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Lifelong Glutathione Deficiency in Mice Increased Lifespan and Delayed Age-Related Motor Declines. 小鼠终生缺乏谷胱甘肽可延长寿命并延缓与年龄相关的运动衰退。
IF 7 2区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-12-03 DOI: 10.14336/AD.2024.1077
J Thomas Mock, Paapa Mensah-Kane, Delaney L Davis, Jessica M Wong, Philip H Vann, Michael J Forster, Nathalie Sumien

Glutathione (GSH) is a crucial redox scavenger, essential for maintaining cellular redox balance. This study explores the long-term effects of chronic GSH deficiency on lifespan, motor function, cognitive performance, redox status and inflammation. GCLM-/- mice, with a 70-90% reduction in GSH levels, were compared to GCLM+/+ controls across their lifespan (5, 10 and 20 months). We assessed lifespan, motor performance using balance and coordination tests, cognitive function through anxiety and memory tests, redox markers, and inflammation markers, particularly TNF-α and IL-6. Biochemical analyses of GSH levels in peripheral tissues and brain regions were conducted to evaluate redox state changes. GCLM-/- mice displayed extended lifespans and improved motor function at young and adult stages, with a delayed onset of motor decline with age. Cognitive function remains largely unaffected, although there are reductions in anxiety-related behaviors and minor deficits in fear-associated memory. Age-related increases in TNF-α, an inflammatory marker, are observed in both genotypes, with GCLM-/- mice showing a less pronounced increase, particularly in females. There were significant GSH reductions in peripheral tissues, with sporadic changes in brain regions. This stress likely triggers compensatory antioxidant responses, modulating inflammation and redox-sensitive pathways. The data suggests that lifelong GSH deficiency provides protective effects against inflammation and motor decline in younger animals but exacerbates these issues in older mice. The study offers insights into potential therapeutic strategies that leverage mild oxidative stress to promote healthy aging, emphasizing the importance of redox state and antioxidant defenses in the aging process.

谷胱甘肽(GSH)是一种重要的氧化还原清除剂,对维持细胞氧化还原平衡至关重要。本研究探讨慢性谷胱甘肽缺乏对寿命、运动功能、认知能力、氧化还原状态和炎症的长期影响。与GCLM+/+对照组相比,GSH水平降低70-90%的GCLM-/-小鼠在其整个生命周期(5、10和20个月)。我们通过平衡和协调测试评估寿命、运动表现,通过焦虑和记忆测试评估认知功能、氧化还原标志物和炎症标志物,特别是TNF-α和IL-6。外周组织和脑区谷胱甘肽水平的生化分析评估氧化还原状态的变化。GCLM-/-小鼠在幼年和成年阶段表现出寿命延长和运动功能改善,随着年龄的增长,运动功能衰退的发生延迟。认知功能基本上没有受到影响,尽管焦虑相关的行为有所减少,恐惧相关的记忆也有轻微缺陷。在两种基因型中都观察到炎症标志物TNF-α的年龄相关增加,GCLM-/-小鼠的增加不太明显,特别是在雌性中。外周组织GSH明显减少,脑区有零星变化。这种压力可能引发代偿性抗氧化反应,调节炎症和氧化还原敏感途径。数据表明,终生GSH缺乏对年轻动物的炎症和运动能力下降有保护作用,但在老年小鼠中会加剧这些问题。该研究为利用轻度氧化应激促进健康衰老的潜在治疗策略提供了见解,强调了氧化还原状态和抗氧化防御在衰老过程中的重要性。
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引用次数: 0
Metabolic Dysfunction in Idiopathic Intracranial Hypertension: Current Theories and Updates. 特发性颅内高压的代谢功能障碍:目前的理论和最新进展。
IF 7 2区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-12-03 DOI: 10.14336/AD.2024.1147
Hui Li, Lu Liu, Yifan Zhou, Huimin Jiang, Weiyue Zhang, Chenxia Zhou, Chuanjie Wu, Chen Zhou, Xunming Ji

