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《Mutation Research/DNAging》1996,316(5-6):209-236
Evolution theory indicates that ageing is caused by progressive accumulation of defects, since the evolutionary optimal level of maintenance is always below the minimum required for indefinite survival. Evolutionary theories also suggest that multiple processes are operating in parallel, but unfortunately they make no predictions about specific mechanisms. To understand and evaluate the many different mechanistic theories of ageing which have been proposed, it is therefore important to understand and study the network of maintenance processes which control cellular homeostatis.In this paper we describe a Network Theory of Ageing which intergrates the contributions of defective mitochodria, aberrant proteins, and free radicals to the ageing process, and which includes the protective effects of antioxidant enzymes and proteolytic scavengers. The model simulations not only cofirm and explain many experimental, age related findings like an increase in the fraction of inactive proteins, a significant rise in protein half-life, an increase in the amount of damaged mitochondria, and a drop in the energy generation per mitochondrion, but they also show interactions between the different theories which could not have been observed without the network approach. In some simulations, for example, the mechanism of the final breakdown seems to be a consequence of the cooperation of mitochondrial and cytoplasmic reactions, the mitochondria being responsible for a long term, gradual change which eventually triggers a short lived cytoplasmic error loop. 相似文献
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《Mutation Research/DNAging》1992,275(3-6):195-208
A comprehensive hypothesis concerning the contribution of mitochondrial DNA (mtDNA) mutations to the human ageing process is reviewed and the implications for cellular bioenergy loss and pharmacological therapy are considered. The central idea is that random mutations in the population of mtDNA molecules of each cell occur throughout life, and that this is a major contributor to the gradual loss of cellular bioenergy capacity within tissues and organs, associated with general senescence and diseases of ageing. An elaboration of four major aspects fo the general proposition, together with relevant supporting data, is presented. (1) An extensive array of deletions in mtDNA of many tissues of humans and other mammals has been observed to occur in an age-related manner. (2) The preservation and selection of fully functional mtDNA molecules in the female germ line cells is proposed to occur via a human mtDNA cycle, in which selective amplification of a limited number of mtDNA templates occurs during oocyte development. This proposal explains the endowment of normal neonates with mtDNA complement minimally contaminated by damaged mtDNA molecules. The phenomena of maternal inheritance and rapid fixation of sequence variants of mtDNA in mammals, as well as selection of cells based on mitochondrial function, are taken into account. (3) Tissue bioenergy mosaics result from accumulated mtDNA damage during ageing, representing different rates of cellular bioenergy loss within individual cells of a tissue. The random segregation of mtDNA during cell division will also further contribute to the tissue energy mosaic. Cells unable to meet their particular bioenergy demand will become non-functional, leading to cell death; the bioenergy threshold is different for the various cell types in the tissues of the body. (4) In order to bioenergetically resuscitate cells and tissues suffering from impaired mitochondrial functions as a result of the ageing process, we prpopse that redox compounds may be used therapeutically in the pharmacological configurations of a by-pass strategy or as a redox sink therapy. The role of these compounds is to maintain at least part of the mitochondrial respiratory chain function (by-pass) as well as to maintain adequate levels of cellular NAD+ (redox sink) for ATP synthesis, predominantly by the cytosolic glycolytic pathway, with some contribution from mitochondrial oxidative phosphorylation. 相似文献
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Advances in understanding of mitochondrial physiology and genetics in relation to pathology have exploded in the last decade. Paralleling this increase has been an active debate about the role of mitochondrial oxidative stress with regard to mitochondrial DNA mutations, aging, and disease. We discuss in a historical context the rapid progress in our understanding of the role of mitochondrial DNA mutations in disease, mitochondrial oxidative stress in aging, and the potential interplay between these two phenomena. 相似文献
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As we age, our skeletal muscle becomes smaller and weaker. In addition, the remaining muscle is more susceptible to damage, particularly following exercise, recovery from damage is severely impaired and muscle is unable to adapt rapidly following sequential periods of exercise. The mechanisms by which skeletal muscle damage occurs are poorly understood and the role that an increased production of free radical species plays in this damage is controversial. However, evidence is emerging which suggests that an increased production of free radicals may act as an activator of the adaptive response in skeletal muscle, resulting in the increased production of antioxidant enzymes and heat shock proteins (HSPs). The increased content of these proteins facilitates rapid remodelling of muscle and provides considerable protection against subsequent periods of damaging exercise. There is considerable evidence that the production of free radicals is modified during the ageing process. The aim of this review is to examine the possible effects of this modification on the ability of muscle cells to respond to stress and the functional effect that this may have on our muscles as we age. 相似文献
