From Oxidative Stress To Cognitive Decline Towards Novel Therapeutic Approaches

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From Oxidative Stress to Cognitive Decline - Towards Novel Therapeutic Approaches

Author : Touqeer Ahmed
Publisher : Frontiers Media SA
ISBN 13 : 2832534104
Total Pages : 193 pages
Book Rating : 4.8/5 (325 download)

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Book Synopsis From Oxidative Stress to Cognitive Decline - Towards Novel Therapeutic Approaches by : Touqeer Ahmed

Download or read book From Oxidative Stress to Cognitive Decline - Towards Novel Therapeutic Approaches written by Touqeer Ahmed and published by Frontiers Media SA. This book was released on 2023-09-01 with total page 193 pages. Available in PDF, EPUB and Kindle. Book excerpt: Oxidative stress plays multiple roles in the pathobiology of several neurodegenerative disorders and Alzheimer’s disease in particular. Increased oxidative stress in the brain is suggested to be associated with aging, greater amounts of easily oxidizable unsaturated fatty acids, higher utilization of oxygen by the brain, mitochondrial-derived free radicals, calcium homeostasis, and glutamate-induced excitotoxicity. Moreover, environmental chemicals/toxins, heavy metals, and an imbalanced diet might increase oxidative stress potentially leading to a decrease in cognitive functions. Cellular health is also dependent on the levels of nicotinamide adenine dinucleotide (NAD+). It has been well documented that NAD+ is an important coenzyme for over 400 different oxidoreductases and turns out to be a relevant factor to the oxidative stress in the brain. Since the last two decades, NAD+ has been shown to be more than a mere regulator of metabolism, but rather may play a key role in the aging process. NAD+ along with sirtuins are important for various neurophysiological functions, and depletion of NAD+ may be associated with compromised physiological and cognitive functions. To protect the brain from oxidative stress, a modest endogenous protective system works in the brain through dedicated enzymatic machinery. Key enzymes are superoxide dismutase and catalase, which provide protection against oxidative stress. Aging, various neurological disorders, and chronic inflammation might also affect the levels of these protective enzymes and reduce their levels. Natural compounds, including polyphenols, can offer protection through NAD+ and various other mechanisms. Based on these factors it is becoming more and more clear that oxidative stress and its devastating effects on cognitive decline represents a major health issue in neurobiology. There is a need to identify potential compounds and therapeutic targets for mitigating oxidative stress and/or to strengthen the protective endogenous mechanisms. Novel approaches aiming to support and provide protective mechanisms in the brain will represent a great success in therapeutics. We welcome all article types focusing on the analysis and investigation of oxidative stress - originated from different sources - and its impairing effects on the brain. We will also accept studies investigating naturally occurring compounds, standard medications, and nutraceuticals that have an impact on oxidative stress, NAD+ metabolism and medical and health applications. For this, the aim of this Research Topic is to provide novel insights on oxidative stress (induced by any mechanism) impact on brain health, and on the strengthening of brain-protective mechanisms, supporting cognitive functions.

Brain Aging

Author : David R. Riddle
Publisher : CRC Press
ISBN 13 : 1420005529
Total Pages : 413 pages
Book Rating : 4.4/5 (2 download)

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Book Synopsis Brain Aging by : David R. Riddle

Download or read book Brain Aging written by David R. Riddle and published by CRC Press. This book was released on 2007-04-19 with total page 413 pages. Available in PDF, EPUB and Kindle. Book excerpt: Recognition that aging is not the accumulation of disease, but rather comprises fundamental biological processes that are amenable to experimental study, is the basis for the recent growth of experimental biogerontology. As increasingly sophisticated studies provide greater understanding of what occurs in the aging brain and how these changes occur

Preventing Cognitive Decline and Dementia

Author : National Academies of Sciences, Engineering, and Medicine
Publisher : National Academies Press
ISBN 13 : 0309459591
Total Pages : 181 pages
Book Rating : 4.3/5 (94 download)

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Book Synopsis Preventing Cognitive Decline and Dementia by : National Academies of Sciences, Engineering, and Medicine

