• 【粘膜免疫系统早期衰老的证据。】 复制标题 收藏 收藏
    DOI:10.4049/jimmunol.165.9.5352 复制DOI
    作者列表:Koga T,McGhee JR,Kato H,Kato R,Kiyono H,Fujihashi K
    BACKGROUND & AIMS: :Despite recent advances in the cellular and molecular analysis of induction and regulation of mucosal immune responses, little is yet known about differences which occur in aging. To address this important issue, we have compared the mucosal and systemic immune responses of aged (12- to 14-mo- or 2-year-old) and young adult (6- to 8-wk-old) C57BL/6 mice. Both aged and young mice were immunized weekly with three oral doses of 1 mg of OVA and 10 microg of cholera toxin (CT) as mucosal adjuvant. Both groups of mice over 1 or 2 years of age showed reduced levels of Ag-specific mucosal or systemic immune responses at day 21. An Ag-specific B cell enzyme-linked immunospot assay confirmed these results at the cellular level. When the Ag-induced cytokine responses were examined at both protein and mRNA levels, CD4(+) T cells from spleen and Peyer's patches of young adult mice revealed elevated levels of IL-4 production; however, these cytokine responses were significantly diminished in aged mice. In contrast to mucosal immunization, mice s. c. immunized with OVA plus CT resulted in impaired OVA-specific but intact CT B subunit-specific immune responses in 12- to 14-mo-old mice although the responses to both Ags were depressed in 2-year-old mice. These results provide the first evidence that the development of age-associated alterations possibly occurs earlier in the mucosal immune system than in the systemic immune compartment.
    背景与目标: : 尽管在诱导和调节粘膜免疫反应的细胞和分子分析方面取得了最新进展,但对衰老中发生的差异知之甚少。为了解决这个重要问题,我们比较了年龄 (12至14岁或2岁) 和年轻 (6至8周龄) C57BL/6小鼠的粘膜和全身免疫反应。每周用三种口服剂量的1 mg OVA和10 microg霍乱毒素 (CT) 作为粘膜佐剂对老年和年轻小鼠进行免疫。在第21天,两组1或2岁以上的小鼠均显示Ag特异性粘膜或全身免疫反应水平降低。Ag特异性b细胞酶联免疫斑点测定法在细胞水平上证实了这些结果。当在蛋白质和mRNA水平上检查Ag诱导的细胞因子反应时,来自成年小鼠脾脏和Peyer斑块的CD4 () T细胞显示出IL-4产生水平升高; 然而,这些细胞因子反应在老年小鼠中显着减弱。与粘膜预防接种相反,用OVA加CT免疫的小鼠s. c.在12至14个月大的小鼠中导致OVA特异性但完整的CT B亚基特异性免疫反应受损,尽管对两种Ags的反应均在2岁小鼠中被抑制。这些结果提供了第一个证据,表明与年龄相关的改变的发展可能在粘膜免疫系统中比在全身免疫室中更早发生。
  • 【衰老对大鼠脑中烟碱和毒蕈碱自身受体功能的影响: 与突触前胆碱能标志物和结合位点的关系。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Araujo DM,Lapchak PA,Meaney MJ,Collier B,Quirion R
    BACKGROUND & AIMS: :The main objective of the present work was to determine whether the regulation of ACh release by nicotinic and muscarinic autoreceptors is compromised in the aged rat brain. For this, the effects of the nicotinic agonist N-methylcarbamylcholine (MCC) and the muscarinic-M2 antagonist AF-DX 116 on ACh release from brain slices of young (3-month-old), adult (9-month-old), and aged (27-month-old) rats were tested. The ability of MCC to enhance spontaneous ACh release in hippocampal, cerebral cortical, and cerebellar slices was only modestly altered with age. In contrast, the sensitivity of muscarinic autoreceptors in the aged hippocampus and cerebral cortex, but not the striatum, to blockade by the muscarinic-M2 antagonist AF-DX 116 was severely attenuated. To assess whether the age-related changes in cholinergic autoreceptor function may be due to deficits in presynaptic cholinergic markers, we tested whether choline acetyltransferase (ChAT) activity, basal and evoked ACh release, and nicotinic and muscarinic binding sites are altered in the aged rats. ChAT activity in forebrain regions was decreased in the aged compared to the young and mature adult rats. Furthermore, the potassium-evoked, but not the spontaneous, release of ACh was markedly depressed in striatal, hippocampal, and cortical slices of aged rats. The densities of nicotinic and muscarinic-M2 binding sites, assessed using 3H-MCC and 3H-AF-DX 116 as selective ligands, respectively, were markedly reduced in homogenates of the striatum, hippocampus, cerebral cortex, and thalamus of aged rats. In contrast, muscarinic-M1 sites, selectively labeled with 3H-pirenzepine, were not affected. Therefore, it appears that age-related decrements in ChAT activity and in muscarinic-M2, but not nicotinic, binding sites in the rat brain are reflected in a decreased function of muscarinic-M2 autoreceptors. However, the positive correlation between loss of ChAT activity, decreased muscarinic-M2 binding sites, and impaired muscarinic autoreceptor function is clearly tissue dependent.
