衰老相关的蛋白稳态失衡

健康细胞利用一系列蛋白质质量调控网络来维持自身蛋白质组的稳定性和功能性,即维持蛋白稳态。但是在衰老过程中普遍出现蛋白稳态失衡的现象,其主要表现是蛋白质合成、折叠和降解之间的平衡被破坏。造成衰老相关蛋白稳态失衡的原因主要有：(1)应激反应相关途径的转录受到抑制;(2)蛋白酶体活性降低和自噬功能出现障碍;(3)核糖体翻译暂停。另外,在衰老过程中细胞主要通过蛋白稳态网络的分子伴侣、蛋白酶体、自噬系统等对蛋白稳态进行调节。本文对衰老过程中造成蛋白稳态失衡的诱因以及蛋白稳态调控的途径进行综述,以期为衰老研究和解决老年健康问题开拓新思路。     

哺乳动物低氧应激代谢成因的研究进展

氧气是哺乳动物机体代谢稳态维持的物质基础,若代谢过程中氧气供给不足,可造成低氧应激。目前,环境低氧、代谢性低氧和携氧细胞功能障碍是造成动物低氧应激的重要成因。目前,低氧对动物机体代谢和组织功能的影响研究主要集中于肺脏、肝脏、消化道、肌肉和乳腺等部位。若处于低氧状态的哺乳动物形成了适应低氧的代谢模式,则可维持其代谢稳态;相反,若动物无法维持低氧状态下的代谢稳态,则会导致机体氧化应激甚至病变。目前,低氧应激在家畜方面的研究主要集中于高原动物代谢适应机制;然而,泌乳期动物机体代谢速率、氧气消耗和自由基水平均较高,但氧在泌乳动物代谢应激形成中的作用及其对泌乳性能的影响,仍有待探索。综述了哺乳动物产生低氧应激的代谢成因与作用结果,旨在探讨哺乳动物低氧应激生物学基础,为进一步从低氧应激调控角度为泌乳动物的健康状况维持提供理论依据。     

生物钟节律与肝脏代谢稳态

生物钟(circadian clock)是机体内在的自主性计时系统,包括视交叉上核(suprachiasmatic nucleus, SCN)中枢生物钟与各组织外周生物钟。分子生物钟的核心机制包括CLOCK/BMAL1二聚体诱导抑制因子CRYs和PERs的转录,CRYs/PERs复合物反馈抑制前者转录活性,进而使这些生物钟核心因子以及节律输出基因的转录水平呈24 h振荡的反馈调节核心环路,以及REV-ERBα和RORα调控BMAL1转录的补充环路。机体大约80%的蛋白编码基因表达呈现明显的昼夜节律性特征,生物钟系统使生物能够适应地球自转所产生的昼夜节律(近日节律),使机体的代谢平衡与能量相互协同。生物钟与代谢稳态相互依存、互为基础,使机体能够高效利用能量,协同机体不同组织,快速适应内外环境变化。肝脏作为机体代谢的中枢器官,其进行的各种生理活动几乎都受到生物钟的控制。生物钟与肝脏代谢调控之间存在多重交互调控机制,两者的交互平衡失调是代谢性疾病的高风险因素。本文主要就肝脏的糖、脂和蛋白质代谢的节律性调控进行了综述,并强调了线粒体功能的振荡,讨论了肝脏代谢对生物钟的反馈调节,并对生物钟研究方法和应用进行展望。     

线粒体稳态失衡与心脏衰老及相关疾病

随着年龄的增长,衰老的心脏会发生左室肥厚、舒张功能不全、瓣膜功能下降、心肌纤维化增加、电传导异常等病理变化.线粒体作为真核细胞中调控代谢的关键细胞器,是细胞内合成ATP的重要场所.由于心脏一刻不停地收缩需要大量ATP提供能量,线粒体稳态对于维持正常的心脏功能至关重要,而线粒体稳态失衡则会导致心脏功能发生异常.本文主要阐述了衰老心脏中线粒体的异常变化,探讨了线粒体形态与数量变化、线粒体代谢异常、线粒体质量控制失衡、线粒体基因组和转录组改变等线粒体稳态失衡在常见衰老相关心脏疾病发生发展中的重要作用,总结了靶向线粒体干预衰老相关心脏疾病的现状与前景,为研究线粒体相关心脏疾病的细胞分子机制,治疗衰老相关的心脏疾病提供新的思路.     

