Mechanisms of Ageing and Development最新文献_第10页

Protective effects and bioinformatic analysis of narciclasine on vascular aging via cross-talk between inflammation and metabolism through inhibiting skeletal muscle-specific ceramide synthase 1 水仙素通过抑制骨骼肌特异性神经酰胺合成酶1在炎症与代谢间的交互作用对血管衰老的保护作用及生物信息学分析

IF 5.3 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-02-01 DOI: 10.1016/j.mad.2024.112021

Zhiyi Fang , Linghuan Wang , Yabin Wang , Yan Ma , Yan Fang , Weiwei Zhang , Ruihua Cao , Yingjie Zhang , Hui Li , Sijia Chen , Lei Tian , Xiaoying Shen , Feng Cao

Objective

The senescence of smooth muscle is one of the independent risk factors in atherosclerosis progression in which the vascular inflammation plays an important role on vascular dysfunction. This study is designed to explore the novel vascular aging biomarkers and screen the potential molecular interventional targets through bioinformatic analysis.

Results

Transcriptional analysis was conducted based on the GSE16487 open access database, which included 15 human vascular tissue samples from two groups: young group (≤ 60 years old, n = 8) and aged group (≥ 75 years old, n = 7). There were 275 differential expression genes (119 upregulated and 156 downregulated genes) with minimum 1.5-fold change between two groups. 9 genes were mainly participated in inflammation-related signaling pathways, in which narciclasine was validated as the most effective candidate for modulation the ceramide synthesis. In vitro and animal study demonstrated that narciclasine reversed vascular aging by inhibiting skeletal muscle-specific ceramide synthase 1 (CerS1), reducing the ceramide level derived from CerS1, and improving fat deposition and circulating glycolipid metabolism.

Conclusion

Narciclasine attenuates vascular aging and modulates the cross-talk between inflammation and metabolism via inhibiting skeletal muscle-specific ceramide synthase 1.

目的：平滑肌衰老是动脉粥样硬化进展的独立危险因素之一，其中血管炎症在血管功能障碍中起重要作用。本研究旨在通过生物信息学分析，探索新的血管老化生物标志物，筛选潜在的分子干预靶点。结果：基于GSE16487开放获取数据库进行转录分析，共纳入青年组（≤60岁，n = 8）和老年组（≥75岁，n = 7）两组15份人血管组织样本，差异表达基因275个（上调119个，下调156个），两组差异表达基因差异最小1.5倍。9个基因主要参与炎症相关的信号通路，其中水仙素被证实是调节神经酰胺合成最有效的候选基因。体外和动物实验表明，水仙素通过抑制骨骼肌特异性神经酰胺合成酶1 （CerS1）、降低CerS1衍生的神经酰胺水平、改善脂肪沉积和循环糖脂代谢来逆转血管衰老。结论：水仙素通过抑制骨骼肌特异性神经酰胺合酶1，减缓血管衰老，调节炎症与代谢的交互作用。

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引用次数: 0

IRF1-RIG-I signaling defects in the aged alveolar epithelial cells may contribute to decreased pulmonary antiviral immune responses 衰老肺泡上皮细胞中的IRF1-RIG-I信号缺陷可能导致肺部抗病毒免疫反应下降。

IF 5.3 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-01-26 DOI: 10.1016/j.mad.2025.112037

Shan Li , Qianqian Lu , Jiao Lu , Xiaotong Song , Yang Gu , Xuefeng Duan , Wei Jiang , Guanglei Gu , Mengli Zheng , Lixin Xie , Min Fang

Background

Alveolar epithelial cells (AECs) are the primary targets of many pathogens and play an important role in sensing viruses and regulating immunity. Yet, little is known about the antiviral responses in the aged AECs.

Methods

The responses of young or aged AECs after viral infection were analyzed using methods such as flow cytometry, quantitative real-time PCR, Western blot detection, and transwell chemotaxis assay. Deep sequencing and KEGG analysis were used to identify key pathways and genes associated with aged AECs, followed by functional analysis.

