence of various supporting substrates, but we used male rats only in our experiments [87, 88]. Figure 3 illustrates that the rates of ROS production strongly depend on the type of supporting substrates, namely pyruvate, glutamate and succinate, and their various mixtures [55, 87, 88]. Thus the
Effect of substrate mixtures on production of ROS by isolated rat heart mitochondria oxidizing palmitoyl-carnitine. The incubation medium contained: Amplex red 2 μM, horse radish peroxidase 2 units, volume 1 ml. The reaction was initiated by addition of 50 μg of mitochondria. Initial rates were measured for 3 minutes. Substrates: 1. Succinate 5 mM; 2. Succinate + pyruvate 2.5 mM + glutamate 5 mM + malate 2 mM; 3. Palmitoyl-carnitine 50 μM + succinate; 4. Palmitoyl-carnitine + succinate + pyruvate + glutamate + malate. Numbers at the traces are the rates of H2O2 production in picomol H2O2/min/mg protein RHM. The rates were corrected for the time control rate with RHM incubated without added substrates. The figure was taken from [
Long time ago physicians noticed that many patients have common features of external appearances and biochemical indices of abnormal metabolism, which included insulin resistance, obesity, atherogenic dyslipidemia and hypertension. By the end of 80s of the 20th century the term “Metabolic syndrome” has been accepted and its own diagnostic code: 277.7 has been assigned by the International Classification, 9th Division, Clinical Modification (ICD-9-CM). However, the current definitions of the metabolic syndrome (MetS) give no clues to the essence of MetS and are mostly just listings of symptoms, for example: “The metabolic syndrome is a constellation of metabolic disorders including obesity, hypertension, and insulin resistance, components, which are risk factors for the development of diabetes, hypertension, cardiovascular, and renal disease” [123, 124]. This “clustering” or “constellation” of risk factors were considered to share underlying causes, mechanisms and features. The diagnosis of MetS is accepted only when at least three out of five symptoms are present in a patient [125, 126]. It was early recognized that people with isolated components, but who do not fit the definition of metabolic syndrome, are not at as high a risk for type 2 diabetes (T2D) or cardiovascular diseases (CVD). For example, people with isolated hypertension or isolated hyperlipidemia are at risk of CVD, or people with isolated obesity are at risk for T2D, but less so than people who meet multiple criteria of MetS [123].
It was expected that a comprehensive definition for the metabolic syndrome and its key features will facilitate research into its causes and lead to pharmacologic and lifestyle treatment approaches [127]. However, analysis of the tremendous amount of publications regarding MetS revealed that more than 30 years after defining MetS, there is still no deep understanding how and why MetS develops. Much of the literature can be roughly divided into supporters and opponents of considering insulin resistance as the primary symptom for the diagnosing MetS [123, 128, 129, 130]. These discrepancies were reflected in the criteria for diagnosing MetS provided by several Institutions, which were thoroughly reviewed in [123]. The discussions become heated by publications that ethnic and racial factors may greatly affect the criteria for diagnosis of MetS [127, 131].
The results of genetics studies on the potential hereditary predisposition to MetS were analyzed by Stančakova and Laakso [132]. They concluded that there is only a limited evidence for common genetic background explaining the clustering of the metabolic trait. Instead, the existing evidence suggests the importance of epigenetic mechanisms [132]. This conclusion supports our earlier suggestion [55, 66, 67] that the external appearances and metabolic features of MetS reflect the genetic properties of our distant ancestors. So far, however, aging and MetS have been commonly regarded as the result of accumulation of different kinds of damages caused by oxidative stress and/or improper life style [8, 9, 10, 11, 133, 134, 135].
As we have stressed earlier, all human beings after birth undergo changes during postembryonic ontogenesis. One of the theories of aging suggests that with the advanced age, the loss of heterochromatin results in altered gene expression [1, 2]. The epigenetic alterations resulting from global heterochromatin loss may be at the root of the various molecular events associated with aging and may tie together the various models of aging [2]. However, the process of ontogenesis in humans suggests that each transition to a new stage switches conversion of a new portion of heterochromatin into euchromatin, and new genes begin to work, and then during transition to a the next stage, the “previous” portion of euchromatin does not turn back into heterochromatin, but becomes lost. Therefore, the so called “general loss” of the heterochromatin with advancing age simply reflects the advancement of individual ontogeny. Evidently, when men and women enter the post-reproductive stage of ontogenesis, they have lost much of the heterochromatin that was present in a newborn baby. The genes that govern the post-reproductive stage were not the subject for natural selection, and therefore they are the same, or almost the same, genes that our distant ancestors had. This can be proved by many qualities in our bodies that appear after the age of 55: bulky body structure, dark spots of myelin in the skin, hair distribution, etc. Evidently, after transition to the post-reproductive stage many metabolic features also become distinct from the previous stages. There is a lot of evidence that elderly people of the northern Europe and Siberia acquire external and metabolic features common to the people living in the Northern Polar Regions. Inhabitants of the North, for example Eskimos, Dolgans, Innuits, do not consume a lot of plant foods rich in carbohydrates. Their diet is based on meat, animal fat and fish.