氧化还原稳态调控机制与肿瘤治疗

肿瘤往往处于高氧化状态,随着研究的不断深入,人们逐渐发现细胞内氧化还原状态与肿瘤的关系高度复杂,其促瘤和抑瘤效应均有报道。明确氧化还原稳态调控机制,有望为精准靶向该机制,提高肿瘤治疗效果带来新的契机。该文将对氧化还原稳态调控机制及其在肿瘤治疗中应用的最新进展作一综述。     

锰离子转运、代谢与稳态平衡调控

金属离子在生命体细胞内的转运、代谢、稳态平衡调控及其相关疾病的研究是生物无机化学、化学生物学和生物医学等研究领域的一个前沿热点。锰被称作“细胞护卫”或“生命体保镖”,在生物体中发挥重要的作用,体内锰离子的含量必须维持在一个恰当的水平,锰缺少或过量都会导致疾病或生物毒性。因此,生物体内锰离子的稳态平衡调控对维持体内锰离子的正常生理功能至关重要。对细菌、出芽酵母、动物的锰离子运输、代谢及其稳态平衡调控的分子机制研究分别进行综述。     

哺乳动物铁稳态分子机制研究进展

铁是机体必需微量元素,参与机体合成血红蛋白、肌红蛋白及多种酶的组成和功能发挥,对维持生命和健康至关重要。近四分之一的世界人口遭受铁缺乏或缺铁性贫血的威胁。此外,部分人群还存在铁过载问题,以脏器铁离子蓄积为主要病理改变的遗传性血色病,其在欧美发病率高达1/200,在中国也有报道。血色病后期多诱发肝脏、胰腺及心脏的功能衰退。铁过少或过多对健康都会造成严重危害,机体需要复杂而精密的调控体系维持铁稳态平衡。铁代谢主要包括小肠吸收、肝脏储存、血液转运、巨噬细胞再循环以及周身细胞利用。过去十多年是铁代谢研究的黄金时期,先后发现众多铁稳态代谢相关基因。该文综述了近年来哺乳动物铁代谢领域的研究进展,并对铁稳态代谢中存在的问题进行了初步讨论,为理解和进一步深入研究铁代谢分子机制提供参考。     

植物叶片衰老过程中叶绿素降解代谢研究进展

本文对近年来植物叶片衰老过程中叶绿素降解代谢研究进展作一介绍,包括叶绿素降解产物分离、检测和命名;叶绿素降解途径及降解酶系。此外,对叶绿素降解意义及今后研究趋势进行了评述。     

自噬在肝稳态调节作用中的研究进展

肝脏是人体最大的消化腺,也是最主要的代谢器官。自20世纪60年代,人们在肝脏溶酶体的研究中提出"自噬"这一概念时,就发现肝脏内的营养水平与激素影响自噬活动。近年来的研究表明,自噬不仅是正常的生理过程,也参与许多病理过程的调节。本文介绍了自噬在健康肝脏中维持稳态的作用,旨在为肝脏生理学及自噬失调相关疾病的治疗提供新思路。     

哺乳动物生物钟与能量代谢的相关研究进展

生物钟广泛存在于各种生物体中,是生命体的一种内源调节机制。哺乳动物生物钟系统与机体营养代谢和能量平衡有着密切的关系。概述了生物钟系统通过营养途径、限速酶途径、核受体途径对哺乳动物机体代谢活动和能量平衡的调控,以及哺乳动物代谢稳态对生物钟系统的影响,从而为从生物钟调控的角度治疗和防控代谢综合征提供新的思路。     