Download or read book Preventing Cognitive Decline and Dementia written by National Academies of Sciences, Engineering, and Medicine and published by National Academies Press. This book was released on 2017-10-05 with total page 181 pages. Available in PDF, EPUB and Kindle. Book excerpt: Societies around the world are concerned about dementia and the other forms of cognitive impairment that affect many older adults. We now know that brain changes typically begin years before people show symptoms, which suggests a window of opportunity to prevent or delay the onset of these conditions. Emerging evidence that the prevalence of dementia is declining in high-income countries offers hope that public health interventions will be effective in preventing or delaying cognitive impairments. Until recently, the research and clinical communities have focused primarily on understanding and treating these conditions after they have developed. Thus, the evidence base on how to prevent or delay these conditions has been limited at best, despite the many claims of success made in popular media and advertising. Today, however, a growing body of prevention research is emerging. Preventing Cognitive Decline and Dementia: A Way Forward assesses the current state of knowledge on interventions to prevent cognitive decline and dementia, and informs future research in this area. This report provides recommendations of appropriate content for inclusion in public health messages from the National Institute on Aging.

Novel Therapeutic Approaches Targeting Oxidative Stress

Author : Pawan Kumar Maurya
Publisher : Academic Press
ISBN 13 : 032390906X
Total Pages : 294 pages
Book Rating : 4.3/5 (239 download)

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Book Synopsis Novel Therapeutic Approaches Targeting Oxidative Stress by : Pawan Kumar Maurya

Download or read book Novel Therapeutic Approaches Targeting Oxidative Stress written by Pawan Kumar Maurya and published by Academic Press. This book was released on 2022-02-18 with total page 294 pages. Available in PDF, EPUB and Kindle. Book excerpt: Novel Therapeutic Approaches Targeting Oxidative Stress investigates the role of oxidative stress in disease and explores the latest methods and approaches to targeting oxidative stress for treatment and diagnosis. The book begins with an introduction to oxidative stress and its significance. Subsequent sections cover biochemical methods for detecting free radicals and novel therapeutic approaches for targeting oxidative stress in a number of different diseases. This includes age-related illnesses, neuropsychiatric disorders such as schizophrenia and bipolar disorder, and neurodegenerative diseases like Alzheimer's and Parkinson's disease. Novel approaches for targeting oxidative stress in cancer and cardiovascular diseases are also explored. The book then moves on to discuss advances in drug delivery systems and detecting oxidative stress biomarkers using biosensors. It concludes with case studies that illustrate the targeting of oxidative stress and future perspectives. - Explores oxidative stress in a variety of diseases, including neurological disorders, cardiovascular diseases, age-related diseases, and cancer - Covers a range of therapeutic approaches to target oxidative stress - Includes chapters on the application of novel drug delivery systems and diagnostic biosensors to oxidative stress - Features case studies illustrating the targeting of oxidative stress

Oxidative Stress and Neurodegenerative Disorders

Author : G. Ali Qureshi
Publisher : Elsevier
ISBN 13 : 0080489494
Total Pages : 795 pages
Book Rating : 4.0/5 (84 download)

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Book Synopsis Oxidative Stress and Neurodegenerative Disorders by : G. Ali Qureshi

Download or read book Oxidative Stress and Neurodegenerative Disorders written by G. Ali Qureshi and published by Elsevier. This book was released on 2007-03-22 with total page 795 pages. Available in PDF, EPUB and Kindle. Book excerpt: Oxidative stress is the result of an imbalance in pro-oxidant/antioxidant homeostasis that leads to the generation of toxic reactive oxygen species. Brain cells are continuously exposed to reactive oxygen species generated by oxidative metabolism, and in certain pathological conditions defense mechanisms against oxygen radicals may be weakened and/or overwhelmed. DNA is a potential target for oxidative damage, and genomic damage can contribute to neuropathogenesis. It is important therefore to identify tools for the quantitative analysis of DNA damage in models on neurological disorders. This book presents detailed information on various neurodegenerative disorders and their connection with oxidative stress. This information will provide clinicians with directions to treat these disorders with appropriate therapy and is also of vital importance for the drug industries for the design of new drugs for treatment of degenerative disorders.* Contains the latest information on the subject of neurodegenerative disorders* Reflects on various factors involved in degeneration and gives suggestions for how to tackle these problems