Again, the clue to understanding the nature of MetS, we can find in the sex associated differences in the energy metabolism and the transition of men and women from reproductive to the post-reproductive stage of ontogenesis, which is commonly regarded as the stage of aging [92]. This usually occurs between the ages of 50 and 55, when women go through menopause. The sharp changes in appearance and metabolism are particularly evident in women during and after the menopause, which increases the risk of MetS by 60% [136]. It is important, that the occurrence of MetS in the post-menopause period does not depend on the body mass index (BMD) and physical activity [137], but may depend in women on the dynamics of estrogen decline with age [138]. Interestingly, studies on sex hormone replacement in animals have shown that males receiving testosterone showed MetS deterioration, while females with estrogen replacement showed improvement in their MetS symptoms such as decreased hypertension [139]. This agrees with the suggestion that the genetically predetermined transition to the post-reproductive stage during normal ontogenesis, which is accompanied by changes in the hormone status, is the major natural cause of MetS. Thus some features of MetS, namely insensitivity to insulin and gain of fat, particularly visceral obesity, simply reflect a new type of metabolism. From this point of view, T2D may result from the excessive consumption of unnecessary carbohydrates at the post-reproductive stage.
In one of the previous sections we provided evidence that women oxidize fatty acids, which are the predominant energy source at all ages, at a slower rate in comparison with men, and thus probably produce ROS at a slower rate [116, 117, 118]. Olivetty et all. [111] studied changes in mononucleated and binucleated myocytes with age in enzymatically dissociated cells. The age interval examined varied from 17 to 95 years. The authors have found that in the course of aging women’s hearts preserved the ventricular myocardial mass, aggregate number of mononucleated and binucleated myocytes, average cell diameter and volume. In contrast, in the men’s hearts the authors observed nearly 1 g/year loss of myocardium, and this phenomenon accounted for the loss of approximately 64 million cells. These detrimental events involved the whole male’s heart. In the remaining cells, myocyte cell volume increased at a rate of 158 microns3/year in the left and 167 microns3/year in the right ventricle. And these changes in the men’s hearts were linear from the age of 17 to 95, whereas in women the structural properties of the heart remained unchanged [111]. Thus, it seems that women enter the post-reproductive stage with relatively “young” heart, whereas in men the aged heart lost many cells and the remaining cells increased their volume, which is a disadvantage for the heart’s energy metabolism.
Among mammalians the human females have a unique duration of post-reproductive longevity [140], which is probably to a large degree associated with the metabolic “protection” that caused slower rate of aging at the reproductive period [122]. There are several reasons to argue that both the accelerated rate of aging of men and the relatively slow aging of women, as well as other sex differences in metabolism and physical performance, are based on the sex differences in fatty acids metabolism. Regardless of age and gender, fats are the major source of energy, carbon and hydrogen for the anaplerotic reactions. Table 1 shows the relative amounts and times of consumption of the three main sources of mitochondrial substrates for obtaining energy and intermediary metabolites for the growth and maintenance of the body.
Source of Energy (Caloric value– kcal/g) | Storage amount (time of consumption) |
---|---|
Blood glucose & Glycogen (CV = 3.81) (CV = 3.12) (CV = 9.3) | Total 4–5 grams (20–30 min) 100–120 gram (1–3 hrs.) Released during catabolism of food, damaged tissue proteins and anaplerotic reactions. The content is highly dynamic. Fat (Kilograms) days |
It is shown that carbohydrates stores are small and must be constantly replenished by gluconeogenesis in the liver. Amino acids reserves are practically absent and they are constantly formed due to the digestion of food proteins, as well as in anaplerotic reactions in mitochondria. Carbohydrates are too precious to be used for obtaining energy. Much of glucose, particularly at young age, is used for the synthesis of RNA and DNA, purine and pyrimidine nucleotides. Only erythrocytes, which have no mitochondria utilize glucose for obtaining ATP by glycolysis and NADPH for reducing glutathione. There is an old myth that brain consumes only glucose for supporting its energy needs. However, most of the lactate and neuromediators glutamate and γ-aminobutyric acid, which are also used by synaptic mitochondria as energy substrates, are synthesized by the astrocytes from the carbon atoms of fatty acids and for expense of energy derived during β-oxidation of fatty acids. Synaptic mitochondria also gladly oxidize fatty acids in the presence of supporting substrates [85, 87].