Results

The retinoic acid-inducible gene I (RIG-I) signaling is defective in aged AECs after influenza A virus (IAV) infection. The interferon regulatory factor 1 (IRF1) binds the promoter of RIG-I gene Ddx58 to activate its expression. The regulation of IRF1 is also defective in AECs from aged mice. Fewer NK cells, monocytes, and T cells are recruited by the cell supernatant from PR8-infected aged AECs. Importantly, IRF1-RIG-I signaling is also impaired in the AECs of elderly people after IAV infection.

Conclusion

Ageing impairs IRF1-RIG-I signaling in AECs, and the defective responses in AECs may contribute to reduced immune cell recruitment and activation in aged individuals after pulmonary viral infection.

背景：肺泡上皮细胞（AECs）是许多病原体的主要靶点，在病毒感知和免疫调节中起着重要作用。然而，对老年aec的抗病毒反应知之甚少。方法：采用流式细胞术、实时荧光定量PCR、Western blot检测、transwell趋化试验等方法分析年轻、老年AECs感染病毒后的反应。采用深度测序和KEGG分析确定与老年AECs相关的关键通路和基因，然后进行功能分析。结果：甲型流感病毒（IAV）感染老年aec后，视黄酸诱导基因I （RIG-I）信号通路存在缺陷。干扰素调节因子1 （IRF1）结合RIG-I基因Ddx58的启动子激活其表达。IRF1的调控在老年小鼠aec中也存在缺陷。pr8感染的老年aec细胞上清中募集的NK细胞、单核细胞和T细胞较少。重要的是，IRF1-RIG-I信号在IAV感染后的老年人aec中也受到损害。结论：衰老损害了AECs中irf1 - rig - 1信号通路，AECs应答缺陷可能导致肺部病毒感染后老年人免疫细胞募集和激活减少。

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引用次数: 0

Mangiferin protects mesenchymal stem cells against DNA damage and cellular aging via SIRT1 activation 芒果苷通过激活SIRT1保护间充质干细胞免受DNA损伤和细胞衰老。

IF 5.3 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-01-26 DOI: 10.1016/j.mad.2025.112038

Gyeong Min Lim , Gwang-Won Cho

The protective effects of mangiferin (MAG) against etoposide- and high glucose (HG)–induced DNA damage and aging were investigated in human bone marrow-mesenchymal stem cells (hBM-MSCs). Etoposide, a topoisomerase II inhibitor, was used to induce double-strand breaks (DSBs) in hBM-MSCs, resulting in increased genotoxicity, elevated levels of the DNA damage sensor ATM and CDKN1A, and decreased levels of the aging markers H3 and H4. MAG activated AMPK and SIRT1, thus protecting against DSB-induced damage. Following long-term exposure to HG, MAG significantly mitigated DNA damage and delayed cellular aging, as evidenced by the preservation of H3, H4, LMNB1, and SIRT1 mRNA levels and reduction in γ-H2AX foci and DSBs. Furthermore, MAG improved genome stability, as indicated by decreased LINE1 expression and increased levels of the heterochromatin marker TRIM28, thereby maintaining H3K9me3 levels. MAG and metformin treatment enhanced cell proliferation, reduced senescence-associated β-galactosidase staining, and lowered the levels of the senescence-associated secretory phenotype factors IL-1A, IL-1B, IL-6, IL-8, CCL2, and CCL20 and senescence marker CDKN1A, CDKN2A and p53. MAG may reduce DNA damage and delay aging in hBM-MSCs under HG conditions, highlighting their potential as therapeutic agents for aging-related diseases.