The Neurobiology of Aging and Alzheimer Disease in Down Syndrome

Author : Elizabeth Head
Publisher : Academic Press
ISBN 13 : 0128188464
Total Pages : 354 pages
Book Rating : 4.1/5 (281 download)

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Book Synopsis The Neurobiology of Aging and Alzheimer Disease in Down Syndrome by : Elizabeth Head

Download or read book The Neurobiology of Aging and Alzheimer Disease in Down Syndrome written by Elizabeth Head and published by Academic Press. This book was released on 2021-08-31 with total page 354 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Neurobiology of Aging and Alzheimer Disease in Down Syndrome provides a multidisciplinary approach to the understanding of aging and Alzheimer disease in Down syndrome that is synergistic and focused on efforts to understand the neurobiology as it pertains to interventions that will slow or prevent disease. The book provides detailed knowledge of key molecular aspects of aging and neurodegeneration in Down Syndrome by bringing together different models of the diseases and highlighting multiple techniques. Additionally, it includes case studies and coverage of neuroimaging, neuropathological and biomarker changes associated with these cohorts. This is a must-have resource for researchers who work with or study aging and Alzheimer disease either in the general population or in people with Down syndrome, for academic and general physicians who interact with sporadic dementia patients and need more information about Down syndrome, and for new investigators to the aging and Alzheimer/Down syndrome arena. - Discusses the complexities involved with aging and Alzheimer's disease in Down syndrome - Summarizes the neurobiology of aging that requires management in adults with DS and leads to healthier aging and better quality of life into old age - Serves as learning tool to orient researchers to the key challenges and offers insights to help establish critical areas of need for further research

Neurodegenerative Diseases

Author : Shamim I. Ahmad
Publisher : Springer Science & Business Media
ISBN 13 : 1461406536
Total Pages : 421 pages
Book Rating : 4.4/5 (614 download)

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Book Synopsis Neurodegenerative Diseases by : Shamim I. Ahmad

Download or read book Neurodegenerative Diseases written by Shamim I. Ahmad and published by Springer Science & Business Media. This book was released on 2012-03-12 with total page 421 pages. Available in PDF, EPUB and Kindle. Book excerpt: The editor of this volume, having research interests in the field of ROS production and the damage to cellular systems, has identified a number of enzymes showing ·OH scavenging activities details of which are anticipated to be published in the near future as confirmatory experiments are awaited. It is hoped that the information presented in this book on NDs will stimulate both expert and novice researchers in the field with excellent overviews of the current status of research and pointers to future research goals. Clinicians, nurses as well as families and caregivers should also benefit from the material presented in handling and treating their specialised cases. Also the insights gained should be valuable for further understanding of the diseases at molecular levels and should lead to development of new biomarkers, novel diagnostic tools and more effective therapeutic drugs to treat the clinical problems raised by these devastating diseases.

World Population Ageing 2020 Highlights

Author : United Nations
Publisher :
ISBN 13 : 9789211483475
Total Pages : 44 pages
Book Rating : 4.4/5 (834 download)

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Book Synopsis World Population Ageing 2020 Highlights by : United Nations

Download or read book World Population Ageing 2020 Highlights written by United Nations and published by . This book was released on 2021-01-06 with total page 44 pages. Available in PDF, EPUB and Kindle. Book excerpt: Drawing on the Household Living Arrangements of Older Persons 2019 Dataset, the World Population Ageing 2020 Highlights will document key patterns and trends of the household living arrangements of older persons around the world. These levels or trends will be described using indicators such as the average number of persons per household, the distribution of older persons by household type, by type of living arrangement and select characteristics of heads of household. The report will also address the impact of living arrangements of older persons on their vulnerability to the COVID-19 (coronavirus) pandemic. It will conclude with a brief discussion of global and regional trends in policies on population ageing based on the most recently available data from the United Nations Inquiry among Governments on Population and Development (2019).