    背景与目标: : 当前工作的主要目的是确定在老年大鼠大脑中烟碱和毒蕈碱自身受体对ACh释放的调节是否受到损害。为此,烟碱激动剂N-甲基氨基甲酰胆碱 (MCC) 和muscarinic-M2拮抗剂af-dx 116对从年轻 (3个月大),成人 (9个月大) 的大脑切片中释放ACh的影响,并测试了年龄 (27个月大) 的大鼠。MCC增强海马,大脑皮层和小脑切片中自发性ACh释放的能力仅随年龄而略有变化。相反,老年海马和大脑皮层 (而不是纹状体) 中毒蕈碱自身受体对muscarinic-M2拮抗剂af-dx 116阻断的敏感性严重减弱。为了评估胆碱能自身受体功能的年龄相关变化是否可能是由于突触前胆碱能标志物的缺陷引起的,我们测试了胆碱乙酰转移酶 (ChAT) 活性,基础和诱发的ACh释放以及烟碱和毒蕈碱结合位点是否在老年大鼠中改变。与年轻和成年大鼠相比,老年人的前脑区域聊天活性降低。此外,在老年大鼠的纹状体,海马和皮质切片中,钾诱发的ACh释放 (而不是自发释放) 明显抑制。分别使用3H-MCC和3H-AF-DX 116作为选择性配体评估的烟碱和muscarinic-M2结合位点的密度在老年大鼠的纹状体,海马,大脑皮层和丘脑的匀浆中显着降低。相反,用3h-哌仑西平选择性标记的muscarinic-M1位点不受影响。因此,似乎与年龄相关的ChAT活动和muscarinic-M2 (而不是烟碱) 结合位点的衰老反映在muscarinic-M2自身受体的功能降低中。然而,ChAT活性丧失,muscarinic-M2结合位点降低和毒蕈碱自身受体功能受损之间的正相关显然是组织依赖性的。
  • 【衰老对大鼠下颌下腺溶酶体酸DNase的影响。】 复制标题 收藏 收藏
    DOI:10.1177/00220345880670011601 复制DOI
    作者列表:Yaegaki K,Ogura R,Kameyama T,Sujaku C,Tonzetich J
    BACKGROUND & AIMS: :Lysosomal and cytoplasmic fractions were prepared from rat submandibular glands for investigation of the release of lysosomal acid DNase in relation to aging. It was found that the acid DNase activity ratio for cytoplasmic/lysosomal fractions in rats aged 27 months was higher than that in three-month-old rats. The release of acid DNase from the lysosomal fraction by shaking was markedly increased in the fraction from the older animals.
    背景与目标: : 从大鼠下颌下腺制备溶酶体和细胞质组分,以研究溶酶体酸DNase的释放与衰老的关系。发现27个月大的大鼠的细胞质/溶酶体组分的酸性DNase活性比高于3个月大的大鼠。在老年动物的部分中,通过摇动从溶酶体部分释放的酸性DNase显着增加。
  • 【住院老年人和家庭护理人员对衰老,损伤和虚弱的预后信息的接受性: 一项定性研究。】 复制标题 收藏 收藏
    DOI:10.1016/j.ijnurstu.2020.103602 复制DOI
    作者列表:Maxwell CA,Mixon AS,Conner E,Phillippi JC
    BACKGROUND & AIMS: BACKGROUND:Frailty is the leading prognosticator for poor outcomes and palliative care among older adults. Delivery of negative prognostic information entails potentially difficult conversations about decline and death. OBJECTIVE:The study aims were to: 1) examine hospitalized older adults' and family caregivers' receptivity to general (vs. individualized) prognostic information about frailty, injury, and one-year outcomes; and 2) determine information needs based on prognostic information. DESIGN:Provision of general prognostic information followed by semi-structured interview questions. We deductively analyzed qualitative data within the context of problematic integration theory. SETTING:An academic medical center in the Southeast region of the U.S. PARTICIPANTS:Purposive sampling was utilized to obtain a distribution of patients across the frailty continuum (non-frail [N=10], pre-frail [N=9], frail [9=6]). Twenty-five older adults (≥ age 65) hospitalized for a primary injury (e.g. fall) and 15 family caregivers of hospitalized patients were enrolled. METHODS:Hospitalized older patients and family caregivers were shown prognostic information about one-year outcomes of injured older adults in the form of simple pictographs. Semi-structured interview questions were administered immediately afterwards. The interviews were audio-recorded, transcribed, and analyzed using qualitative content analysis. Demographic and medical information data were used to contextualize the responses during analysis. RESULTS:Overall, participants (patients [56%], caregivers [73%]) were open to receiving prognostic information. A small number of family caregivers (N=3) expressed reservations about the frankness of the information and suggested delivery through a softer approach or not at all. Qualitative data was coded using categories and constructs of problematic integration theory. Four codes (personalizing the evidence, vivid understanding, downhill spiral, realities of aging) reflected probabilistic and evaluative orientation categories of problematic integration theory. One code (fatalism vs. hope) represented manifestations of ambivalence and ambiguity in the theory; and another code (exceptionalism) represented divergence and impossibility. Two codes (role of thought processes, importance of faith) reflected forms of resolutions as described in problematic integration theory. Information needs based on prognostic information revealed four additional codes: give it to me straight, what can I do? what can I expect? and how can I prevent decline? A consistently reported desire of both patients and caregivers was for honesty and hope from providers. CONCLUSION:This study supports the use of general prognostic information in conversations about aging, injury, frailty and patient outcomes. Incorporating prognostic information into communication aids can facilitate shared decision making before end-of-life is imminent.