Idiopathic intracranial hypertension (IIH) is a disease characterized by increased intracranial pressure (ICP) without identifiable secondary causes. While the increased ICP is a critical diagnostic feature, the underlying pathophysiological mechanisms remain unclear. Previous theories have suggested cerebrospinal fluid (CSF) overproduction, impaired reabsorption, or circulatory obstruction as potential causes. Emerging evidence indicates that IIH may not be solely a central nervous system disorder but also a systemic metabolic disorder. Metabolic and hormonal dysregulation features, including hyperleptinemia, adipocyte leptin hypersecretion, increased insulin resistance, and androgen excess, have been noted in IIH. Furthermore, the targeted blockade of the cortisol-producing enzyme 11β-hydroxysteroid dehydrogenase type 1 has demonstrated therapeutic potential in treating IIH. Consequently, the role of metabolic dysfunction and hormonal imbalance in IIH warrants consideration. This review aims to provide a comprehensive update on current theories regarding the mechanisms of metabolic dysfunction in IIH.

特发性颅内高压(IIH)是一种以颅内压(ICP)升高为特征的疾病,没有明确的继发原因。虽然ICP升高是一个关键的诊断特征,但其潜在的病理生理机制尚不清楚。先前的理论认为脑脊液(CSF)产生过多,再吸收受损或循环阻塞是潜在的原因。新出现的证据表明,IIH可能不仅仅是一种中枢神经系统疾病,也是一种全身性代谢紊乱。代谢和激素失调的特征,包括高瘦素血症、脂肪细胞瘦素高分泌、胰岛素抵抗增加和雄激素过量,已经在IIH中被注意到。此外,靶向阻断皮质醇生成酶11β-羟基类固醇脱氢酶1型已被证明在治疗IIH方面具有治疗潜力。因此,代谢功能障碍和激素失衡在IIH中的作用值得考虑。本文综述了IIH中代谢功能障碍机制的最新理论。
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引用次数: 0
Role of AMPK and Sirtuins in Aging Heart: Basic and Translational Aspects. AMPK和Sirtuins在心脏老化中的作用:基础和转化方面。
IF 7 2区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-12-03 DOI: 10.14336/AD.2024.1216
Maria Luisa Barcena, Muhammad Aslam, Kristina Norman, Christiane Ott, Yury Ladilov

Aging is a key risk factor for numerous diseases, including cardiac diseases. High energy demands of the heart require precise cellular energy sensing to prevent metabolic stress. AMPK and sirtuins are key intracellular metabolic sensors regulating numerous cell functions, like mitochondrial function and biogenesis, autophagy, and redox balance. However, their function is impaired during the aging process leading to mitochondrial dysfunction, oxidative stress, and inflammation culminating in cardiovascular diseases. The underlying molecular mechanisms leading to dysfunction of metabolic sensing in the aging heart are complex and comprise both intracellular and systemic age-related alterations. In this study, we overview the current knowledge on the impact of aging on cardiac metabolic sensing, with a focus on AMPK and sirtuins, while mTOR pathway was only marginally considered. A particular focus was given to systemic factors, e.g., inflammation, vascular diseases, and microbiome.

衰老是包括心脏疾病在内的多种疾病的主要风险因素。心脏的高能量需求需要精确的细胞能量感应来防止代谢压力。AMPK 和 sirtuins 是调节线粒体功能和生物生成、自噬和氧化还原平衡等多种细胞功能的关键细胞内代谢传感器。然而,它们的功能在衰老过程中受损,导致线粒体功能障碍、氧化应激和炎症,最终引发心血管疾病。导致衰老心脏代谢传感功能障碍的潜在分子机制非常复杂,包括细胞内和系统性的年龄相关变化。在本研究中,我们概述了目前有关衰老对心脏代谢传感影响的知识,重点是 AMPK 和 sirtuins,而 mTOR 通路只被略微考虑。我们还特别关注了系统性因素,如炎症、血管疾病和微生物组。
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引用次数: 0
Brain Regulates Neuronal Activity Directly through the Heartbeat: A New Pathway of Heart-Brain Interaction. 大脑通过心跳直接调节神经元活动:心脑相互作用的新途径。
IF 7 2区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-11-28 DOI: 10.14336/AD.2024.1083
Zhitian Wang, Junjian Zhang, Qing-Guo Ren
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引用次数: 0
Harnessing BDNF Signaling to Promote Resilience in Aging. 利用BDNF信号促进衰老恢复能力。
IF 7 2区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-11-27 DOI: 10.14336/AD.2024.0961
Jamshid Faraji, Gerlinde A S Metz