Nutraceuticals in Brain Health and Beyond

Author : Dilip Ghosh
Publisher : Academic Press
ISBN 13 : 0128206101
Total Pages : 478 pages
Book Rating : 4.1/5 (282 download)

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Book Synopsis Nutraceuticals in Brain Health and Beyond by : Dilip Ghosh

Download or read book Nutraceuticals in Brain Health and Beyond written by Dilip Ghosh and published by Academic Press. This book was released on 2020-11-12 with total page 478 pages. Available in PDF, EPUB and Kindle. Book excerpt: Nutraceuticals in Brain Health and Beyond focuses on a variety of health disorders where intervention with nutritional supplements prove valuable, such as Alzheimer's, Parkinson's, autism, and attention-deficit disorder in children. In addition, Nutraceuticals in Brain Health and Beyond addresses "herb-nutra psychiatry" which is a field of research focused on developing a comprehensive, cohesive, and scientifically rigorous evidence base to shift conceptual thinking around the role of diet and nutrition in mental health.Intended for nutrition researchers, nutritionists, dieticians, regulatory bodies, health professionals, and students studying related fields, Nutraceuticals in Brain Health and Beyond will be a useful reference in understanding the links between nutrition and brain health. - Addresses nutritional psychiatry and cognitive health at all stages of the lifespan - Contains extensive coverage of vitamins, minerals, botanicals, and other nutrients - Offers novel insight into cognitive dysfunctions including depression and other neurodegenerative disorders - Explores the role of genomics and epigenetics, including discussion of the gut–brain axis

Neuropsychiatric Disorders

Author : Manfred Gerlach
Publisher : Springer Science & Business Media
ISBN 13 : 3211735747
Total Pages : 326 pages
Book Rating : 4.2/5 (117 download)

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Book Synopsis Neuropsychiatric Disorders by : Manfred Gerlach

Download or read book Neuropsychiatric Disorders written by Manfred Gerlach and published by Springer Science & Business Media. This book was released on 2007-12-28 with total page 326 pages. Available in PDF, EPUB and Kindle. Book excerpt: This multidisciplinary book includes current research papers and reviews in the areas of basic neuroscience, neural mechanisms underlying neurodegenerative disorders. It further includes new approaches for neuroprotective treatments, clinical, neurobiological and treatment aspects of psychiatric disorders. The book was conceived as a celebration of the professional life and work of Peter Riederer to mark the occasion of his retirement.

Role of Nrf2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches

Author : Javier Egea
Publisher : Frontiers Media SA
ISBN 13 : 2889633160
Total Pages : 257 pages
Book Rating : 4.8/5 (896 download)

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Book Synopsis Role of Nrf2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches by : Javier Egea

Download or read book Role of Nrf2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches written by Javier Egea and published by Frontiers Media SA. This book was released on 2020-01-02 with total page 257 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Diet and Nutrition in Dementia and Cognitive Decline

Author : Colin R Martin
Publisher : Academic Press
ISBN 13 : 0124079393
Total Pages : 1246 pages
Book Rating : 4.1/5 (24 download)

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Book Synopsis Diet and Nutrition in Dementia and Cognitive Decline by : Colin R Martin

Download or read book Diet and Nutrition in Dementia and Cognitive Decline written by Colin R Martin and published by Academic Press. This book was released on 2014-12-30 with total page 1246 pages. Available in PDF, EPUB and Kindle. Book excerpt: Diet and Nutrition in Dementia and Cognitive Decline offers researchers and clinicians a single authoritative source which outlines the complex interrelationships between cognitive decline, dementia and the way diet can be modified to improve outcomes. In a cross-disciplinary field like dementia research and practice, clinicians and researchers need a comprehensive resource which will quickly help them identify a range of nutritional components and how they affect cognitive decline and the development of dementia. While the focus is on clinical applications, the book also features landmark and innovative preclinical studies that have served as the foundation of rigorous trials. Chapters explore the evidence of how nutritional components, either in the diet or supplements, can either impede the development to, or progression from, the onset of dementia. Authors investigate how conditions and processes overlap between defined conditions and present studies which show that dietary components may be equally effective in a number of conditions characterized by declining cognition or dementia. This book represents essential reading for researchers and practicing clinicians in nutrition, dietetics, geriatrics, nursing, neurology, and psychology, as well as researchers, such as neuroscientists, molecular and cellular biochemists, interested in dementia. http://www.acnr.co.uk/2015/07/diet-and-nutrition-in-dementia-and-cognitive-decline/ - Explores the complex interrelationships between cognitive decline, dementia and the way diet can be modified to improve outcomes - Focuses on both clinical nutrition applications and the innovative preclinical studies that serve as the foundation for rigorous trials - Covers specific conditions and mechanisms in dementias, as well as general aspects, risk factors, lifestyle and guidelines for practitioners - Organizes chapter content in terms of the molecular, mechanistic, epidemiologic, and practical, so that correlations can be observed across conditions