    背景与目标:
  • 【产后热量限制的叠加可保护衰老的男性宫内生长受限的后代免受代谢不良的影响。】 复制标题 收藏 收藏
    DOI:10.1210/en.2012-1206 复制DOI
    作者列表:Dai Y,Thamotharan S,Garg M,Shin BC,Devaskar SU
    BACKGROUND & AIMS: :Intrauterine growth restriction (IUGR) results in dysregulated glucose homeostasis and adiposity in the adult. We hypothesized that with aging, these perturbations will wane, and superimposition of postnatal growth restriction (PNGR) on IUGR [intrauterine and postnatal growth restriction (IPGR)] will reverse the residual IUGR phenotype. We therefore undertook hyperinsulinemic-euglycemic clamp, energy balance, and physical activity studies during fed, fasted, and refed states, in light and dark cycles, on postweaned chow diet-fed more than 17-month aging male IUGR, PNGR, and IPGR vs. control (CON) rat offspring. Hyperinsulinemic-euglycemic clamp revealed similar whole-body insulin sensitivity and physical activity in the nonobese IUGR vs. CON, despite reduced heat production and energy expenditure. Compared with CON and IUGR, IPGR mimicking PNGR was lean and growth restricted with increased physical activity, O(2) consumption (VO(2)), energy intake, and expenditure. Although insulin sensitivity was no different in IPGR and PNGR, skeletal muscle insulin-induced glucose uptake was enhanced. This presentation proved protective against the chronologically earlier (5.5 months) development of obesity and dysregulated energy homeostasis after 19 wk on a postweaned high-fat diet. This protective role of PNGR on the metabolic IUGR phenotype needs future fine tuning aimed at minimizing unintended consequences.
    背景与目标: : 宫内生长受限 (IUGR) 导致成人葡萄糖稳态失调和肥胖。我们假设随着年龄的增长,这些扰动将减弱,并且产后生长限制 (PNGR) 对IUGR [宫内和产后生长限制 (IPGR)] 的叠加将逆转残留的IUGR表型。因此,我们对断奶后饮食喂养超过17个月的雄性IUGR,PNGR和IPGR与对照 (CON) 大鼠后代进行了高胰岛素血症-正常血糖钳夹,能量平衡和体力活动研究。尽管热量产生和能量消耗减少,但高胰岛素-正常血糖钳夹在非肥胖IUGR与CON中显示出相似的全身胰岛素敏感性和身体活动。与CON和IUGR相比,模仿PNGR的IPGR是瘦弱的,并且生长受到体力活动,O(2) 消耗 (VO(2)),能量摄入和支出增加的限制。尽管IPGR和PNGR的胰岛素敏感性没有不同,但骨骼肌胰岛素诱导的葡萄糖摄取增强。该报告证明对断奶后高脂饮食19周后肥胖的时间较早 (5.5个月) 和能量稳态失调具有保护作用。PNGR对代谢IUGR表型的这种保护作用需要未来的微调,以最大程度地减少意外后果。
  • 【散发性包涵体肌炎的初级肌肉培养物中的衰老增加。】 复制标题 收藏 收藏
    DOI:10.1016/j.neurobiolaging.2008.08.011 复制DOI
    作者列表:Morosetti R,Broccolini A,Sancricca C,Gliubizzi C,Gidaro T,Tonali PA,Ricci E,Mirabella M
    BACKGROUND & AIMS: :Ageing is thought to participate to the pathogenesis of sporadic inclusion-body myositis (s-IBM). Although the regenerative potential of s-IBM muscle is reduced in vivo, age-related abnormalities of satellite cells possibly accounting for the decline of muscle repair have not been demonstrated. Here we show that proliferation rate and clonogenicity of s-IBM myoblasts are significantly lower and doubling time is longer than normal age-matched controls, indicating that proliferative capacity of s-IBM muscles becomes exhausted earlier. Telomere shortening is detected in s-IBM cells suggesting premature senescence. Differently from controls, s-IBM myoblasts show increased active beta-catenin mainly localized within myonuclei, indicating active Wnt stimulation. After many rounds of muscle growth, only s-IBM myoblasts accumulate congophilic inclusions and immunoreactive Abeta(1-40) deposits. Therefore, s-IBM myoblasts seem to have a constitutively impaired regenerative capacity and the intrinsic property, upon sufficient aging in vitro, to accumulate Abeta. Our results might be valuable in understanding molecular mechanisms associated with muscle aging underlying the defective regeneration of s-IBM muscle and provide new clues for future therapeutic strategies.