As a key member of the neurotrophin family in the central nervous system, brain-derived neurotrophic factor (BDNF) plays a critical role in the maintenance and plasticity of the nervous system. Its innate neuroprotective advantage can also be shared with the brain when normal aging-dependent processes challenge neural circuits. The intricate relationship between BDNF and resilience during the aging process signifies the molecular mechanisms that underlie the maintenance and protection of brain function, such as cognition, movement and psychological well-being. As BDNF is crucial for neuronal growth and survival, it can also promote resilience against age-related functional decline and frailty, even if it fails to entirely prevent aging-related functional decline. In the present review, we discuss BDNF function from a neuroprotective perspective and how it may promote resilience in aging. We emphasize briefly the principal, well-known cellular hallmarks of brain aging and how BDNF may restrict such disabling molecular dynamics and enhance overall functional resilience in aging. Insight into the molecular pathways through which BDNF reduces age-related brain dysfunctions and/or improves resilience, provides a foundation for developing targeted interventions to promote mental well-being in an aging population.

作为中枢神经系统神经营养素家族的重要成员,脑源性神经营养因子(BDNF)在神经系统的维持和可塑性方面发挥着关键作用。当正常的衰老过程对神经回路提出挑战时,大脑也可以分享它与生俱来的神经保护优势。BDNF 与衰老过程中的恢复力之间错综复杂的关系标志着维持和保护大脑功能(如认知、运动和心理健康)的分子机制。由于 BDNF 对神经元的生长和存活至关重要,因此即使它不能完全防止与衰老相关的功能衰退,也能促进对与衰老相关的功能衰退和虚弱的恢复力。在本综述中,我们将从神经保护的角度讨论 BDNF 的功能,以及它如何促进衰老过程中的恢复力。我们简要强调了众所周知的大脑衰老的主要细胞特征,以及 BDNF 如何限制这些致残分子动态并增强衰老过程中的整体功能恢复力。深入了解 BDNF 减少与年龄有关的大脑功能障碍和/或提高复原力的分子途径,为开发有针对性的干预措施以促进老龄人口的精神健康奠定了基础。
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引用次数: 0
APOE ε4 and Insulin Resistance Influence Path-Integration-Based Navigation through Distinct Large-Scale Network Mechanisms. APOE ε4和胰岛素抵抗通过不同的大尺度网络机制影响路径整合导航。
IF 7 2区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-11-25 DOI: 10.14336/AD.2024.0975
Karel M Lopez-Vilaret, Marina Fernandez-Alvarez, Anne Bierbrauer, Nikolai Axmacher, Jose L Cantero, Mercedes Atienza

Path integration (PI), which supports navigation without external spatial cues, is facilitated by grid cells in the entorhinal cortex. These cells are often impaired in individuals at risk for Alzheimer's disease (AD). However, other brain systems can compensate for this impairment, especially when spatial cues are available. From a graph-theoretical perspective, this compensatory mechanism might manifest through changes in network segregation, indicating shifts in distinct functional roles among specialized brain regions. This study explored whether similar compensatory mechanisms are active in APOE ε4 carriers and individuals with elevated insulin resistance, both susceptible to entorhinal cortex dysfunction. We applied a graph-theoretical segregation index to resting-state fMRI data from two cohorts (aged 50-75) to assess PI performance across virtual environments. Although insulin resistance did not directly impair PI performance, individuals with higher insulin resistance demonstrated better PI with less segregated brain networks, regardless of spatial cue availability. In contrast, the APOE effect was cue-dependent: ε4 heterozygotes outperformed ε3 homozygotes in the presence of local landmarks, linked to increased sensorimotor network segregation. When spatial cues were absent, ε4 carriers exhibited reduced PI performance due to lower segregation in the secondary visual network. Controlling cortical thickness and intracortical myelin variability mitigated these APOE effects on PI, with no similar adjustment made for insulin resistance. Our findings suggest that ε4 carriers depend on cortical integrity and spatial landmarks for successful navigation, while insulin-resistant individuals may rely on less efficient neural mechanisms for processing PI. These results highlight the importance of targeting insulin resistance to prevent cognitive decline, particularly in aging navigation and spatial cognition.