Table 1 shows that carbohydrates stores are small and must be constantly replenished by gluconeogenesis in the liver. Amino acids reserves are practically absent and they are constantly formed due to the digestion of food proteins, as well as in anaplerotic reactions in mitochondria. Carbohydrates are too precious to be used for obtaining energy. Much of glucose, particularly at young age, is used for the synthesis of RNA and DNA, purine and pyrimidine nucleotides. Only erythrocytes, which have no mitochondria utilize glucose for obtaining ATP by glycolysis and NADPH for reducing glutathione. There is an old myth that brain consumes only glucose for supporting its energy needs. However, most of the lactate and neuromediators glutamate and γ-aminobutyric acid, which are also used by synaptic mitochondria as energy substrates, are synthesized by the astrocytes from the carbon atoms of fatty acids and for the expense of energy derived during β-oxidation of fatty acids. Synaptic mitochondria also gladly oxidize fatty acids in the presence of supporting substrates [85, 87].
The energetic efficiency of β-oxidation of fatty acids in the presence of supporting substrates is the only combination of substrates capable to support the highest rates of oxidative phosphorylation in the heart during maximal physical loads. The efficiency is achieved by the reduction of not only NADH/NAD+ system in mitochondria, but also by reduction of the membrane pool of ubiquinol/ubiquinone. Therefore, during β-oxidation of fatty acids, electrons enter the respiratory chain not only from Complex I, but mainly through complexes II and III. However, when the energy demands by the organ’s functions diminish, the excess of energy in mitochondria may redirect electrons for production of the superoxide radicals, and thus HO2• [66, 88]. Oxidation by mitochondria of the NAD-dependent substrates cannot provide high rates of ATP and ROS production because NADH-dehydrogenase activity of Complex I is the rate limiting step [141].
Brandt [21] observed that the rate of ROS production may be increased, when mitochondria have abundant supply of substrates and low level of ATP consumption (low functional load), and diminish when consumption of energy is high, or the substrate supply is limiting. This explains why the symptoms of MetS strongly depend on the life style. This is probably the main reason why men start aging faster and earlier then women. At the age of 45–50, many men reduce physical activity, eat too much and abuse alcohol, which dramatically accelerates ROS production.
After menopause, the women’s hormonal status becomes closer to that of men, and therefore they also must utilize fatty acids as the main substrates for energy production. At the post-reproductive stage of ontogenesis, we can assume that both men and women have metabolic pattern similar to their distant ancestors, who did not consume a lot of carbohydrates. This may explain the origin of the insulin resistance at MetS. This is not a pathology rather than a new physiological reality due to metabolic reprogramming at the post-reproductive stage. With low insulin sensitivity, most consumed carbohydrates are directed to the synthesis of lipids, which accelerates obesity, first of all visceral obesity. Excessive food consumption plus lower physical and mental activities accelerate production of superoxide radicals, and, thus, perhydroxyl radicals. This accelerates IPLP yielding harmful products, which have proinflammatory activities, cause damages to proteins, cardiolipin and PEA resulting in mitochondrial dysfunctions and accelerating aging.
For a long time, these gradually accumulating various functional disorders and structural damages are not accompanied by specific clinical manifestations. In people predisposed to an earlier aging, the clinical symptoms may be unspecific and look like frailty. With time, the accumulated wear and tear will cause development of clinical symptoms, like acute heart failure, Alzheimer’s disease, or something else, and finally death.
Literature show diminished fatty acids oxidation and developments of MetS symptoms in the females without estrogen that can be normalized by administration of estrogen [142, 143]. We do not think that those publications contradict to our conclusions presented in this Chapter, because those experiments have been done on young animals 7–8 weeks old.
In this Chapter we have presented evidence that activation of IPLP by hydroperoxyl radical, protonated form of superoxide radical, provides explanation to the slow and inevitable mechanism of aging and resolves many objections against MFRTA in the current paradigms. We also have shown that focusing only on the damages, which accompany aging, is not very helpful, because it gives no answers on why and when aging actually starts, and why women age slower and live longer than men. We have explained the idea that aging is, first of all, the process of development in time, when men and women go through a number of genetically predetermined stages. Because men and women have different biological roles, they also have different metabolic strategies. Fatty acids at all stages of ontogeny are the main substrates for provision of energy and intermediate metabolites for the growth and maintenance. The energetic efficiency of β-oxidation of fatty acids is controlled by the type of mitochondrial metabolites that oxidize simultaneously with fatty acids. However, this results in a significant increase in oxidative stress. We suggest that sex hormones determine the type and quantity of supporting substrates, which result in different rates of energy production and oxidative stress. Women consume more fatty acids with lower efficiency, and thus age at a slower pace. When men and women enter the post-reproductive stage of the ontogeny, the type of metabolism also changes because this last stage of ontogeny is controlled by ancient genes of our distant predecessors. In Figure 4 we summarized the available information as a scheme, which shows the approximate differences between men and women in ROS production during ontogeny. The metabolic syndrome, which usually begin developing after the age of 45 in men and 55 in women, reflects two main events: the transition to the post-reproductive stage of ontogeny, and the new type of metabolism. Because fatty acids become the major substrates for the energy production in all organs, the rate of ROS production, and, consequently, the rate of aging may increase dramatically. The specific symptoms of the MetS prevailing in particular individuals will depend on the genetic background of their ancestors and the life style.