    背景与目标: : 衰老被认为参与了散发性包涵体肌炎 (s-IBM) 的发病机理。尽管体内s-IBM肌肉的再生潜力降低,但尚未证明与年龄相关的卫星细胞异常可能导致肌肉修复下降。在这里,我们显示s-IBM成肌细胞的增殖率和克隆性明显低于正常年龄匹配的对照组,并且倍增时间更长,这表明s-IBM肌肉的增殖能力更早耗尽。在s-IBM细胞中检测到端粒缩短,提示过早衰老。与对照组不同,s-IBM成肌细胞显示主要位于肌核内的活性 β-catenin增加,表明Wnt刺激活跃。经过多轮肌肉生长后,只有s-IBM成肌细胞积累了嗜血包涵体和免疫反应性Abeta(1-40) 沉积物。因此,在体外充分老化后,s-IBM成肌细胞似乎具有组成性受损的再生能力和内在特性,以积累Abeta。我们的结果可能对理解与s-IBM肌肉再生缺陷相关的肌肉老化相关的分子机制有价值,并为未来的治疗策略提供新的线索。
  • 【衰老器官和组织中的长非编码rna。】 复制标题 收藏 收藏
    DOI:10.1111/1440-1681.12795 复制DOI
    作者列表:Xing W,Gao W,Mao G,Zhang J,Lv X,Wang G,Yan J
    BACKGROUND & AIMS: :The aging process directly impacts bodily functions on multiple levels, including a reduced ability to resist stress, damage and disease. Besides changes in metabolic control, the aging process coincides with the altered long non-coding RNAs (lncRNAs) expression, which are ≥200nt long class of non-protein coding RNAs. The majority of non-coding transcripts of mammalian organs and tissues are expressed in developmentally regulated and cell-type specific manners. Specific altered lncRNA level has been involved in induction and maintenance of the whole human body aging with highly specific spatial andtemporal expression patterns. Furthermore, many lncRNAs are transcribed in sense, antisense and bidirectional manners in the mammalian genome. They play a vital role in regulating organ or tissue differentiation during aging by binding with miRNA or proteins to act as a decoy. Recently, the correlation between lncRNAs and aging has been studied intensely. Here, we have summarized some examples of known and novel lncRNAs that have been implicated in the aging process in the whole mammalian body and we discuss these patterns, conservation and characters during aging. This may further promote the development of research on lncRNAs and the aging process.
    背景与目标: : 衰老过程在多个层面上直接影响身体功能,包括抵抗压力、损伤和疾病的能力降低。除了代谢控制的变化外,衰老过程还与长非编码rna (lncRNAs) 表达的改变相吻合,长非编码rna是 ≥ 200nt长的非蛋白质编码rna。哺乳动物器官和组织的大多数非编码转录本以发育调节和细胞类型特定的方式表达。特定改变的lncRNA水平已参与诱导和维持具有高度特异性的时空表达模式的整个人体衰老。此外,许多lncrna在哺乳动物基因组中以有义,反义和双向方式转录。它们通过与miRNA或蛋白质结合作为诱饵,在衰老过程中调节器官或组织的分化中起着至关重要的作用。最近,人们对lncRNAs与衰老之间的相关性进行了深入研究。在这里,我们总结了一些已知和新型lncrna的例子,这些例子与整个哺乳动物体内的衰老过程有关,我们讨论了衰老过程中的这些模式,保存和特征。这可能会进一步促进lncRNAs和衰老过程研究的发展。
  • 【胸腺与衰老: 形态学、放射学和功能概述。】 复制标题 收藏 收藏
    DOI:10.1007/s11357-013-9564-5 复制DOI
    作者列表:Rezzani R,Nardo L,Favero G,Peroni M,Rodella LF
    BACKGROUND & AIMS: :Aging is a continuous process that induces many alterations in the cytoarchitecture of different organs and systems both in humans and animals. Moreover, it is associated with increased susceptibility to infectious, autoimmune, and neoplastic processes. The thymus is a primary lymphoid organ responsible for the production of immunocompetent T cells and, with aging, it atrophies and declines in functions. Universality of thymic involution in all species possessing thymus, including human, indicates it as a long-standing evolutionary event. Although it is accepted that many factors contribute to age-associated thymic involution, little is known about the mechanisms involved in the process. The exact time point of the initiation is not well defined. To address the issue, we report the exact age of thymus throughout the review so that readers can have a nicely pictured synoptic view of the process. Focusing our attention on the different stages of the development of the thymus gland (natal, postnatal, adult, and old), we describe chronologically the morphological changes of the gland. We report that the thymic morphology and cell types are evolutionarily preserved in several vertebrate species. This finding is important in understanding the similar problems caused by senescence and other diseases. Another point that we considered very important is to indicate the assessment of the thymus through radiological images to highlight its variability in shape, size, and anatomical conformation.