Decreased plasma and tissue levels of vitamin C in a rat model of aging: implications for antioxidative defense

Aging is an independent risk factor for the development of cardiovascular and many other diseases. The aging process is known to be associated with increased oxidative stress, possibly related to an age-inherent loss of antioxidant capacity. Vitamin C is a major naturally occurring antioxidant. Thus, we investigated its role in a rat model of aging. Vitamin C in plasma and tissues as well as malondialdehyde in the heart were measured in young (6 months old) and old (27-30 months old) F1 (F344 x BN) healthy male rats fed a normal diet. In old rats, vitamin C plasma levels were found to be decreased (p<0.02) as compared with young animals. Furthermore, there was a tissue-specific distribution: in the heart, liver, kidney, lungs, and skeletal muscle, vitamin C decreased with age (p<0.005 to p<0.05), while no significant differences could be observed in the aortic wall and in the brain. Organs of the digestive tract rather showed an increase of vitamin C levels with age. Oxidative stress, determined representatively in the heart by measuring malondialdehyde tissue levels, exhibited an age-dependent increase (p<0.05). A distinct pattern of specific tissue distribution of vitamin C suggests a differential age-associated regulation. As vitamin C decreased concomitantly to an increase in cardiac lipid peroxidation, its supplementation may be useful to prevent age-related oxidative stress and tissue aging.     

Relación entre el perfil oxidativo y el índice de diversidad de la dieta en adultos mayores de una zona urbano-marginal de Costa Rica

Background and objectiveThe older we get, the greater the production of reactive oxygen species and therefore the greater the oxidative stress, which is related to the deterioration of the health of older adults. This study analyzed the relationship between the oxidative profile and the dietary diversity index in an urban-marginal population of older adults in Costa Rica.MethodsEighty-eight older adults were studied and various markers of oxidative stress, serum glucose levels, lipid profile, and some micronutrients were determined. In addition, the body mass index (BMI) was calculated and the dietary diversity index (DDI) was determined.ResultsLipid peroxidation and DNA oxidation, a mean plasma antioxidant capacity percentage of 39.54 ± 10.67%, which decreased with age, were evidenced. 67% of the participants had alterations in glycemia, 73% had one or more alterations in blood lipid levels, 55% had insufficient vitamin D levels, and 68.6% were overweight. The average IDD was 4.91 points, indicating that the diet was not very diverse. No relationship was found between IDD and nutritional status, between nutritional status and oxidative stress, nor between biochemical variables and oxidative stress.ConclusionThe adults studied presented high oxidative stress, a high percentage of overweight, and a low IDD. A higher IDD was associated with a lower blood concentration of MDA and a higher % PAC.     

PKM2调控肿瘤细胞代谢的研究进展

肿瘤细胞代谢的最重要特征是消耗大量的糖并产生乳酸。M2-型丙酮酸激酶2(PKM2)在这种代谢表型中发挥决定性的作用,体内外实验均发现PKM2的过表达可明显增强Warburg效应,促进肿瘤生长。然而关于PKM2调节肿瘤细胞代谢的机制仍然不是很清楚。当前的研究也提出了一些新颖的PKM2调节肿瘤代谢的观点。在总结当前认识的同时,提出一些本领域的未来可能的研究方向,重点突出肿瘤细胞中关于PKM2活性和特异性的争议,并对PKM2潜在的治疗策略进行讨论。     

Chronic intake of red wine polyphenols by young rats prevents aging-induced endothelial dysfunction and decline in physical performance: role of NADPH oxidase