A schematic presentation of approximate differences between men and women in ROS production during ontogeny. The figure was created based on the data presented in Refs. [
This work was supported by funding from National Institute of Health (R01HL144943).
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He is an academic staff member of the Department of Reproduction and Artificial Insemination, Selçuk University, Turkey. He manages several studies on sperms and embryos and is an editorial board member for several international journals. His studies include sperm cryobiology, in vitro fertilization, and embryo production in animals.",institutionString:"Selçuk University, Faculty of Veterinary Medicine",institution:null},{id:"90846",title:"Prof.",name:"Yusuf",middleName:null,surname:"Bozkurt",slug:"yusuf-bozkurt",fullName:"Yusuf Bozkurt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/90846/images/system/90846.jpg",biography:"Yusuf Bozkurt has a BSc, MSc, and Ph.D. from Ankara University, Turkey. He is currently a Professor of Biotechnology of Reproduction in the field of Aquaculture, İskenderun Technical University, Turkey. His research interests include reproductive biology and biotechnology with an emphasis on cryo-conservation. He is on the editorial board of several international peer-reviewed journals and has published many papers. Additionally, he has participated in many international and national congresses, seminars, and workshops with oral and poster presentations. He is an active member of many local and international organizations.",institutionString:"İskenderun Technical University",institution:{name:"İskenderun Technical University",country:{name:"Turkey"}}},{id:"61139",title:"Dr.",name:"Sergey",middleName:null,surname:"Tkachev",slug:"sergey-tkachev",fullName:"Sergey Tkachev",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61139/images/system/61139.png",biography:"Dr. Sergey Tkachev is a senior research scientist at the Institute of Fundamental Medicine and Biology, Kazan Federal University, Russia, and at the Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia. He received his Ph.D. in Molecular Biology with his thesis “Genetic variability of the tick-borne encephalitis virus in natural foci of Novosibirsk city and its suburbs.” His primary field is molecular virology with research emphasis on vector-borne viruses, especially tick-borne encephalitis virus, Kemerovo virus and Omsk hemorrhagic fever virus, rabies virus, molecular genetics, biology, and epidemiology of virus pathogens.",institutionString:"Russian Academy of Sciences",institution:{name:"Russian Academy of Sciences",country:{name:"Russia"}}},{id:"310962",title:"Dr.",name:"Amlan",middleName:"Kumar",surname:"Patra",slug:"amlan-patra",fullName:"Amlan Patra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/310962/images/system/310962.jpg",biography:"Amlan K. Patra, FRSB, obtained a Ph.D. in Animal Nutrition from Indian Veterinary Research Institute, India, in 2002. He is currently an associate professor at West Bengal University of Animal and Fishery Sciences. He has more than twenty years of research and teaching experience. He held previous positions at the American Institute for Goat Research, The Ohio State University, Columbus, USA, and Free University of Berlin, Germany. His research focuses on animal nutrition, particularly ruminants and poultry nutrition, gastrointestinal electrophysiology, meta-analysis and modeling in nutrition, and livestock–environment interaction. He has authored around 175 articles in journals, book chapters, and proceedings. Dr. Patra serves on the editorial boards of several reputed journals.",institutionString:null,institution:{name:"West Bengal University of Animal and Fishery Sciences",country:{name:"India"}}},{id:"53998",title:"Prof.",name:"László",middleName:null,surname:"Babinszky",slug:"laszlo-babinszky",fullName:"László Babinszky",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/53998/images/system/53998.png",biography:"László Babinszky is Professor Emeritus, Department of Animal Nutrition Physiology, University of Debrecen, Hungary. He has also worked in the Department of Animal Nutrition, University of Wageningen, Netherlands; the Institute for Livestock Feeding and Nutrition (IVVO), Lelystad, Netherlands; the Agricultural University of Vienna (BOKU); the Institute for Animal Breeding and Nutrition, Austria; and the Oscar Kellner Research Institute for Animal Nutrition, Rostock, Germany. In 1992, Dr. Babinszky obtained a Ph.D. in Animal Nutrition from the University of Wageningen. His main research areas are swine and poultry nutrition. He has authored more than 300 publications (papers, book chapters) and edited four books and fourteen international conference proceedings.",institutionString:"University of Debrecen",institution:{name:"University of Debrecen",country:{name:"Hungary"}}},{id:"201830",title:"Dr.",name:"Fernando",middleName:"Sanchez",surname:"Davila",slug:"fernando-davila",fullName:"Fernando Davila",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201830/images/5017_n.jpg",biography:"I am a professor at UANL since 1988. My research lines are the development of reproductive techniques in small ruminants. We also conducted research on sexual and social behavior in males.