路径整合(PI)支持在没有外部空间线索的情况下进行导航,它是由内嗅皮层的网格细胞促进的。这些细胞在有阿尔茨海默病(AD)风险的个体中经常受损。然而,其他大脑系统可以弥补这种损害,特别是当空间线索可用时。从图论的角度来看,这种代偿机制可能通过网络隔离的变化表现出来,表明在特定的大脑区域中不同的功能角色发生了变化。本研究探讨了类似的代偿机制是否在APOE ε4携带者和胰岛素抵抗升高的个体中活跃,这两个个体都容易发生内嗅皮质功能障碍。我们将图理论分离指数应用于两个队列(50-75岁)的静息状态fMRI数据,以评估虚拟环境中PI的表现。尽管胰岛素抵抗并不直接影响PI的表现,但无论空间线索可用性如何,高胰岛素抵抗的个体在较少隔离的脑网络中表现出更好的PI。相反,APOE效应是线索依赖的:在存在局部标志的情况下,ε4杂合子优于ε3纯合子,这与感觉运动网络分离的增加有关。当空间线索缺失时,ε4载波在次级视觉网络中的分离程度较低,导致PI性能下降。控制皮质厚度和皮质内髓磷脂变异性减轻了APOE对PI的影响,而对胰岛素抵抗没有类似的调节。我们的研究结果表明,ε4携带者依赖于皮质完整性和空间标记来成功导航,而胰岛素抵抗个体可能依赖于效率较低的神经机制来处理PI。这些结果强调了针对胰岛素抵抗预防认知能力下降的重要性,特别是在老年导航和空间认知方面。
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引用次数: 0
Aging Deteriorates Blood Brain Barrier Function and Polarizes Adaptive T Cell Expansion Contributing to Neurocognitive Damage in Experimental Cirrhosis. 衰老恶化血脑屏障功能和极化适应性T细胞扩增促进实验性肝硬化的神经认知损伤。
IF 7 2区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-11-23 DOI: 10.14336/AD.2024.0932
Sebastiań Martínez-López, María Salud García-Gutiérrez, Francisco Navarrete, Isabel Gómez-Hurtado, Pedro Zapater, Enrique Ańgel, Oriol Juanola, Juan L López-Cánovas, Paula Boix, Manel C Hadid, Amaya Puig-Kröger, Manuel D Gahete, Jorge Manzanares, Esther Caparrós, Rubén Francés

Cirrhosis incidence is significantly increased with age and frequently complicated with neurocognitive dysfunction. We have evaluated the contribution of aging to neuroinflammation in the liver-brain axis in advanced chronic liver disease. Young (6-week-old) and old (9-month-old) mice were included in a 12-week protocol of CCl4-induced cirrhosis. Liver damage, neuromotor and cognitive capacities, blood brain barrier integrity and function, liver and brain T cell subpopulations and ammonia levels were evaluated. Timp1 and Acta2 gene expression was upregulated in old cirrhotic mice. Increased liver damage was confirmed histologically by Sirius red staining, expression of alpha-SMA, collagen 1-alpha1 and vimentin in aged CCl4-treated mice. Aging further compromised the neuromotor and cognition capabilities in cirrhotic animals. Stress axis components Crh and its receptor Nr3c1 gene expression levels were upregulated in the paraventricular nucleus and hippocampus of old cirrhotic mice. CCl4-damage significantly increased ammonia levels in the liver, brain and serum of cirrhotic mice. Circulating ammonia was significantly higher in old cirrhotic mice. Significant correlations were established between brain ammonia, neuromotor capabilities and results on the object recognition tests. A decreased integrity of blood brain barrier was accompanied by astrocyte activation and increased apoptosis-linked cleaved Caspase 3 in old cirrhotic mice. Liver resident CD4+ T-cell subpopulations were contracted in cirrhosis, although they showed a pro-inflammatory Th17 profile. Liver and brain resident CD8+ T-cell subpopulations were expanded in old cirrhotic animals, along with reduced tissue cytolytic activity. CD8+ T cell expansion and reduced perforin levels in the brain correlated with neuromotor and cognitive dysfunction. In conclusion, aging aggravates liver fibrosis, worsens neuromotor and cognitive functions and shifts liver and brain adaptive T cell profiles compromising the BBB integrity in experimental advanced chronic liver disease. Results strengthen the impact of aging in the liver-brain axis and neuroinflammation in cirrhosis.