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Obesity among the elderly is a growing public health concern. Among the various factors that may contribute to the current rates of obesity is the rewarding aspect of highly palatable foods and beverages, which may lead to overconsumption and excess caloric intake. The present review describes recent research supporting the hypothesis that, for some individuals, the consumption these highly palatable foods and beverages may lead to the development of addictive-like behaviors. In particular, the authors consider the relevance of this hypothesis to the ageing population. 相似文献
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Mitochondrial changes are at the centre of a wide range of maladies, including diabetes, neurodegeneration and ageing-related dysfunctions. Here we describe innovative optical and magnetic resonance spectroscopic methods that non-invasively measure key mitochondrial fluxes, ATP synthesis and O(2) uptake, to permit the determination of mitochondrial coupling efficiency in vivo (P/O: half the ratio of ATP flux to O(2) uptake). Three new insights result. First, mitochondrial coupling can be measured in vivo with the rigor of a biochemical determination and provides a gold standard to define well-coupled mitochondria (P/O approximately 2.5). Second, mitochondrial coupling differs substantially among muscles in healthy adults, from values reflective of well-coupled oxidative phosphorylation in a hand muscle (P/O = 2.7) to mild uncoupling in a leg muscle (P/O = 2.0). Third, these coupling differences have an important impact on cell ageing. We found substantial uncoupling and loss of cellular [ATP] in a hand muscle indicative of mitochondrial dysfunction with age. In contrast, stable mitochondrial function was found in a leg muscle, which supports the notion that mild uncoupling is protective against mitochondrial damage with age. Thus, greater mitochondrial dysfunction is evident in muscles with higher type II muscle fibre content, which may be at the root of the preferential loss of type II fibres found in the elderly. Our results demonstrate that mitochondrial function and the tempo of ageing varies among human muscles in the same individual. These technical advances, in combination with the range of mitochondrial properties available in human muscles, provide an ideal system for studying mitochondrial function in normal tissue and the link between mitochondrial defects and cell pathology in disease. 相似文献
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Mitochondrial uncoupling proteins: from mitochondria to the regulation of energy balance 总被引:8,自引:1,他引:7
The coupling of oxygen consumption to ADP phosphorylation is incomplete, as is particularly evident in brown adipocyte mitochondria which use a regulated uncoupling mechanism to dissipate heat produced by substrate oxidation. In brown adipose tissue, uncoupling is effected by a specific protein in the inner mitochondrial membrane referred to as uncoupling protein-1 (UCP1). UCP1 gene disruption in mice has confirmed UCP1's role in cold-induced thermogenesis. Genetic analysis of human cohorts has suggested that UCP1 plays a minor role in the control of fat content and body weight. The recent cloning of UCP2 and UCP3, two homologues of UCP1, has boosted research on the importance of respiration control in metabolic processes, metabolic diseases and energy balance. UCP2 is widely expressed in different organs whereas UCP3 is mainly present in skeletal muscle. The chromosomal localization of UCP2 as well as UCP2 mRNA induction by a lipid-rich diet in obesity-resistant mice suggested that UCP2 is involved in diet-induced thermogenesis. A strong linkage between markers in the vicinity of human UCP2 and UCP3 (which are adjacent genes) and resting metabolic rate was calculated. UCPs are known or supposed to participate in basal and regulatory thermogenesis, but their exact biochemical and physiological functions have yet to be elucidated. UCPs may constitute novel targets in the development of drugs designed to modulate substrate oxidation. However, very recent data suggest an important role for the UCPs in the control of production of free radicals by mitochondria, and in response to oxidants. 相似文献
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Mitochondrial ageing of a polar and a temperate mud clam 总被引:4,自引:0,他引:4
We investigated mitochondrial ageing in a temperate (Mya arenaria) and an Antarctic (Laternula elliptica) mud clam, with similar lifestyle (benthic filter feeders) but different maximum life spans (MLSP), 13 and 36 years, respectively. The short-lived temperate M. arenaria showed a more pronounced decrease in mitochondrial function (respiration, respiratory control ratio, proton leak, membrane potential) with age than the long-lived Antarctic L. elliptica. H2O2 generation rates at habitat temperature were far higher in the short-lived M. arenaria compared to L. elliptica. Reactive oxygen species (ROS) production as proportion of the mitochondrial oxygen consumption rate (%H2O2/O2) increased significantly with age in M. arenaria, whereas in L. elliptica the proportion remained unchanged. Lower rates of mitochondrial H2O2 generation were presumably due to mild uncoupling as L. elliptica mitochondria showed higher proton leak compared to M. arenaria mitochondria. The results are discussed in to the light of the "Free Radical-Rate of Living theory", (Pearl, R., 1928. The Rate of Living. Alfred Knopf, New York; Harman, D., 1956. Aging: a theory based on free radical and radiation biology. J. Gerontol. 11, 298-300) and the "Uncoupling to Survive" hypothesis (Brand, M.D., 2000. Uncoupling to survive? The role of mitochondrial inefficiency in ageing. Exp. Gerontol. 35, 811-820). 相似文献