研究了芒果苷（MAG）对人骨骨髓间充质干细胞（hBM-MSCs） DNA损伤和衰老的保护作用。依托oposide是一种拓扑异构酶II抑制剂，用于诱导hBM-MSCs中的双链断裂（DSBs），导致遗传毒性增加，DNA损伤传感器ATM和CDKN1A水平升高，衰老标志物H3和H4水平降低。MAG激活AMPK和SIRT1，从而防止dsb引起的损伤。长期暴露于HG后，MAG显著减轻了DNA损伤并延缓了细胞衰老，这可以通过保存H3、H4、LMNB1和SIRT1 mRNA水平以及减少γ-H2AX灶和dsb来证明。此外，MAG提高了基因组的稳定性，如LINE1表达降低和异染色质标记TRIM28水平升高所表明的，从而维持了H3K9me3水平。MAG和二甲双胍处理增强细胞增殖，降低衰老相关β-半乳糖苷酶染色，降低衰老相关分泌表型因子IL-1A、IL-1B、IL-6、IL-8、CCL2和CCL20以及衰老标志物CDKN1A、CDKN2A和p53的水平。MAG可能减少HG条件下hBM-MSCs的DNA损伤和延缓衰老，突出其作为衰老相关疾病治疗剂的潜力。

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引用次数: 0

Deciphering the role of cytokines in aging: Biomarker potential and effective targeting 解读细胞因子在衰老中的作用：生物标志物潜力和有效靶向。

IF 5.3 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-01-18 DOI: 10.1016/j.mad.2025.112036

Panagiotis Poulios, Stamoulis Skampouras, Christina Piperi

Aging is often characterized by chronic inflammation, immune system dysregulation, and cellular senescence with chronically elevated levels of pro-inflammatory cytokines. These small glycoproteins are mainly secreted by immune cells, mediating intercellular communication and immune system modulation through inflammatory signaling. Their pro- and anti-inflammatory effects make them a noteworthy research topic as well as a promising ally in combating inflammation and the aging process. Cytokines exert a synergistic role in aging and disease and may prove useful biomarkers of tissue-specific dysregulation, disease diagnosis and monitoring, presenting potential therapeutic options as anti-inflammatory and senolytic medications. In this review, we address the cellular and molecular mechanisms implicating cytokines in the aging process and related diseases, highlighting their biomarker potential. We focus on the current therapeutic strategies, including specific pharmaceutical agents, supplements, a balanced diet, and healthy habits such as exercise, stress management, and caloric restriction.

衰老通常以慢性炎症、免疫系统失调和细胞衰老为特征，并伴有促炎细胞因子水平的长期升高。这些小糖蛋白主要由免疫细胞分泌，通过炎症信号介导细胞间通讯和免疫系统调节。它们的促炎和抗炎作用使其成为一个值得关注的研究课题，也是对抗炎症和衰老过程的有希望的盟友。细胞因子在衰老和疾病中发挥协同作用，可能被证明是组织特异性失调、疾病诊断和监测的有用生物标志物，作为抗炎和抗衰老药物提供潜在的治疗选择。在这篇综述中，我们讨论了细胞因子在衰老过程和相关疾病中的细胞和分子机制，并强调了它们的生物标志物潜力。我们关注当前的治疗策略，包括特定的药物，补充剂，均衡的饮食和健康的习惯，如运动，压力管理和热量限制。

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引用次数: 0

Corrigendum to “Characterization of a natural model of adult mice with different rate of aging” [Mech. Ageing Dev. 222 (2024), 111991] “具有不同衰老速率的成年小鼠自然模型的特征”的勘误表。人口老龄化发展[j].中国农业科学，2012,31(1),1991。

IF 5.3 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-01-17 DOI: 10.1016/j.mad.2025.112027

Judith Félix , Estefanía Díaz-Del Cerro , Antonio Garrido , Mónica De la Fuente

引用次数: 0

The effect of torque teno virus (TTV) infection on clinical outcomes, genomic integrity, and mortality in COPD patients 转矩病毒（TTV）感染对慢性阻塞性肺病患者临床结局、基因组完整性和死亡率的影响

IF 5.3 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-01-14 DOI: 10.1016/j.mad.2024.112024

Patrizia Russo , Francesca Milani , Dolores Limongi , Carla Prezioso , Federica Novazzi , Francesca Drago Ferrante , Fabrizio Maggi , Guido Antonelli , Stefano Bonassi

Introduction

Torque Teno Virus (TTV), an "orphan" virus with unclear pathology, has been associated with various diseases and immune dysfunctions. This study investigates the link between TTV viremia and clinical markers in patients with severe to very severe COPD undergoing respiratory rehabilitation.