Oxidative Stress Revisited - Major Role in Vascular Diseases

Author : Cristina M. Sena
Publisher : Frontiers Media SA
ISBN 13 : 2889630587
Total Pages : 158 pages
Book Rating : 4.8/5 (896 download)

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Book Synopsis Oxidative Stress Revisited - Major Role in Vascular Diseases by : Cristina M. Sena

Download or read book Oxidative Stress Revisited - Major Role in Vascular Diseases written by Cristina M. Sena and published by Frontiers Media SA. This book was released on 2019-10-21 with total page 158 pages. Available in PDF, EPUB and Kindle. Book excerpt: Oxidative stress is an underlying factor in health and disease. Reactive oxygen species are produced as a result of normal cellular metabolism. The subsequent altered redox state between the formation and the neutralization of pro-oxidants results in their increased levels and therefore leads to cellular damage. Different research disciplines have increased our knowledge of the importance of this cell redox status and the recognition of oxidative stress as a process with implications for many pathophysiological states. Genetic and environmental factors, nutrition and lifestyle may indicate a pro-oxidative and pro-inflammatory state, linked to alterations in cellular structure and function. Oxidative stress emerges as a common, unifying factor in several conditions including diabetes and cardiovascular diseases. This eBook aims to provide novel data regarding the role played by oxidative stress and inflammation in the development of chronic diseases and the different classes of therapeutics from the bench to the clinic, stressing the awareness of these concepts for the treatment of disease. In addition, articles addressing an overview of the role of oxidative stress in vascular diseases reviewing some current concepts indicating that oxidative stress and inflammation are key mechanisms linking vascular diseases and current state-of-the-art approaches to monitor, prevent and inhibit oxidative stress will be highlighted. There is a close relation between oxidative stress, inflammation and cardiovascular diseases. Despite the great amount of investigation carried out in the field, there are still uncertainties about the mechanisms by which free radicals can modify tissues such as perivascular adipose tissue that ultimately will reflect on vascular function. This eBook will focus on articles that can explore and identify these mechanisms. Concurrent with this understanding of oxidative stress milieu, it is necessary to recognize the need for new pharmacological tools effective in restoring oxidative balance. The abundance of new information and the paradigm shift in our understanding of how antioxidants and other redox-active drugs work in a wide variety of vascular diseases will be specifically highlighted. This eBook will provide a comprehensive, up-to-date source of information on the design and mechanistic, pharmacological, and medicinal aspects of redox-active therapeutics. Finally, a unique feature of the eBook is to provide a way to foster an enthralling discussion revisiting old paradigms and finding new solutions for the treatment of vascular diseases. The topic will include original research articles, hypotheses, perspectives and (mini)reviews from experts in the field. The next decade shows promise for the translation of this body of knowledge to novel human therapeutics and this eBook will enable to increment our knowledge in this field.

Multiple Sclerosis

Author : Ian S. Zagon
Publisher :
ISBN 13 : 9780994438133
Total Pages : 137 pages
Book Rating : 4.4/5 (381 download)

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Book Synopsis Multiple Sclerosis by : Ian S. Zagon

Download or read book Multiple Sclerosis written by Ian S. Zagon and published by . This book was released on 2017 with total page 137 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Frontiers in Clinical Drug Research – Dementia: Volume 2

Author : José Juan Antonio Ibarra Arias
Publisher : Bentham Science Publishers
ISBN 13 : 9815039482
Total Pages : 277 pages
Book Rating : 4.8/5 (15 download)

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Book Synopsis Frontiers in Clinical Drug Research – Dementia: Volume 2 by : José Juan Antonio Ibarra Arias