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《Mechanisms of ageing and development》2001,121(1-3):113-121
Protein transduction can be described as the direct uptake by the cell of exogenous proteins/peptides or protein/peptide:chemical complexes, as a result of a specific property of the protein/peptide component. In this review, the three most widely studied protein transducing activities are described, with particular emphasis on the TAT protein transduction domain. Current progress in protein transduction technology suggests the potential development of a variety of molecular and cell biology tools that will enable researchers to by-pass conventional genetic routes for modulating the cells’ biological activity, thus negating many of the problems associated with genetic intervention. The potential application of this class of molecule in the development of tools for the study of senescent populations is discussed. 相似文献
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Ford KG Darling D Souberbielle B Farzaneh F 《Mechanisms of ageing and development》2000,121(1-3):113-121
Protein transduction can be described as the direct uptake by the cell of exogenous proteins/peptides or protein/peptide:chemical complexes, as a result of a specific property of the protein/peptide component. In this review, the three most widely studied protein transducing activities are described, with particular emphasis on the TAT protein transduction domain. Current progress in protein transduction technology suggests the potential development of a variety of molecular and cell biology tools that will enable researchers to by-pass conventional genetic routes for modulating the cells' biological activity, thus negating many of the problems associated with genetic intervention. The potential application of this class of molecule in the development of tools for the study of senescent populations is discussed. 相似文献
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Jäger D Holtz J Redpath NT Müller SP Pönicke K Heinroth-Hoffmann I Werdan K Müller-Werdan U 《Mechanisms of ageing and development》2002,123(10):1305-1319
The involvement of elongation factor-2 (EEF-2), a key-protein of peptide-chain elongation, in the slowing down of protein synthesis during cardiac ageing was addressed. EEF-2 was measured in rat heart extracts and isolated rat cardiomyocytes (CM) from newborn and adult rats using sodium-dodecylsulphate polyacrylamide gel electrophoresis after specific labeling with [32P]ADP-ribosylation or immunoblot. The age-dependent proportional content of several eucaryotic elongation factor-2 (eEF-2) subtypes in rat CM and rat heart extracts was compared using one-dimensional isoelectric focusing. EEF-2 was considerably reduced in the hearts of adult compared to neonatal rats (P<0.01). EEF-2 was also significantly decreased in isolated CM from adult versus newborn rats and during prolonged cultivation of neonatal CM. Cellular ageing was combined with reduced protein synthesis. During adolescence the eEF-2 variants shifted to acidic subtypes. Young adult and old rats revealed similar amounts and subtype distribution of cardiac eEF-2. Only the more acidic eEF-2 variants appeared to contain phosphorylated eEF-2. We concluded that total cardiac eEF-2 and its subtype pattern might play an important role in developmental and age-related proteomic changes. 相似文献
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Locomotor functional decline and loss in muscle mass with age is virtually a universal characteristic that has been documented in several species, including worms, fruit flies, rodents, non-human primates and humans. The age-related loss of muscle mass and strength (sarcopenia) represents an important risk factor for disability and mortality in older subjects and has been linked with cellular energy deficit and increased apoptosis at old age. Many key theories on aging describing the mechanisms underlying sarcopenia are now focused on the mitochondria because of their dichotomous role in controlling life and death processes within myocytes. Mitochondria represent the main producers of cellular energy in the form of adenosine triphosphate, but are also considered a key regulatory center of apoptosis. Unknown factors leading to a decrease in aerobic energy efficiency are linked with mitochondrial mutations which may result into apoptosis. Moreover, deregulation of autophagy (degradation and recycling of long-lived protein and organelles, such as the mitochondria) in post-mitotic tissue might also be responsible for the age-associated cellular energy failure. Alterations in specific signaling pathways, such as AMP-activated protein kinases, play a role in both cell survival response and apoptotic response depending on energy depletion. Evidence supports that apoptosis occurring in aging skeletal muscle may be due, in part, to the progressive decline in mitochondrial function and the resulting energy depletion within the cell. In turn, mitochondrial dysfunction is partly due to the accumulation of oxidative damage to macromolecules, including mitochondrial DNA, RNA and proteins, essential components for optimal functioning of mitochondria. Evidence concerning these series of events leading to energy depletion and apoptosis are discussed. 相似文献
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Jiro Watari Kentaro Moriichi Hiroki Tanabe Ryu Sato Mikihiro Fujiya Hiroto Miwa Kiron M Das & Yutaka Kohgo 《Histopathology》2009,55(3):261-269
Aims: Intestinal metaplasia is considered to be a precursor lesion in both Barrett's and intestinal-type gastric cancer. The aim was to clarify the differences in molecular pathology between specialized intestinal metaplasia (SIM) in Barrett's oesophagus (BO), cardiac (CIM) and gastric intestinal metaplasia (GIM).