Methods

We analyzed 102 elderly COPD patients, stratified by TTV viremia levels (< or ≥ 4 log10 copies/mL). Clinical markers—including mortality, inflammatory-oxidative parameters (Lymphocyte/Monocyte, Neutrophil/Lymphocyte, and Platelet/Lymphocyte ratios), IL-6 (measured via ELISA assay), and DNA damage (assessed via comet assay)—were evaluated.

Results

Of the patients, 62.75 % had TTV viremia levels > 4 log₁₀ copies/mL. No associations were found between TTV levels and sex or obesity. However, higher TTV viremia correlated with increased DNA damage and significantly lower 5-year survival probability.

Conclusion

Patients with TTV levels ≥ 4 log₁₀ copies/mL exhibited the lowest survival probability, though DNA damage emerged as a stronger determinant of outcomes. This study raises key scientific questions on the role of TTV in COPD. Specifically, it explores whether TTV may serve as a potential marker for poor prognosis in COPD and whether rehabilitation strategies for these patients could be customized based on DNA damage and/or viremia.

简介：TTV （Torque Teno Virus）是一种病理不明确的“孤儿”病毒，与多种疾病和免疫功能障碍有关。本研究探讨重度至极重度COPD患者呼吸康复过程中TTV病毒血症与临床标志物之间的关系。方法：我们分析了102例老年COPD患者，按TTV病毒血症水平（<或≥4 log10拷贝/mL）分层。评估临床指标，包括死亡率、炎症氧化参数（淋巴细胞/单核细胞、中性粒细胞/淋巴细胞和血小板/淋巴细胞比率）、IL-6（通过ELISA测定）和DNA损伤（通过彗星测定）。结果：62.75 %的患者TTV病毒血症水平为> 4 log10拷贝/mL。没有发现电视电视水平与性或肥胖之间的联系。然而，较高的TTV病毒血症与DNA损伤增加和5年生存率显著降低相关。结论：TTV水平≥ 4 log10拷贝/mL的患者生存率最低，尽管DNA损伤是预后的一个更强的决定因素。这项研究提出了TTV在COPD中的作用的关键科学问题。具体来说，它探讨了TTV是否可以作为COPD预后不良的潜在标志物，以及这些患者的康复策略是否可以根据DNA损伤和/或病毒血症进行定制。

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引用次数: 0

The role of the LINC complex in ageing and microgravity LINC复合物在衰老和微重力中的作用。

IF 5.3 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-01-14 DOI: 10.1016/j.mad.2025.112028

Ivana Lansweers , Sharon van Rijthoven , Jack J.W.A. van Loon

The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex plays a crucial role in connecting the nuclear envelope to the cytoskeleton, providing structural support to the nucleus and facilitating mechanical signaling between the extracellular environment and the nucleus. Research in mechanobiology onboard the International Space Station (ISS) and in simulated microgravity (SMG) highlight the importance of gravity in functional mechanotransduction. Although the altered gravity research regarding mechanobiology has been greatly focused on the cytoskeleton and the extracellular matrix (ECM), recent research demonstrates that SMG also induces changes in nuclear mechanics and gene expression patterns, which have been shown to be LINC complex dependent. Additionally, dysregulation of the LINC complex disrupts nuclear integrity which leads to nuclear shape abnormalities in both Hutchinson-Gilford Progeria Syndrome (HGPS) and aged cells, which highlights the significance of the LINC complex and related proteins in ageing and age-related disorders. Interestingly, as the effects of spaceflight closely resemble those found in the elderly, the microgravity environment seems to induce an accelerated ageing phenotype in astronauts. Therefore, this review will explore the role of the LINC complex and related proteins in ageing and in microgravity, to further elucidate the interplay between loss of gravitational loading and ageing.