肝硬化的发病率随着年龄的增长而显著增加,并常伴有神经认知功能障碍。我们已经评估了衰老对晚期慢性肝病肝脑轴神经炎症的贡献。幼龄(6周龄)和老年(9月龄)小鼠被纳入为期12周的ccl4诱导肝硬化方案。评估肝损伤、神经运动和认知能力、血脑屏障完整性和功能、肝和脑T细胞亚群和氨水平。Timp1和Acta2基因在老年肝硬化小鼠中表达上调。经天狼星红染色、α - sma、胶原蛋白1- α和vimentin的表达,证实老龄ccl4处理小鼠肝损伤加重。衰老进一步损害了肝硬化动物的神经运动和认知能力。应激轴组分Crh及其受体Nr3c1基因在老年肝硬化小鼠室旁核和海马中的表达水平上调。ccl4损伤显著增加肝硬化小鼠肝脏、大脑和血清中的氨水平。老年肝硬化小鼠循环氨明显升高。脑氨、神经运动能力和目标识别测试结果之间存在显著相关性。在老年肝硬化小鼠中,血脑屏障完整性的降低伴随着星形胶质细胞的激活和凋亡相关的cleaved Caspase 3的增加。肝脏常驻CD4+ t细胞亚群在肝硬化中收缩,尽管它们显示促炎Th17谱。老年肝硬化动物的肝脏和脑驻留CD8+ t细胞亚群扩大,同时组织细胞溶解活性降低。脑内CD8+ T细胞扩增和穿孔素水平降低与神经运动和认知功能障碍相关。总之,在实验性晚期慢性肝病患者中,衰老会加重肝纤维化,恶化神经运动和认知功能,改变肝脏和大脑适应性T细胞谱,损害血脑屏障的完整性。结果肝硬化肝脑轴衰老和神经炎症的影响增强。
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引用次数: 0
Histone Methylation, Energy Metabolism, and Alzheimer's Disease. 组蛋白甲基化、能量代谢与阿尔茨海默病
IF 7 2区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-11-22 DOI: 10.14336/AD.2024.0899
Jiaqi Fu, Li An

Alzheimer's disease (AD) is an insidious, progressive, and irreversible neurodegenerative disease characterized by the deposition of extracellular amyloid β-protein (Aβ) to form senile plaques and abnormal phosphorylation of intracellular tau protein to form neuronal fiber tangles. The pathogenesis of AD is complex, and there are several hypotheses, primarily including the Aβ cascade hypothesis, the neurofibrillary tangle hypothesis, the inflammatory hypothesis, and the cholinergic hypothesis. It has been suggested that the dysregulation of multiple energy metabolic pathways, especially mitochondria metabolism, may be related to the severity of AD pathology and disease symptoms in the brain. The modification of histone (lysine) methylation, an actively regulated and reversible process, is closely related to energy metabolism and plays a crucial role in AD development. In summary, histone methylation, energy metabolism, and AD restricted and regulated each other. Here, we review the advances in the correlation between histone methylation, energy metabolism, and AD. This can provide further insights into the mechanisms underlying AD pathogenesis and its control.