Download or read book Frontiers in Clinical Drug Research – Dementia: Volume 2 written by José Juan Antonio Ibarra Arias and published by Bentham Science Publishers. This book was released on 2021-11-09 with total page 277 pages. Available in PDF, EPUB and Kindle. Book excerpt: Among neurodegenerative diseases, those that lead to a state of dementia are the aim of several investigations. Dementia is a chronic disease the prevalence of which is increasing worldwide. The number of dementia patients in the world is approximately 50 million, and it is estimated that the number of patients will reach 131.5 million by 2050. This increase will be accompanied by a significant increase in medical expenditures and other expenses, especially for elderly patients. Therefore, the maintenance cost of dementia in the future is expected to be quite high. For this reason, several investigations aim, firstly, to describe the key mechanisms involved in the origin of dementia and, secondly, to establish preventive and therapeutic strategies in order to understand and mitigate this debilitating pathology. This volume of Frontiers in Clinical Drug Research - Dementia explores the current comorbidities that cause cognitive impairment and the current management alternatives for clinical cases of dementia. The reviews contributed in these volume will provide readers with a current perspective on the subject. The topics covered in this volume include: - Comorbidities inducing mild cognitive impairment - an evaluation of the risk caused by some pathological conditions - Tau-targeted therapy in Alzheimer's disease - history and current state - Emerging nanotherapeutic strategies in Alzheimer's disease - Implication of dehydroepiandrosterone on dementia related to oxidative stress - Polyphenol compounds as potential therapeutic agents in Alzheimer’s disease The volume is a timely update on dementia treatment for clinical physicians, neurologists, gerontologists, pharmaceutical and medicinal chemistry researchers, and physiologists.

Cognitive Aging

Author : Institute of Medicine
Publisher : National Academies Press
ISBN 13 : 0309368650
Total Pages : 300 pages
Book Rating : 4.3/5 (93 download)

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Book Synopsis Cognitive Aging by : Institute of Medicine

Download or read book Cognitive Aging written by Institute of Medicine and published by National Academies Press. This book was released on 2015-07-21 with total page 300 pages. Available in PDF, EPUB and Kindle. Book excerpt: For most Americans, staying "mentally sharp" as they age is a very high priority. Declines in memory and decision-making abilities may trigger fears of Alzheimer's disease or other neurodegenerative diseases. However, cognitive aging is a natural process that can have both positive and negative effects on cognitive function in older adults - effects that vary widely among individuals. At this point in time, when the older population is rapidly growing in the United States and across the globe, it is important to examine what is known about cognitive aging and to identify and promote actions that individuals, organizations, communities, and society can take to help older adults maintain and improve their cognitive health. Cognitive Aging assesses the public health dimensions of cognitive aging with an emphasis on definitions and terminology, epidemiology and surveillance, prevention and intervention, education of health professionals, and public awareness and education. This report makes specific recommendations for individuals to reduce the risks of cognitive decline with aging. Aging is inevitable, but there are actions that can be taken by individuals, families, communities, and society that may help to prevent or ameliorate the impact of aging on the brain, understand more about its impact, and help older adults live more fully and independent lives. Cognitive aging is not just an individual or a family or a health care system challenge. It is an issue that affects the fabric of society and requires actions by many and varied stakeholders. Cognitive Aging offers clear steps that individuals, families, communities, health care providers and systems, financial organizations, community groups, public health agencies, and others can take to promote cognitive health and to help older adults live fuller and more independent lives. Ultimately, this report calls for a societal commitment to cognitive aging as a public health issue that requires prompt action across many sectors.

Systems Biology of Free Radicals and Antioxidants

Author : Ismail Laher
Publisher : Springer
ISBN 13 : 9783642300172
Total Pages : 0 pages
Book Rating : 4.3/5 (1 download)

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Book Synopsis Systems Biology of Free Radicals and Antioxidants by : Ismail Laher

Download or read book Systems Biology of Free Radicals and Antioxidants written by Ismail Laher and published by Springer. This book was released on 2014-06-16 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The focus of this collection of illustrated reviews is to discuss the systems biology of free radicals and anti-oxidants. Free radical induced cellular damage in a variety of tissues and organs is reviewed, with detailed discussion of molecular and cellular mechanisms. The collection is aimed at those new to the field, as well as clinicians and scientists with long standing interests in free radical biology. A feature of this collection is that the material also brings insights into various diseases where free radicals are thought to play a role. There is extensive discussion of the success and limitations of the use of antioxidants in several clinical settings.