    背景与目标: : 衰老是一个连续的过程,会导致人类和动物不同器官和系统的细胞结构发生许多变化。此外,它与感染,自身免疫和肿瘤过程的易感性增加有关。胸腺是负责产生免疫活性T细胞的主要淋巴器官,并且随着年龄的增长,它会萎缩和功能下降。胸腺内卷在所有拥有胸腺的物种 (包括人类) 中的普遍性表明这是一个长期的进化事件。尽管人们公认许多因素会导致与年龄相关的胸腺内卷,但对该过程中涉及的机制知之甚少。启动的确切时间点没有很好的定义。为了解决这个问题,我们在整个评论中报告了胸腺的确切年龄,以便读者可以对该过程有很好的了解。我们将注意力集中在胸腺发育的不同阶段 (出生,出生后,成年和老年),我们按时间顺序描述了腺体的形态变化。我们报告说,在几种脊椎动物物种中,胸腺形态和细胞类型在进化上得以保留。这一发现对于理解衰老和其他疾病引起的类似问题非常重要。我们认为非常重要的另一点是通过放射学图像指示对胸腺的评估,以突出其形状,大小和解剖构象的可变性。
  • 【神经表现的保真度降低是正常衰老中情景记忆下降的基础。】 复制标题 收藏 收藏
    DOI:10.1093/cercor/bhx130 复制DOI
    作者列表:Zheng L,Gao Z,Xiao X,Ye Z,Chen C,Xue G
    BACKGROUND & AIMS: :Emerging studies have emphasized the importance of the fidelity of cortical representation in forming enduring episodic memory. No study, however, has examined whether there are age-related reductions in representation fidelity that can explain memory declines in normal aging. Using functional MRI and multivariate pattern analysis, we found that older adults showed reduced representation fidelity in the visual cortex, which accounted for their decreased memory performance even after controlling for the contribution of reduced activation level. This reduced fidelity was specifically due to older adults' poorer item-specific representation, not due to their lower activation level and variance, greater variability in neuro-vascular coupling, or decreased selectivity of categorical representation (i.e., dedifferentiation). Older adults also showed an enhanced subsequent memory effect in the prefrontal cortex based on activation level, and their prefrontal activation was associated with greater fidelity of representation in the visual cortex and better memory performance. The fidelity of cortical representation thus may serve as a promising neural index for better mechanistic understanding of the memory declines and its compensation in normal aging.
    背景与目标: : 新兴研究强调了皮质表示的保真度在形成持久的情景记忆中的重要性。然而,没有研究检查是否存在与年龄相关的代表保真度降低,可以解释正常衰老时的记忆力下降。使用功能MRI和多变量模式分析,我们发现老年人在视觉皮层中的表现保真度降低,即使在控制了激活水平降低的贡献后,他们的记忆表现也会降低。保真度的降低是特别由于老年人的项目特异性表现较差,而不是由于其激活水平和差异较低,神经-血管偶联的变异性较大或分类表现的选择性降低 (即去分化)。老年人还显示出基于激活水平的前额叶皮层增强的后续记忆效应,并且他们的前额叶激活与视觉皮层中更大的表现保真度和更好的记忆性能相关。因此,皮质表示的保真度可以作为一种有前途的神经指标,以更好地从机械上理解记忆力下降及其在正常衰老中的补偿。
  • 【骨骼肌作为研究组织衰老和年轻化的实验选择模型。】 复制标题 收藏 收藏
    DOI:10.1186/s13395-020-0222-1 复制DOI
    作者列表:Etienne J,Liu C,Skinner CM,Conboy MJ,Conboy IM
    BACKGROUND & AIMS: :Skeletal muscle is among the most age-sensitive tissues in mammal organisms. Significant changes in its resident stem cells (i.e., satellite cells, SCs), differentiated cells (i.e., myofibers), and extracellular matrix cause a decline in tissue homeostasis, function, and regenerative capacity. Based on the conservation of aging across tissues and taking advantage of the relatively well-characterization of the myofibers and associated SCs, skeletal muscle emerged as an experimental system to study the decline in function and maintenance of old tissues and to explore rejuvenation strategies. In this review, we summarize the approaches for understanding the aging process and for assaying the success of rejuvenation that use skeletal muscle as the experimental system of choice. We further discuss (and exemplify with studies of skeletal muscle) how conflicting results might be due to variations in the techniques of stem cell isolation, differences in the assays of functional rejuvenation, or deciding on the numbers of replicates and experimental cohorts.
