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Bondy Stephen C. - Aging and Age-Related Disorders

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Bondy Stephen C. Aging and Age-Related Disorders

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General Aspects of Aging -- Protein Redox-Regulation Mechanisms in Aging -- Nitrosative Stress in Aging -- Its Importance and Biological Implications in NF-?B Signaling -- Intervention with Multiple Micronutrients Including Dietary and Endogenous Antioxidants for Healthy Aging -- Advanced Glycation End Products, RAGE, and Aging -- Sirtuins and Mammalian Aging -- Estrogenic Modulation of Longevity by Induction of Antioxidant Enzymes -- Mitochondrial Respiratory Function Decline in Aging and Life-Span Extension by Caloric Restriction -- Methylglyoxal, Oxidative Stress, and Aging -- The Cardiovascular System -- Novel Strategies for Neurovascular Longevity During Aging -- Oxidative Stress in Vascular Disease -- The Role of Mitochondrial Reactive Oxygen Species Formation for Age-Induced Vascular Dysfunction -- Aging, Oxidative Stress, and Cardiovascular Disorders -- Oxidative Stress, Aging, and Cardiovascular Disease -- Antioxidation in Prevention of Cardiovascular Diseases -- An Effect of Polyphenols -- Vascular Aging and Oxidative Stress: Hormesis and Adaptive Cellular Pathways -- Role of Oxidative Stress in Mediating Elevated Blood Pressure with Aging -- The Nervous System -- Melatonin, Oxidative Stress, and the Aging Brain -- The SAM Strain of Mice, a Higher Oxidative Stress, Age-Dependent Degenerative Disease, and Senescence Acceleration Model -- Antioxidants Combined with Behavioral Enrichment Can Slow Brain Aging -- Role of Nitric Oxide in Neurodegeneration and Vulnerability of Neuronal Cells to Nitric Oxide Metabolites and Reactive Oxygen Species -- Free Radical-Mediated Damage to Brain in Alzheimers Disease: Role of Acrolein and Preclinical Promise of Antioxidant Polyphenols -- An Epigenetic Model for Susceptibility to Oxidative DNA Damage in the Aging Brain and Alzheimers Disease.;Features that characterize the aging process include the gradual accumulation of cell damage after prolonged exposure to oxidative and inflammatory events over a lifetime. In addition to the accretion of lesions, the intrinsic levels of pro-oxidant and aberrant immune responses are elevated with age. These adverse events are often further enhanced by the chronic and slow progressing diseases that characterize the senescent brain and cardiovascular system. The incidence of some disorders such as Alzheimers disease and vascular diseases are sufficiently prevalent in the extreme elderly that these disorders can arguably be considered normal. Aging and Aging-Related Disorders examines the interface between normal and pathological aging, and illustrates how this border can sometimes be diffuse. It explores and illustrates the processes underlying the means by which aging becomes increasingly associated with inappropriate levels of free radical activity and how this can serve as a platform for the progression of age-related diseases. The book provides chapters that examine the interactive relationship between systems in the body that can enhance or sometimes even limit cellular longevity. In addition, specific redox mechanisms in cells are discussed. Another important aspect for aging discussed here is the close relationship between the systems of the body and exposure to environmental influences of oxidative stress that can affect both cellular senescence and a cells nuclear DNA. What may be even more interesting to note is that these external stressors are not simply confined to illnesses usually associated with aging, but can be evident in maturing and young individuals. A broad range of internationally recognized experts have contributed to this book. Their aim is to successfully highlight emerging knowledge and therapy for the understanding of the basis and development of aging-related disorders.