Aging is associated with oxidative stress-mediated endothelial dysfunction and decline in physical performance, which promote cardiovascular diseases. This study examined whether chronic intake of red wine polyphenols (RWPs), a rich source of natural antioxidants, prevents aging-related impairment of vascular function and physical exercise capacity. Vascular reactivity from 12, 20 and 40 week-old rats was assessed in organ chambers. Rats received from week 16 to 40 either solvent, RWPs or the antioxidant and NADPH oxidase inhibitor, apocynin. Aging was associated with blunted endothelium-dependent relaxations, oxidative stress (dihydroethidine staining), and an upregulation of eNOS, arginase I, NADPH oxidase p22phox and nox1 subunits, and AT1 and AT2 receptors (assessed by immunohistochemistry) in the mesenteric artery. RWPs and apocynin improved the endothelial dysfunction, normalized oxidative stress and the expression of the different proteins. RWPs also improved aging-related decline in physical exercise. Thus, intake of RWPs protects against aging-induced endothelial dysfunction and decline in physical performance. These effects likely involve the ability of RWPs to normalize oxidative stress and the expression of proteins involved in the formation of NO and the angiotensin II pathway.     

Antiaging effect of dietary chitosan supplementation on glutathione-dependent antioxidant system in young and aged rats

Aging has been defined as the changes that occur in living organisms with the passage of time that lead to functional impairment and ultimately to death. Free radical-induced oxidative damage has long been thought to be the most important consequence of the aging process. In the present study, an attempt has been made to study the salubrious effects of dietary supplementation of chitosan on glutathione-dependent antioxidant defense system in young and aged rats. The dietary supplementation of chitosan significantly reduced the age-associated dyslipidemic abnormalities noted in the levels of total cholesterol, HDL-cholesterol, and LDL-cholesterol in plasma and heart tissue. Its administration significantly (P < 0.05) attenuated the oxidative stress in the heart tissue of aged rats through the counteraction of free radical formation by maintaining the enzymatic [glutathione peroxidase (GPx) and glutathione reductase (GR)] and non-enzymatic [reduced glutathione (GSH)] status at levels comparable to that of normal young rats. Our results conclude that dietary intake of chitosan restores the depleted myocardial antioxidant status and suggest that it could be an effective therapeutic agent in treatment of age-associated disorders where hypercholesterolemia and oxidative stress are the major causative factors.     

Phosphatidylinositol Transfer Protein Expression Altered by Aging and Parkinson Disease

1. Phosphatidylinositol transfer proteins (PI-TP) are responsible for the transport of phosphatidylinositol (PI) and other phospholipids from endoplasmic reticulum to the other membranes and indirectly for lipid mediated signaling. Till now little is known about PI-TPs in brain aging and neurodegeneration. The aim of this study was to investigate expression of PI-TP in the brain during aging and in animal's model of Parkinson disease (PD) induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Moreover, in vitro, effect of 1-methyl-4-phenyl-pyridine cation (MPP⁺) on PI-TP, tyrosine hydroxylase (TH) protein level, and viability of cells was investigated.2. Wistar rats 4, 24, and 36 months old and C57/BL mice and rat pheochromocytoma (PC12) cell line were used for the studies. Mice C57/BL received three injections of MPTP in saline at 2 h intervals in a total dose of 40 mg/kg and then after 3, 7, and 14 days they were used for the investigation. PC12 cells were treated with increasing concentration (50–300 μM) of MPP⁺ for 24 h at 37°C. The level of PI-TP_{α and β} and TH were determined using Western Blot analysis.3. Our data indicated that PI-TP_{α and β} level decreased in brain of 36 months old rat by 20% comparing to the control value (4 months old). In animal's model of PD, PI-TP_{α and β} level was significantly lower by 85, 69, 64% in striatum at 3, 7, and 14 days after MPTP injection, respectively, compared to the control value. MPP⁺ decreased PI-TP_{α and β}, TH expression, and viability of PC12 cells in a dose-dependent manner. H₂O₂, menadione, and NO donor significantly decreased the PI-TP level and viability of PC12 cells.4. Our results indicate the lower protein expression of PI-TP_{α and β} in aged brain and in PD and suggest that oxidative stress may be responsible for the alteration of PI-TP.     