    背景与目标: : 骨骼肌是哺乳动物中年龄最敏感的组织之一。其驻留干细胞 (即卫星细胞,SCs),分化细胞 (即肌纤维) 和细胞外基质的显着变化导致组织稳态,功能和再生能力下降。基于跨组织衰老的保守性,并利用肌纤维和相关SCs的相对较好的表征,骨骼肌成为研究旧组织功能下降和维持并探索复兴策略的实验系统。在这篇综述中,我们总结了使用骨骼肌作为首选实验系统的理解衰老过程和分析年轻化成功的方法。我们进一步讨论 (并以骨骼肌研究为例),由于干细胞隔离技术的差异,功能复兴测定的差异或决定重复和实验队列的数量,可能导致相互矛盾的结果。
  • 【衰老和吗啡给药对小鼠纹状体钙调蛋白和钙调蛋白调节酶的影响。】 复制标题 收藏 收藏
    DOI:10.1111/j.1471-4159.1985.tb08726.x 复制DOI
    作者列表:Hoskins B,Ho IK,Meydrech EF
    BACKGROUND & AIMS: :Male ICR mice, young (25-days old), mature (3-months old), and old (22 months), were injected with morphine sulfate (10 mg/kg, s.c.) or were implanted with morphine pellets (75 mg). Controls received saline injections or placebo pellets. One hour after injections and 72 h after pellet implantations, the mice were decapitated and striatal regions were removed for the following analyses: calmodulin (CaM) levels via radioimmunoassay and activities of cyclic nucleotide phosphodiesterases, adenylate and guanylate cyclases, and Ca2+, Mg2+-ATPase. Acute morphine treatment produced the following: (1) increases in calmodulin levels in the young and old mice while having no effect on mature levels; (2) increases in activities of guanylate cyclase of mature mice while decreasing those of the old mice; (3) no effects on activity of adenylate cyclase; (4) decreased activity of cyclic AMP-phosphodiesterase in young mice only; (5) decreased activity of Ca2+, Mg2+-ATPase in the old mice only. The only changes found in striata from morphine-tolerant mice when compared with age-matched controls were elevations in cyclic GMP-phosphodiesterase activities in all three age groups. Differences in control values of the three age groups were as follows: CaM levels, mature greater than old greater than young; Ca2+, Mg2+-ATPase activity, old greater than mature-young. The results indicate age-induced changes in cellular regulation and biochemical responses to morphine.
    背景与目标: : 年轻 (25天大),成熟 (3个月大) 和年龄 (22个月大) 的雄性ICR小鼠注射硫酸吗啡 (10 mg/kg,s.c.) 或植入吗啡颗粒 (75 mg)。对照组接受生理盐水注射或安慰剂颗粒。注射后1小时和颗粒植入后72小时,将小鼠斩首并去除纹状体区域进行以下分析: 通过放射免疫测定法测定钙调蛋白 (CaM) 水平以及环核苷酸磷酸二酯酶,腺苷酸和鸟苷酸环化酶以及Ca2的活性,mg2-atpase。急性吗啡处理产生以下结果 :( 1) 年轻和老年小鼠的钙调蛋白水平升高,而对成熟水平无影响; (2) 成熟小鼠鸟苷酸环化酶活性增加,而老年小鼠的鸟苷酸环化酶活性降低; (3) 对腺苷酸环化酶活性无影响; (4) 仅在年轻小鼠中降低环AMP-磷酸二酯酶的活性; (5) 仅在老年小鼠中降低Ca2,Mg2-ATPase的活性。与年龄匹配的对照组相比,吗啡耐受小鼠的纹状体中发现的唯一变化是所有三个年龄组的环GMP-磷酸二酯酶活性均升高。三个年龄组的对照值差异如下: CaM水平,成熟大于年龄大于年轻; Ca2,mg2-atpase活性,老大于成熟-年轻。结果表明,年龄引起的细胞调节和对吗啡的生化反应的变化。
  • 【衰老过程中胸腺细胞和骨髓单核细胞中ABCB1和ABCC活性的独立调节。】 复制标题 收藏 收藏
    DOI:10.1111/j.1365-3083.2007.01965.x 复制DOI
    作者列表:Kyle-Cezar F,Echevarria-Lima J,Rumjanek VM
    BACKGROUND & AIMS: :Aging modifies a number of functional and phenotypic parameters of cells from the immune system. In this study, the activities of two members of the superfamily of ATP-binding cassette (ABC) transport proteins, ABCB1 and ABCC (measured by rhodamine 123 efflux and Fluo-3 efflux respectively), were compared in murine bone marrow cells and thymocytes of young (3-4 weeks old), adult (2-3 months old) and old (18 months old) mice. ABCB1 activity was shown to be age regulated in murine bone marrow mononuclear cells and thymocytes. In the bone marrow, the increased amount of cells with ABCB1 activity observed in old mice was restricted to the c-kit(-)Sca-1(+) and c-kit(+)Sca-1(+) subpopulations. Only a small percentage of c-kit(+) cells in the thymus had ABCB1 activity, and this subpopulation increased with age. In the thymus, old age augmented this activity in the CD4(-) CD8(-) double-negative cells and in the CD4(+) and CD8(+) single-positive populations. The activity of another ABC transporter, the ABCC-related activity, was also modified by age in the bone marrow. However, the age-related increase was observed in the subpopulations were ABCB1 was not modified, namely the non-progenitor population (c-kit(-)Sca-1(-)cells) and c-kit(+)Sca-1(-) cells. Nearly, all thymocytes expressed the ABCC1 molecule in an active form and aging did not affect this pattern. This study demonstrates an independent upregulation of ABCB1 and ABCC activities during the aging process. The increases were observed in different subsets of cells but followed a developmentally regulated pattern. The functions played by these transporters and alterations in aging are discussed.