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Part 1
General Aspects of Aging
Stephen Bondy and Kenneth Maiese (eds.) Oxidative Stress in Applied Basic Research and Clinical Practice Aging and Age-Related Disorders 10.1007/978-1-60761-602-3_1 Springer Science+Business Media, LCC 2010
Protein Redox-Regulation Mechanisms in Aging
Ufuk akatay 1
(1)
Central Laboratory of Clinical Biochemistry, Istanbul Faculty of Medicine, Istanbul University, Istanbul, 34390, Turkey
Ufuk akatay
Email:
Abstract
The perspicuity of the general mechanisms of in vivo protein oxidation was achieved in the 1980s and that of the redox-homeostasis mechanisms of reactive oxygen species (ROS)/antioxidants in the 1990s. Publications in the scientific literature dealing with protein redox-regulation mechanisms in aging have appeared only within the past 1015 years. As is well known, the group of protein disulfide oxidoreductases, such as thioredoxin (Trx), glutaredoxin, and Trx-dependent oxidoreductases, as well as methionine sulfoxide reductase (Msr), and the mechanisms related to these systems work synergistically to regulate the level of oxidized proteins and to repair mildly oxidatively modified proteins, keeping a balanced redox potential to maintain the function of aging cells. The proteolytic enzyme systems such as proteasome complexes, caspases, and the Lon protease, which are regulated by redox mechanisms, eliminate oxidized proteins. These mechanisms, in turn, affect redox homeostasis of proteins in aging cells. The ubiquitination and sumoylation of proteins are other mechanisms by which selectively oxidized proteins are targeted for degradation and compartmentalization with such specificity believed to be necessary for maintenance of cellular redox homeostasis. However, some of the extensively oxidized proteins of an unrepairable nature can escape degradation pathways and form high-molecular-weight aggregates that accumulate with age. Such oxidized protein aggregates can become cytotoxic and have been associated with a large number of age-related disorders, including Alzheimers disease, Parkinsons disease, cataractogenesis, and cancer. Considering the variations that have emerged in redox-regulation mechanisms and antioxidant systems related to age-related disorders, it is found that these are of an extremely complex nature. Work communicated to us in the current scientific literature now shows the extent of oxidative protein damage in aged subjects and in age-related disorders. Future research will probably be concerned with understanding the relationship between the aforementioned redox-regulatory proteins and age-related disorders. Such scientific progress will bring preventive and therapeutic approaches to control altered redox homeostasis in these disorders.
Keywords
Aging Protein oxidation Oxidative protein damage Redox regulation
Introduction
Since the completion of the Human Genome Project in 2002 and the recognition that this cannot provide all the answers to the etiology of age-related diseases, attention has turned to assessing changes in the expressed proteins of a given genome. Proteins are highly sensitive to oxidative modifications by reactive oxygen species (ROS) and reactive nitrogen species (RNS). In addition, native proteins can be modified by highly reactive aldehydes and ketones produced during ROS-mediated oxidation of lipids and glycated proteins during the aging process [].
On the other hand, a broad community of investigators focused on the role of protein oxidation in the etiology and/or progression of several age-related diseases [].
Because protein oxidation mechanisms and their markers in aging and age-related disorders have been treated extensively in various reviews and textbooks, including those by the aforementioned leading authors, we have chosen not to deal with the same material in this chapter and concentrate instead on protein redox-regulation mechanisms in the aging cell.
Postmitotic Aging and Redox Homeostasis
Aging is a progressive decline in an organisms adaptability and consequent increase in morbidity and mortality. It largely depends on changes occurring in long-lived postmitotic cells (nondividing cells), such as neurons, cardiac myocytes, and retinal pigment epithelial cells [].
Fig 1 Proteins can become oxidatively modified by a large number of reactions - photo 1
Fig. 1
Proteins can become oxidatively modified by a large number of reactions involving ROS, reactive aldehydes, and ketones. Intracellular degradation pathways and repair systems maintain redox homeostasis of the proteins in aging postmitotic cells. Oxidized proteins are generally destined for proteolysis by the lysosomal system, proteasome, small ubiquitin-like modifier (SUMO), and the Lon protease but can escape degradation and form high-molecular-weight aggregates that accumulate with aging. Depending on the type and degree of the oxidative modification, intracellular elimination of oxidatively modified proteins materializes in the different cellular compartments by either degradation or repair systems including the group of protein disulfide oxidoreductases, such as Trx/Trx reductase, glutaredoxin, and Msr. The accumulation of oxidized proteins is known to be linked to age-related diseases such as Alzheimers disease, Parkinsons disease, and cancer
Postmitotic tissues of high energy demand are at greater risk of being damaged by free radicals, consistent with the notion that signs of oxidative damage usually start to appear at these body sites [].
These cells are very rarely (or never) replaced because of the division and differentiation of stem cells, causing the accumulation of biological waste materials (e.g., lipofuscin, irreversibly damaged mitochondria, and aberrant proteins) that gradually replace normal structures, leading to functional decay and cell death [].
A variety of age-related diseases, such as neurodegenerative disease, and the physiologic aging process are characterized by the intracellular or extracellular accumulation of oxidized proteins [] of proteins are other crucial mechanisms by which selectively oxidized proteins are targeted for degradation with such specificity believed to be necessary for maintenance of cellular redox homeostasis in the aging cell.
Although the SUMO system was only discovered 10 years ago, extensive studies in the past few years have demonstrated that sumoylation is a remarkably versatile regulatory mechanism of protein functions involved in the regulation of diverse cellular process. SUMO can either regulate the functional activity of a target protein by direct sumoylation or indirectly regulate a signaling pathway via sumoylation of a key signaling molecule. SUMO proteases may also act as redox sensors and effectors modulating the desumoylation pathway and specific cellular responses to oxidative stress. Recent evidence indicated that equilibrium between SUMO conjugationdeconjugation under high oxidative stress could be affected by ROS [].
Other evidence was provided previously by the finding that overexpression of antioxidant enzymes that prevent the generation of excess free radicals, such as superoxide dismutase (SOD) and catalase []. It is worthwhile to mention that the germ line of egg and sperm has been maintained alive and safe from senescence and oxidative damage for more than a billion years. Because multicellular organisms are able to reproduce with germ-line cells before senescence of their soma, which incapacitates them, there was never any evolutionary impetus to develop biochemical mechanisms of preventing senescence in their postmitotic cells. Notably, both Drosophila melanogaster and Caenorhabditis elegans are mostly composed of postmitotic cells; the results from these invertebrates are much more supportive of the free radical theory of aging than are results from rat.
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