Oxidation of glutathione and cysteine in human plasma associated with smoking

Cigarette smoking contributes to the development or progression of numerous chronic and age-related disease processes, but detailed mechanisms remain elusive. In the present study, we examined the redox states of the GSH/GSSG and Cys/CySS couples in plasma of smokers and nonsmokers between the ages of 44 and 85 years (n = 78 nonsmokers, n = 43 smokers). The Cys/CySS redox in smokers (−64 ± 16 mV) was more oxidized than nonsmokers (− 76 ± 11 mV; p < .001), with decreased Cys in smokers (9 ± 5 μM) compared to nonsmokers (13 ± 6 μM; p < .001). The GSH/GSSG redox was also more oxidized in smokers (−128 ± 18 mV) than in nonsmokers (−137 ± 17 mV; p = .01) and GSH was lower in smokers (1.8 ± 1.3 μM) than in nonsmokers (2.4 ± 1.0; p < .005). Although the oxidation of GSH/GSSG can be explained by the role of GSH in detoxification of reactive species in smoke, the more extensive oxidation of the Cys pool shows that smoking has additional effects on sulfur amino acid metabolism. Cys availability and Cys/CySS redox are known to affect cell proliferation, immune function, and expression of death receptor systems for apoptosis, suggesting that oxidation of Cys/CySS redox or other perturbations of cysteine metabolism may have a key role in chronic diseases associated with cigarette smoking.     

Oxidative stress in brain aging, neurodegenerative and vascular diseases: an overview

According to the free radical theory, aging can be considered as a progressive, inevitable process partially related to the accumulation of oxidative damage into biomolecules -- nucleic acids, lipids, proteins or carbohydrates -- due to an imbalance between prooxidants and antioxidants in favor of the former. More recently also the pathogenesis of several diseases has been linked to a condition of oxidative stress. In this review we focus our attention on the evidence of oxidative stress in aging brain, some of the most important neurodegenerative diseases -- Alzheimer's disease (AD), mild cognitive impairment (MCI), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) -- and in two common and highly disabling vascular pathologies--stroke and cardiac failure. Particular attention will be given to the current knowledge about the biomarkers of oxidative stress that can be possibly used to monitor their severity and outcome.     

Mitochondrial damage and intralysosomal degradation in cellular aging

Normal mitochondrial respiration is associated with a continuous production of superoxide and hydrogen peroxide, inevitably resulting in minor macromolecular damage. Damaged cellular components are not completely turned over by autophagy and other cellular repair systems, leading to a progressive age-related accumulation of biological “garbage” material, such as defective mitochondria, cytoplasmic protein aggregates and an intralysosomal undegradable material, lipofuscin. These changes primarily affect neurons, cardiac myocytes and other long-lived postmitotic cells that neither dilute this “garbage” by mitotic activity, nor are replaced by newly differentiated cells. Defective mitochondria are insufficient in ATP production and often generate increased amounts of reactive oxygen species, further enhancing oxidative stress. Lipofuscin-loaded lysosomes, in turn, poorly turn over mitochondria that gradually leads to the overload of long-lived postmitotic cells with “garbage” material, decreased adaptability and eventual cell death.     

Aging as a catabolic malfunction

Cellular degradative processes, which include lysosomal (autophagic) and proteasomal degradation, as well as catabolism of proteins by cytosolic and mitochondrial proteases, provide for a continuous turnover of cellular components, such as damaged or obsolete biomolecules and organelles. Inherent insufficiency of these degradative processes results in progressive accumulation within long-lived postmitotic cells of biological ‘garbage’ (waste material), such as various oxidized proteins, functionally effete mitochondria, and lipofuscin (age pigment), an intralysosomal, polymeric, undegradable material. There is increasing evidence that lipofuscin hampers lysosomal degradative capacity, thus promoting the aggravation of accumulated damage at old age. Being rich in redox-active iron, lipofuscin granules also may exacerbate oxidative stress levels in senescent cells. Thus, increasing the efficiency of cellular degradative pathways and preventing involvement of iron in oxidant-induced lysosomal and cellular damage may be potential strategies for anti-aging interventions.