    背景与目标: : 衰老改变了免疫系统细胞的许多功能和表型参数。在这项研究中,比较了ATP结合盒 (ABC) 转运蛋白超家族的两个成员ABCB1和ABCC (分别通过罗丹明123外排和Fluo-3外排测量) 在小鼠骨髓细胞和胸腺细胞中的活性 (3-4周龄),成年 (2-3个月大) 和大 (18个月大) 小鼠。ABCB1活性在小鼠骨髓单核细胞和胸腺细胞中被年龄调节。在骨髓中,在老年小鼠中观察到的具有ABCB1活性的细胞数量的增加仅限于c-kit(-)Sca-1 () 和c-kit () Sca-1 () 亚群。胸腺中只有一小部分c-kit () 细胞具有ABCB1活性,并且该亚群随着年龄的增长而增加。在胸腺中,老年人在CD4(-) CD8(-) 双阴性细胞以及CD4 () 和CD8 () 单阳性人群中增强了这种活性。另一种ABC转运蛋白的活性,即ABCC相关活性,也因骨髓中的年龄而改变。然而,在ABCB1未修饰的亚群中观察到年龄相关的增加,即非祖细胞群 (c-kit(-)Sca-1(-) 细胞) 和c-kit(+)Sca-1(-) 细胞。几乎所有胸腺细胞都以活性形式表达ABCC1分子,并且衰老不会影响这种模式。这项研究证明了老化过程中ABCB1和ABCC活性的独立上调。在不同的细胞亚群中观察到增加,但遵循发育调节的模式。讨论了这些转运蛋白的功能以及衰老的改变。
  • 【与衰老相关的组蛋白乙酰转移酶KAT6B的减少与造血干细胞分化的改变有关。】 复制标题 收藏 收藏
    DOI:10.1016/j.exphem.2020.01.014 复制DOI
    作者列表:Khokhar ES,Borikar S,Eudy E,Stearns T,Young K,Trowbridge JJ
    BACKGROUND & AIMS: :Aged hematopoietic stem cells (HSCs) undergo biased lineage priming and differentiation toward production of myeloid cells. A comprehensive understanding of gene regulatory mechanisms causing HSC aging is needed to devise new strategies to sustainably improve immune function in aged individuals. Here, a focused short hairpin RNA screen of epigenetic factors reveals that the histone acetyltransferase Kat6b regulates myeloid cell production from hematopoietic progenitor cells. Within the stem and progenitor cell compartment, Kat6b is highly expressed in long-term (LT)-HSCs and is significantly decreased with aging at the transcript and protein levels. Knockdown of Kat6b in young LT-HSCs causes skewed production of myeloid cells at the expense of erythroid cells both in vitro and in vivo. Transcriptome analysis identifies enrichment of aging and macrophage-associated gene signatures alongside reduced expression of self-renewal and multilineage priming signatures. Together, our work identifies KAT6B as a novel epigenetic regulator of hematopoietic differentiation and a target to improve aged immune function.
    背景与目标: : 衰老的造血干细胞 (hsc) 经历偏向的谱系引发和分化,向髓系细胞的产生分化。需要全面了解导致HSC衰老的基因调控机制,以设计新的策略来可持续地改善老年人的免疫功能。在这里,表观遗传因子的聚焦短发夹RNA筛选揭示了组蛋白乙酰转移酶Kat6b调节造血祖细胞产生的髓系细胞。在干细胞和祖细胞区室中,Kat6b在长期 (LT)-hsc中高度表达,并且随着转录本和蛋白质水平的老化而显着降低。在年轻的LT-hsc中敲除Kat6b会导致髓样细胞产生偏斜,而在体外和体内均牺牲红系细胞。转录组分析确定了衰老和巨噬细胞相关基因特征的富集,以及自我更新和多谱系引发特征的表达减少。我们的工作共同确定KAT6B是造血分化的新型表观遗传调节剂,也是改善老年免疫功能的靶标。
  • 【在预测老年人成功衰老方面,腰围与身高比优于经典人体测量指标; 对ATTICA和medi流行病学研究的分析。】 复制标题 收藏 收藏
    DOI:10.1080/0361073X.2020.1716155 复制DOI
    作者列表:Koloverou E,Foscolou A,Gkouvas K,Tyrovolas S,Matalas AL,Polychronopoulos E,Chrysohoou C,Pitsavos C,Panagiotakos DB
    BACKGROUND & AIMS: :Background/Study context: The aim of the present work was to investigate the association of Waist-to-Height Ratio (WHtR) with Successful Aging (SA) status and compare it to classic anthropometric indices, among middle-aged and older individuals.Methods: Among various socio-demographic, clinical and lifestyle characteristics, height, weight, waist circumference (WC), Waist-to-Hip Ratio (WHR) and WHtR of the Greek participants, over 50 years old, enrolled in the ATTICA (n = 1,128) and the MEDIS (n = 2,221) in relation to SA; SA was evaluated using the validated Successful Aging Index (SAI, range 0-10) comprising of health-related, social, lifestyle, and clinical parameters.Results: WHtR was inversely associated with SAI with every 0.1-unit increase, lowering SAI by almost 0.5 units (b-coefficient±SE: -4.71 ± 0.26; 95%CI: -5.21, -4.20). Also, WHtR was more strongly associated with SAI (b = -0.352), surpassing the effect of age and sex (b = -0.347 and 0.11, respectively). With respect to the other anthropometric indices (weight, height, WC, WHR), WHtR exhibited the highest explanatory ability (Adjusted R2 = 0.345); the higher the adjusted R2 the higher explanatory ability.Conclusions: WHtR was revealed as the best determinant of successful aging, with respect to other anthropometric indices (weight, height, WC, WHR). The present findings are of significant public health importance for better understanding the role of body mass distribution on the aging process.