\nI am Mexican and study my professional career as an engineer in agriculture and animal science at UANL. Then take a masters degree in science in Germany (Animal breeding). Take a doctorate in animal science at the UANL.",institutionString:null,institution:{name:"Universidad Autónoma de Nuevo León",country:{name:"Mexico"}}},{id:"309250",title:"Dr.",name:"Miguel",middleName:null,surname:"Quaresma",slug:"miguel-quaresma",fullName:"Miguel Quaresma",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309250/images/9059_n.jpg",biography:"Miguel Nuno Pinheiro Quaresma was born on May 26, 1974 in Dili, Timor Island. He is married with two children: a boy and a girl, and he is a resident in Vila Real, Portugal. He graduated in Veterinary Medicine in August 1998 and obtained his Ph.D. degree in Veterinary Sciences -Clinical Area in February 2015, both from the University of Trás-os-Montes e Alto Douro. He is currently enrolled in the Alternative Residency of the European College of Animal Reproduction. He works as a Senior Clinician at the Veterinary Teaching Hospital of UTAD (HVUTAD) with a role in clinical activity in the area of livestock and equine species as well as to support teaching and research in related areas. He teaches as an Invited Professor in Reproduction Medicine I and II of the Master\\'s in Veterinary Medicine degree at UTAD. Currently, he holds the position of Chairman of the Portuguese Buiatrics Association. He is a member of the Consultive Group on Production Animals of the OMV. He has 19 publications in indexed international journals (ISIS), as well as over 60 publications and oral presentations in both Portuguese and international journals and congresses.",institutionString:"University of Trás-os-Montes and Alto Douro",institution:{name:"University of Trás-os-Montes and Alto Douro",country:{name:"Portugal"}}},{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",biography:"Rita Payan Carreira earned her Veterinary Degree from the Faculty of Veterinary Medicine in Lisbon, Portugal, in 1985. She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. She is also a frequent referee for various journals.",institutionString:null,institution:{name:"University of Évora",country:{name:"Portugal"}}},{id:"283019",title:"Dr.",name:"Oudessa",middleName:null,surname:"Kerro Dego",slug:"oudessa-kerro-dego",fullName:"Oudessa Kerro Dego",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/283019/images/system/283019.png",biography:"Dr. Kerro Dego is a veterinary microbiologist with training in veterinary medicine, microbiology, and anatomic pathology. Dr. Kerro Dego is an assistant professor of dairy health in the department of animal science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. He received his D.V.M. (1997), M.S. (2002), and Ph.D. (2008) degrees in Veterinary Medicine, Animal Pathology and Veterinary Microbiology from College of Veterinary Medicine, Addis Ababa University, Ethiopia; College of Veterinary Medicine, Utrecht University, the Netherlands and Western College of Veterinary Medicine, University of Saskatchewan, Canada respectively. He did his Postdoctoral training in microbial pathogenesis (2009 - 2015) in the Department of Animal Science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. Dr. Kerro Dego’s research focuses on the prevention and control of infectious diseases of farm animals, particularly mastitis, improving dairy food safety, and mitigation of antimicrobial resistance. Dr. Kerro Dego has extensive experience in studying the pathogenesis of bacterial infections, identification of virulence factors, and vaccine development and efficacy testing against major bacterial mastitis pathogens. Dr. Kerro Dego conducted numerous controlled experimental and field vaccine efficacy studies, vaccination, and evaluation of immunological responses in several species of animals, including rodents (mice) and large animals (bovine and ovine).",institutionString:"University of Tennessee at Knoxville",institution:{name:"University of Tennessee at Knoxville",country:{name:"United States of America"}}},{id:"251314",title:"Dr.",name:"Juan Carlos",middleName:null,surname:"Gardón Poggi",slug:"juan-carlos-gardon-poggi",fullName:"Juan Carlos Gardón Poggi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/251314/images/system/251314.jpeg",biography:"Juan Carlos Gardón Poggi received University degree from the Faculty of Agrarian Science in Argentina, in 1983. Also he received Masters Degree and PhD from Córdoba University, Spain. He is currently a Professor at the Catholic University of Valencia San Vicente Mártir, at the Department of Medicine and Animal Surgery. He teaches diverse courses in the field of Animal Reproduction and he is the Director of the Veterinary Farm. He also participates in academic postgraduate activities at the Veterinary Faculty of Murcia University, Spain. His research areas include animal physiology, physiology and biotechnology of reproduction either in males or females, the study of gametes under in vitro conditions and the use of ultrasound as a complement to physiological studies and development of applied biotechnologies. Routinely, he supervises students preparing their doctoral, master thesis or final degree