核骨架与细胞骨架连接物（Linker of Nucleoskeleton and Cytoskeleton， LINC）复合物在连接核包膜与细胞骨架、为细胞核提供结构支持以及促进细胞外环境与细胞核之间的机械信号传导方面起着至关重要的作用。国际空间站（ISS）和模拟微重力（SMG）上的力学生物学研究强调了重力在功能机械转导中的重要性。虽然关于力学生物学的重力改变研究主要集中在细胞骨架和细胞外基质（ECM）上，但最近的研究表明，SMG也会诱导核力学和基因表达模式的变化，这些变化已被证明是LINC复合物依赖的。此外，LINC复合物的失调破坏了核完整性，导致Hutchinson-Gilford早衰综合征（HGPS）和衰老细胞的核形状异常，这突出了LINC复合物和相关蛋白在衰老和年龄相关疾病中的重要性。有趣的是，由于太空飞行的影响与老年人的影响非常相似，微重力环境似乎会导致宇航员加速衰老。因此，本文将探讨LINC复合物及其相关蛋白在衰老和微重力环境中的作用，以进一步阐明重力负荷丧失与衰老之间的相互作用。

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引用次数: 0

Insights into age-related osteoporosis from senescence-based preclinical models and human accelerated aging paradigms 从基于衰老的临床前模型和人类加速衰老范式深入了解与年龄相关的骨质疏松症。

IF 5.3 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-01-11 DOI: 10.1016/j.mad.2025.112025

Robert J. Pignolo , Abhishek Chandra

Preclinical models of age-related osteoporosis have been developed based on the accumulation and clearance of senescent cells. The former include animal models based on telomere dysfunction and focal radiation; the latter based on genetic and pharmacological targeting (i.e., removal) of senescent cells. The weight of evidence using these models suggests that cellular senescence plays a key role in the pathophysiology of aging-onset bone loss with the senescence-associated secretory phenotype (SASP) mediating local and systemic deleterious effects on the skeleton. Mitochondrial dysfunction has also been implicated in senescence and age-related comorbidities, including osteoporosis, and knock-in mutations in the mtDNA polymerase gamma (Polg) gene in mice may recapitulate similar respiratory chain complex defects in aged individual with osteoporosis. This and other contributions to senile osteoporosis may also be identified by the careful evaluation of non-genetic paradigms of human accelerated aging. Premature aging syndromes, especially those with a prominent bone loss phenotype, include clinical scenarios of skeletal unloading, premature ovarian failure and survival from childhood cancers. These non-hereditary progeroid syndromes implicate the involvement of lineage switching to an adipogenic fate, inhibition of Wnt signaling, increased osteoclastogenesis and activation frequency of osteoclasts, as well as the substantial burden of senescent cell accumulation.

年龄相关性骨质疏松症的临床前模型已经建立在衰老细胞积累和清除的基础上。前者包括基于端粒功能障碍和局灶辐射的动物模型；后者基于衰老细胞的遗传和药理学靶向（即去除）。使用这些模型的证据表明，细胞衰老在衰老性骨质流失的病理生理学中起着关键作用，衰老相关分泌表型（SASP）介导局部和全身骨骼的有害影响。线粒体功能障碍也与衰老和年龄相关的合并症有关，包括骨质疏松症，小鼠mtDNA聚合酶γ (Polg)基因的敲入突变可能在老年骨质疏松症患者中重现类似的呼吸链复合物缺陷。这和其他对老年性骨质疏松症的贡献也可以通过对人类加速衰老的非遗传范式的仔细评估来确定。早衰综合征，尤其是骨质流失表型突出的早衰综合征，包括骨骼卸载、卵巢早衰和儿童癌症存活等临床症状。这些非遗传性类早老性综合征涉及谱系转换到脂肪形成命运，抑制Wnt信号，增加破骨细胞生成和破骨细胞激活频率，以及衰老细胞积累的实质性负担。