    背景与目标: 背景/研究背景: 当前工作的目的是调查腰围与身高比 (WHtR) 与成功衰老 (SA) 状态的关联,并将其与中老年人的经典人体测量指数进行比较。方法: 在各种社会人口统计学中,50岁以上希腊参与者的临床和生活方式特征,身高,体重,腰围 (WC),腰臀比 (WHR) 和WHtR,与SA相关的ATTICA (n = 1,128) 和medi (n = 2,221); 使用包含健康相关、社会、生活方式和临床参数的已验证的成功衰老指数 (SAI,范围0-10) 评估SA。结果: 每增加0.1单位,WHtR与SAI成反比,SAI降低近0.5单位 (b系数 ± SE: -4.71 ± 0.26; 95% CI: -5.21,-4.20)。而且,WHtR与SAI的相关性更强 (b = -0.352),超过了年龄和性别的影响 (b = -0.347和0.11)。关于其他人体测量指标 (体重,身高,WC,WHR),WHtR表现出最高的解释能力 (调整后的R2 = 0.345); 调整后的R2越高,解释能力就越高。结论: WHtR被揭示为成功衰老的最佳决定因素,关于其他人体测量指数 (体重、身高、WC、WHR)。目前的发现对于更好地了解体重分布在衰老过程中的作用具有重要的公共卫生重要性。
  • 【糖原磷酸化酶缺失酵母的氧化应激和时间老化。】 复制标题 收藏 收藏
    DOI:10.1016/j.freeradbiomed.2008.08.021 复制DOI
    作者列表:Favre C,Aguilar PS,Carrillo MC
    BACKGROUND & AIMS: :Chronological aging in yeast resembles aging in mammalian, postmitotic tissues. Such chronological aging begins with entrance into the stationary phase after the nutrients are exhausted. Many changes in metabolism take place at this moment, and survival in this phase strongly depends on oxidative-stress resistance. In this study, hypo- and hyperglycogenic phenotypes of Saccharomyces cerevisiae strains with deletions of carbohydrate-metabolism enzymes were selected, and a comparison of their chronological longevities was made. Stress sensitivity, ROS, and apoptosis markers during aging were analyzed in the emerged candidates. Among the strains that accumulated greater amounts of glycogen, the deletion of glycogen phosphorylase, gph1delta, was unique in showing a shortened life span, stress intolerance, and higher levels of ROS during its survival. The transcription of superoxide dismutase genes during survival was three- to fourfold lower in gph1delta. Extra copies of SOD1/2 counteracted the stress sensitivity and the accelerated aging of gph1delta. In conclusion, the lack of gph1 produced a rapidly aging strain, which could be attributed, at least in part, to the weakened stress resistance associated with the decreased expression of both SODs. Gph1p seems to be a candidate in a scenario that could link early metabolic changes with other targets of the stress response during stationary-phase survival.
    背景与目标: : 酵母的时间老化类似于哺乳动物有丝分裂后组织的老化。这种按时间顺序排列的衰老始于营养物质耗尽后进入固定相。此时发生了许多代谢变化,并且在此阶段的生存在很大程度上取决于抗氧化应激的抗性。在这项研究中,选择了具有碳水化合物代谢酶缺失的酿酒酵母菌株的低糖和高糖表型,并比较了它们的时间长度。在出现的候选者中分析了衰老过程中的应激敏感性,ROS和凋亡标志物。在积累大量糖原的菌株中,糖原磷酸化酶gph1delta的缺失是独特的,其寿命缩短,应激不耐受和生存期间ROS水平较高。在gph1delta中,存活期间超氧化物歧化酶基因的转录降低了三到四倍。额外的SOD1/2副本抵消了gph1delta的应力敏感性和加速老化。总之,缺乏gph1会产生快速老化的菌株,这至少部分归因于与两种sod表达降低相关的抗逆性减弱。在可以将早期代谢变化与静止期生存期间的应激反应的其他目标联系起来的情况下,Gph1p似乎是候选者。

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