projects.",institutionString:null,institution:{name:"Valencia Catholic University Saint Vincent Martyr",country:{name:"Spain"}}},{id:"309529",title:"Dr.",name:"Albert",middleName:null,surname:"Rizvanov",slug:"albert-rizvanov",fullName:"Albert Rizvanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309529/images/9189_n.jpg",biography:'Albert A. Rizvanov is a Professor and Director of the Center for Precision and Regenerative Medicine at the Institute of Fundamental Medicine and Biology, Kazan Federal University (KFU), Russia. He is the Head of the Center of Excellence “Regenerative Medicine” and Vice-Director of Strategic Academic Unit \\"Translational 7P Medicine\\". Albert completed his Ph.D. at the University of Nevada, Reno, USA and Dr.Sci. at KFU. He is a corresponding member of the Tatarstan Academy of Sciences, Russian Federation. Albert is an author of more than 300 peer-reviewed journal articles and 22 patents. He has supervised 11 Ph.D. and 2 Dr.Sci. dissertations. Albert is the Head of the Dissertation Committee on Biochemistry, Microbiology, and Genetics at KFU.\nORCID https://orcid.org/0000-0002-9427-5739\nWebsite https://kpfu.ru/Albert.Rizvanov?p_lang=2',institutionString:"Kazan Federal University",institution:{name:"Kazan Federal University",country:{name:"Russia"}}},{id:"210551",title:"Dr.",name:"Arbab",middleName:null,surname:"Sikandar",slug:"arbab-sikandar",fullName:"Arbab Sikandar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210551/images/system/210551.jpg",biography:"Dr. Arbab Sikandar, PhD, M. Phil, DVM was born on April 05, 1981. He is currently working at the College of Veterinary & Animal Sciences as an Assistant Professor. He previously worked as a lecturer at the same University. \nHe is a Member/Secretory of Ethics committee (No. CVAS-9377 dated 18-04-18), Member of the QEC committee CVAS, Jhang (Regr/Gen/69/873, dated 26-10-2017), Member, Board of studies of Department of Basic Sciences (No. CVAS. 2851 Dated. 12-04-13, and No. CVAS, 9024 dated 20/11/17), Member of Academic Committee, CVAS, Jhang (No. CVAS/2004, Dated, 25-08-12), Member of the technical committee (No. CVAS/ 4085, dated 20,03, 2010 till 2016).\n\nDr. Arbab Sikandar contributed in five days hands-on-training on Histopathology at the Department of Pathology, UVAS from 12-16 June 2017. He received a Certificate of appreciation for contributions for Popularization of Science and Technology in the Society on 17-11-15. He was the resource person in the lecture series- ‘scientific writing’ at the Department of Anatomy and Histology, UVAS, Lahore on 29th October 2015. He won a full fellowship as a principal candidate for the year 2015 in the field of Agriculture, EICA, Egypt with ref. to the Notification No. 12(11) ACS/Egypt/2014 from 10 July 2015 to 25th September 2015.; he received a grant of Rs. 55000/- as research incentives from Director, Advanced Studies and Research, UVAS, Lahore upon publications of research papers in IF Journals (DR/215, dated 19-5-2014.. He obtained his PhD by winning a HEC Pakistan indigenous Scholarship, ‘Ph.D. fellowship for 5000 scholars – Phase II’ (2av1-147), 17-6/HEC/HRD/IS-II/12, November 15, 2012. \n\nDr. Sikandar is a member of numerous societies: Registered Veterinary Medical Practitioner (life member) and Registered Veterinary Medical Faculty of Pakistan Veterinary Medical Council. The Registration code of PVMC is RVMP/4298 and RVMF/ 0102.; Life member of the University of Veterinary and Animal Sciences, Lahore, Alumni Association with S# 664, dated: 6-4-12. ; Member 'Vets Care Organization Pakistan” with Reference No. VCO-605-149, dated 05-04-06. :Member 'Vet Crescent” (Society of Animal Health and Production), UVAS, Lahore.",institutionString:"University of Veterinary & Animal Science",institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}},{id:"311663",title:"Dr.",name:"Prasanna",middleName:null,surname:"Pal",slug:"prasanna-pal",fullName:"Prasanna Pal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311663/images/13261_n.jpg",biography:null,institutionString:null,institution:{name:"National Dairy Research Institute",country:{name:"India"}}},{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",country:{name:"United Kingdom"}}},{id:"283315",title:"Prof.",name:"Samir",middleName:null,surname:"El-Gendy",slug:"samir-el-gendy",fullName:"Samir El-Gendy",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRduYQAS/Profile_Picture_1606215849748",biography:"Samir El-Gendy is a Professor of anatomy and embryology at the faculty of veterinary medicine, Alexandria University, Egypt. Samir obtained his PhD in veterinary science in 2007 from the faculty of veterinary medicine, Alexandria University and has been a professor since 2017. Samir is an author on 24 articles at Scopus and 12 articles within local journals and 2 books/book chapters. His research focuses on applied anatomy, imaging techniques and computed tomography. Samir worked as a member of different local projects on E-learning and he is a board member of the African Association of Veterinary Anatomists and of anatomy societies and as an associated author at local and international journals. Orcid: https://orcid.org/0000-0002-6180-389X",institutionString:null,institution:{name:"Alexandria