Methods and results: Eighty-eight SIM cases with BO, 30 CIM cases and 52 GIM cases in patients with or without Helicobacter pylori infectionwere analysed for genetic instability and Das-1. Microsatellite instability and a loss of heterozygosity were evaluated at five microsatellite loci. The incidence of genetic instability was 55.7% in SIM, 40.0% in CIM and 23.1% in GIM, revealing a significant difference between SIM and GIM ( P < 0.0005). For each microsatellite marker analysed, there were obvious differences in frequency among the three conditions. Das-1 reactivity was significantly higher in SIM than in CIM or GIM ( P < 0.0001, both). Interestingly, both genetic instability and Das-1 reactivity in SIM showed a significantly higher incidence in patients with H. pylori infection than in those without ( P < 0.005 and P < 0.01, respectively).
Conclusions: SIM is distinct from CIM and GIM, and the pathogenesis of SIM, like that of GIM, is associated to some degree with H. pylori infection in a Japanese population. 相似文献
Methods and results: Eighty-eight SIM cases with BO, 30 CIM cases and 52 GIM cases in patients with or without Helicobacter pylori infectionwere analysed for genetic instability and Das-1. Microsatellite instability and a loss of heterozygosity were evaluated at five microsatellite loci. The incidence of genetic instability was 55.7% in SIM, 40.0% in CIM and 23.1% in GIM, revealing a significant difference between SIM and GIM ( P < 0.0005). For each microsatellite marker analysed, there were obvious differences in frequency among the three conditions. Das-1 reactivity was significantly higher in SIM than in CIM or GIM ( P < 0.0001, both). Interestingly, both genetic instability and Das-1 reactivity in SIM showed a significantly higher incidence in patients with H. pylori infection than in those without ( P < 0.005 and P < 0.01, respectively).
Conclusions: SIM is distinct from CIM and GIM, and the pathogenesis of SIM, like that of GIM, is associated to some degree with H. pylori infection in a Japanese population. 相似文献
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Radiation-induced genomic instability (RIGI) challenges the long-standing notion that radiation's effects derive solely from nuclear impact. In RIGI it is the unirradiated progeny that can display phenotypic changes at delayed times after irradiation of the parental cell. RIGI might well provide the driving force behind the development of radiation-induced tumorigenesis as most cancer cells even in pre-neoplastic states display multiple genetic alterations. Thus, understanding RIGI may help elucidate the mechanisms underlying radiation-induced carcinogenesis. One characteristic of clones of genetically unstable cells is that many exhibit persistently increased levels of reactive oxygen species (ROS). Furthermore, oxidants enhance and antioxidants diminish radiation-induced instability. However, much about the mechanisms behind the initiation and perpetuation of RIGI remains unknown and we examine the evidence for the hypothesis that oxidative stress and mitochondrial dysfunction may be involved in perpetuating the unstable phenotype in some cell clones surviving ionizing radiation. 相似文献
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线粒体DNA 3243、3316点突变与2型糖尿病 总被引:5,自引:0,他引:5
目的研究2型糖尿病患者中线粒体tRNA^Leu(UUR)基因3243A/G突变和NADH脱氢酶亚单位1基因(ND1)基因3316G/A突变的发生频率及其与2型糖尿病的相关性。方法应用聚合酶链反应及限制性片段长度多态性技术检测225例中国云南2型糖尿病患者和195名无糖尿病家族史的健康对照者有无3243A/G突变和3316G/A突变,并经DNA直接测序确证。结果2型糖尿病患者中3316G/A突变者5例(2.22%),195例对照者中突变者2例(1.03%),突变发生率在两组间差异无统计学意义(P=0.4576);两组中无线粒体3243A/G突变。结论线粒体tRNA^Leu(UUR)基因3243A/G突变在中国云南2型糖尿病人群中发生频率低,可能不是云南人群中2型糖尿病的常见病因。线粒体ND1基因3316G/A突变可能仅为人群中线粒体基因组的正常多态。其他的遗传、环境及子宫内因素需要进一步研究。 相似文献