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引用次数: 0

Expression of concern: Regulation of β-amyloid levels in the brain of cholesterol-fed rabbit, a model system for sporadic Alzheimer’s disease 关注表达：散发性阿尔茨海默病模型系统——胆固醇喂养家兔大脑中β-淀粉样蛋白水平的调节

IF 5.1 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-01-01

R.P. Jaya Prasanthi, Eric Schommer, Sarah Thomasson, Alex Thompson, Gwen Feist, Othman Ghribi

引用次数: 0

Prenatal glucocorticoid exposure and congenital abdominal wall defects: Involvement of CXCR4 – SDF-1 signaling 产前糖皮质激素暴露与先天性腹壁缺陷：CXCR4-SDF-1信号的参与。

IF 5.3 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2024-11-22 DOI: 10.1016/j.mad.2024.112008

Martin Bablok , Gabriela Morosan-Puopolo , Imadeldin Yahya , Morris Gellisch , Matthias Nissen , Jochen Hubertus , Beate Brand-Saberi

Developmental defects of the ventral abdominal wall, such as gastroschisis, have been associated with prenatal stress exposure. To investigate this further, dexamethasone (DEX), a synthetic glucocorticoid, was administered to fertilized chicken eggs on day 1 of incubation to simulate stress, and embryonic development was subsequently analyzed through in-situ hybridization, immunohistochemistry, and histological methods. Significant developmental abnormalities were displayed by DEX-treated embryos, including open abdomens, reduced MYOG expression in the abdominal wall, and disrupted muscle fiber formation, as indicated by altered Myosin heavy chain patterns. Additionally, early markers of muscle development, such as Pax3, and the CXCR4-SDF-1 signaling axis, crucial for the migration of myogenic precursors of the dermomyotome, were markedly affected. Significant alterations in the expression of mesenchymal markers, including Vimentin and Fibronectin in the lateral plate mesoderm, were observed, alongside alterations in Pitx2, BMP4 and TFAP2A expression. Importantly, a downregulation of Glucocorticoid Receptors was identified, emphasizing the chronic stress exposure. These results provide critical insights into how DEX interferes with key developmental pathways, particularly those involving chemokines like CXCR4 and SDF-1, and other markers of mesodermal differentiation. An advancement in the understanding of the mechanisms underlying ventral abdominal wall defects in the context of prenatal stress is provided by this research, with potential implications for preventing these congenital anomalies.

腹壁发育缺陷（如胃畸形）与产前应激暴露有关。为了进一步研究这个问题，在受精卵孵化第1天给受精卵注射合成糖皮质激素地塞米松（DEX）来模拟应激，随后通过原位杂交、免疫组化和组织学方法分析胚胎发育情况。经DEX处理的胚胎显示出明显的发育异常，包括腹部张开、腹壁MYOG表达减少、肌纤维形成中断（肌球蛋白重链模式改变）。此外，肌肉发育的早期标志物（如 Pax3）和 CXCR4-SDF-1 信号轴也受到明显影响，而 CXCR4-SDF-1 信号轴对真皮肌瘤肌原前体的迁移至关重要。除了 Pitx2、BMP4 和 TFAP2A 的表达发生变化外，还观察到包括侧板中胚层中的波形蛋白（Vimentin）和纤连蛋白（Fibronectin）在内的间质标记物的表达发生了显著变化。重要的是，发现糖皮质激素受体下调，强调了慢性应激暴露。这些结果提供了关于DEX如何干扰关键发育途径的重要见解，特别是那些涉及趋化因子（如CXCR4和SDF-1）及其他中胚层分化标志物的途径。这项研究加深了人们对产前应激背景下腹壁缺损机制的认识，对预防这些先天性畸形具有潜在的意义。

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引用次数: 0