University",country:{name:"Egypt"}}},{id:"246149",title:"Dr.",name:"Valentina",middleName:null,surname:"Kubale",slug:"valentina-kubale",fullName:"Valentina Kubale",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246149/images/system/246149.jpg",biography:"Valentina Kubale is Associate Professor of Veterinary Medicine at the Veterinary Faculty, University of Ljubljana, Slovenia. Since graduating from the Veterinary faculty she obtained her PhD in 2007, performed collaboration with the Department of Pharmacology, University of Copenhagen, Denmark. She continued as a post-doctoral fellow at the University of Copenhagen with a Lundbeck foundation fellowship. She is the editor of three books and author/coauthor of 23 articles in peer-reviewed scientific journals, 16 book chapters, and 68 communications at scientific congresses. Since 2008 she has been the Editor Assistant for the Slovenian Veterinary Research journal. She is a member of Slovenian Biochemical Society, The Endocrine Society, European Association of Veterinary Anatomists and Society for Laboratory Animals, where she is board member.",institutionString:"University of Ljubljana",institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"258334",title:"Dr.",name:"Carlos Eduardo",middleName:null,surname:"Fonseca-Alves",slug:"carlos-eduardo-fonseca-alves",fullName:"Carlos Eduardo Fonseca-Alves",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/258334/images/system/258334.jpg",biography:"Dr. Fonseca-Alves earned his DVM from Federal University of Goias – UFG in 2008. He completed an internship in small animal internal medicine at UPIS university in 2011, earned his MSc in 2013 and PhD in 2015 both in Veterinary Medicine at Sao Paulo State University – UNESP. Dr. Fonseca-Alves currently serves as an Assistant Professor at Paulista University – UNIP teaching small animal internal medicine.",institutionString:null,institution:{name:"Universidade Paulista",country:{name:"Brazil"}}},{id:"245306",title:"Dr.",name:"María Luz",middleName:null,surname:"Garcia Pardo",slug:"maria-luz-garcia-pardo",fullName:"María Luz Garcia Pardo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/245306/images/system/245306.png",biography:"María de la Luz García Pardo is an agricultural engineer from Universitat Politècnica de València, Spain. She has a Ph.D. in Animal Genetics. Currently, she is a lecturer at the Agrofood Technology Department of Miguel Hernández University, Spain. Her research is focused on genetics and reproduction in rabbits. The major goal of her research is the genetics of litter size through novel methods such as selection by the environmental sensibility of litter size, with forays into the field of animal welfare by analysing the impact on the susceptibility to diseases and stress of the does. Details of her publications can be found at https://orcid.org/0000-0001-9504-8290.",institutionString:null,institution:{name:"Miguel Hernandez University",country:{name:"Spain"}}},{id:"350704",title:"M.Sc.",name:"Camila",middleName:"Silva Costa",surname:"Ferreira",slug:"camila-ferreira",fullName:"Camila Ferreira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/350704/images/17280_n.jpg",biography:"Graduated in Veterinary Medicine at the Fluminense Federal University, specialist in Equine Reproduction at the Brazilian Veterinary Institute (IBVET) and Master in Clinical Veterinary Medicine and Animal Reproduction at the Fluminense Federal University. She has experience in analyzing zootechnical indices in dairy cattle and organizing events related to Veterinary Medicine through extension grants. I have experience in the field of diagnostic imaging and animal reproduction in veterinary medicine through monitoring and scientific initiation scholarships. I worked at the Equus Central Reproduction Equine located in Santo Antônio de Jesus – BA in the 2016/2017 breeding season. I am currently a doctoral student with a scholarship from CAPES of the Postgraduate Program in Veterinary Medicine (Pathology and Clinical Sciences) at the Federal Rural University of Rio de Janeiro (UFRRJ) with a research project with an emphasis on equine endometritis.",institutionString:null,institution:null},{id:"41319",title:"Prof.",name:"Lung-Kwang",middleName:null,surname:"Pan",slug:"lung-kwang-pan",fullName:"Lung-Kwang Pan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41319/images/84_n.jpg",biography:null,institutionString:null,institution:null},{id:"125292",title:"Dr.",name:"Katy",middleName:null,surname:"Satué Ambrojo",slug:"katy-satue-ambrojo",fullName:"Katy Satué Ambrojo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/125292/images/system/125292.jpeg",biography:"Katy Satué Ambrojo received her Veterinary Medicine degree, Master degree in Equine Technology and doctorate in Veterinary Medicine from the Faculty of Veterinary, CEU-Cardenal Herrera University in Valencia, Spain.Dr. Satué is accredited as a Private University Doctor Professor, Doctor Assistant, and Contracted Doctor by AVAP (Agència Valenciana d'Avaluació i Prospectiva) and currently, as a full professor by ANECA (since January 2022). To date, Katy has taught 22 years in the Department of Animal Medicine and Surgery at the CEU-Cardenal Herrera University in undergraduate courses in Veterinary Medicine (General Pathology, integrated into the Applied Basis of Veterinary Medicine module of the 2nd year, Clinical Equine I of 3rd year, and Equine Clinic II of 4th year). Dr. Satué research activity is in the field of Endocrinology, Hematology, Biochemistry, and Immunology in the Spanish Purebred mare. She has directed 5 Doctoral Theses and 5 Diplomas of Advanced Studies, and participated in 11 research projects as a collaborating researcher. She has written 2 books and 14 book chapters in international publishers related to the area, and 68 scientific publications in international journals. Dr. Satué has attended 63 congresses, participating with 132 communications in international congresses and 19 in national congresses related to the area. Dr. Satué is a scientific reviewer for various prestigious international journals such as Animals, American Journal of Obstetrics and Gynecology, Veterinary Clinical Pathology, Journal of Equine Veterinary Science, Reproduction in Domestic Animals, Research Veterinary Science, Brazilian Journal of Medical and Biological Research, Livestock Production Science and Theriogenology, among others. Since 2014 she has been responsible for the Clinical Analysis Laboratory of the CEU-Cardenal Herrera University Veterinary Clinical Hospital.",institutionString:null,institution:null},{id:"201721",title:"Dr.",name:"Beatrice",middleName:null,surname:"Funiciello",slug:"beatrice-funiciello",fullName:"Beatrice Funiciello",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201721/images/11089_n.jpg",biography:"Graduated from the University of Milan in 2011, my post-graduate education included CertAVP modules mainly on equines (dermatology and internal medicine) and a few on small animal (dermatology and anaesthesia) at the University of Liverpool. After a general CertAVP (2015) I gained the designated Certificate in Veterinary Dermatology (2017) after taking the synoptic examination and then applied for the RCVS ADvanced Practitioner status. After that, I completed the Postgraduate Diploma in Veterinary Professional Studies at the University of Liverpool (2018). My main area of work is cross-species veterinary dermatology.",institutionString:null,institution:null},{id:"291226",title:"Dr.",name:"Monica",middleName:null,surname:"Cassel",slug:"monica-cassel",fullName:"Monica Cassel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/291226/images/8232_n.jpg",biography:'Degree in Biological Sciences at the Federal University of Mato Grosso with scholarship for Scientific Initiation by FAPEMAT (2008/1) and CNPq (2008/2-2009/2): Project \\"Histological evidence of reproductive activity in lizards of the Manso region, Chapada dos Guimarães, Mato Grosso, Brazil\\". Master\\\'s degree in Ecology and Biodiversity Conservation at Federal University of Mato Grosso with a scholarship by CAPES/REUNI program: Project \\"Reproductive biology of Melanorivulus punctatus\\". PhD\\\'s degree in Science (Cell and Tissue Biology Area) \n at University of Sao Paulo with scholarship granted by FAPESP; Project \\"Development of morphofunctional changes in ovary of Astyanax altiparanae Garutti & Britski, 2000 (Teleostei, Characidae)\\". She has experience in Reproduction of vertebrates and Morphology, with emphasis in Cellular Biology and Histology. She is currently a teacher in the medium / technical level courses at IFMT-Alta Floresta, as well as in the Bachelor\\\'s degree in Animal Science and in the Bachelor\\\'s degree in Business.',institutionString:null,institution:null},{id:"442807",title:"Dr.",name:"Busani",middleName:null,surname:"Moyo",slug:"busani-moyo",fullName:"Busani Moyo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Gwanda State University",country:{name:"Zimbabwe"}}},{id:"439435",title:"Dr.",name:"Feda S.",middleName:null,surname:"Aljaser",slug:"feda-s.-aljaser",fullName:"Feda S. Aljaser",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"423023",title:"Dr.",name:"Yosra",middleName:null,surname:"Soltan",slug:"yosra-soltan",fullName:"Yosra Soltan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Alexandria University",country:{name:"Egypt"}}},{id:"349788",title:"Dr.",name:"Florencia Nery",middleName:null,surname:"Sompie",slug:"florencia-nery-sompie",fullName:"Florencia Nery Sompie",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sam Ratulangi University",country:{name:"Indonesia"}}},{id:"428600",title:"MSc.",name:"Adriana",middleName:null,surname:"García-Alarcón",slug:"adriana-garcia-alarcon",fullName:"Adriana García-Alarcón",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"428599",title:"MSc.",name:"Gabino",middleName:null,surname:"De La Rosa-Cruz",slug:"gabino-de-la-rosa-cruz",fullName:"Gabino De La Rosa-Cruz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"428601",title:"MSc.",name:"Juan Carlos",middleName:null,surname:"Campuzano-Caballero",slug:"juan-carlos-campuzano-caballero",fullName:"Juan Carlos Campuzano-Caballero",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}}]}},subseries:{item:{id:"95",type:"subseries",title:"Urban Planning and Environmental Management",keywords:"Circular Economy, Contingency Planning and Response to Disasters, Ecosystem Services, Integrated Urban Water Management, Nature-based Solutions, Sustainable Urban Development, Urban Green Spaces",scope:"