阿尔茨海默病(AD)是一种潜伏的、进行性的、不可逆的神经退行性疾病,其特征是细胞外淀粉样β蛋白(Aβ)沉积形成老年斑,细胞内tau蛋白异常磷酸化形成神经元纤维缠结。阿尔茨海默病的发病机制是复杂的,目前有几种假说,主要包括Aβ级联假说、神经原纤维缠结假说、炎症假说和胆碱能假说。有研究认为,多种能量代谢途径,特别是线粒体代谢的失调可能与AD病理的严重程度和脑内疾病症状有关。组蛋白(赖氨酸)甲基化修饰是一个积极调控的可逆过程,与能量代谢密切相关,在AD的发展中起着至关重要的作用。综上所述,组蛋白甲基化、能量代谢和AD相互制约和调节。在此,我们综述了组蛋白甲基化、能量代谢和AD之间相关性的研究进展。这可以为阿尔茨海默病的发病机制及其控制提供进一步的见解。
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引用次数: 0
The Organ-Joint Axes in Osteoarthritis: Significant Pathogenesis and Therapeutic Targets. 骨关节炎的器官-关节轴:重要的发病机制和治疗目标。
IF 7 2区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-11-22 DOI: 10.14336/AD.2024.1223
Dinglong Yang, Yujing Chen, Junfei Guo, Xin Xu, Mingyi Yang, Jiale Xie, Ke Xu, Peng Xu

Osteoarthritis (OA), a prevalent age-related disease, is increasingly recognized as a multifactorial condition. This comprehensive review provides a multifaceted perspective on the organ-joint crosstalk contributing to OA, transcending the traditional focus on local joint pathology. Based on current research, we discussed the brain-joint, gut-joint, muscle-joint interactions in the etiology and progression of OA. In brain-joint axis, the neuroendocrine regulation, circadian rhythms, and leptin signaling influence joint tissues. We also discussed the role of prostaglandin E2 in skeletal interoception and its potential as a therapeutic target. The gut-joint axis is underscored by the impact of gut microbiota dysbiosis on systemic inflammation and metabolic disorders, both of which are implicated in OA pathogenesis. Furthermore, age-related sarcopenia, characterized by muscle mass and strength loss, is identified as a significant risk factor. Sarcopenia may contribute to OA progression through compromised mechanical support, systemic inflammation, and muscle-derived myokines. Finally, we synthesize the evidence supporting the modulation of circadian rhythm, skeletal interoception, gut microbiome, and muscle mass as innovative strategies for OA management. The organ-joint crosstalk is integral to the complex pathogenesis of OA, highlighting the multifactorial nature of OA and the potential for targeted therapeutic interventions. By integrating these multidimensional perspectives, we aim to enhance our understanding of OA pathogenesis and explore potential pharmacological targets.

骨关节炎(OA)是一种常见的与年龄有关的疾病,越来越被认为是一种多因素疾病。这篇全面的综述提供了一个多方面的角度来研究器官-关节的相互作用对OA的影响,超越了传统的对局部关节病理的关注。基于目前的研究,我们讨论了脑关节,肠关节,肌肉关节的相互作用在OA的病因和进展。在脑-关节轴,神经内分泌调节、昼夜节律和瘦素信号影响关节组织。我们还讨论了前列腺素E2在骨骼间感受中的作用及其作为治疗靶点的潜力。肠道菌群失调对全身性炎症和代谢紊乱的影响强调了肠关节轴,这两者都与OA发病机制有关。此外,与年龄相关的肌肉减少症,以肌肉质量和力量损失为特征,被认为是一个重要的危险因素。骨骼肌减少症可能通过机械支持受损、全身性炎症和肌肉源性肌因子促进OA进展。最后,我们综合了支持昼夜节律、骨骼间感受、肠道微生物群和肌肉质量调节作为OA管理创新策略的证据。器官-关节串扰是OA复杂发病机制的组成部分,突出了OA的多因素性质和靶向治疗干预的潜力。通过整合这些多维视角,我们旨在提高我们对OA发病机制的理解并探索潜在的药理靶点。
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引用次数: 0
Exercise Types: Physical Activity Mitigates Cardiac Aging and Enhances Mitochondrial Function via PKG-STAT3-Opa1 Axis. 运动类型:体育锻炼通过 PKG-STAT3-Opa1 轴缓解心脏衰老并增强线粒体功能
IF 7 2区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-11-19 DOI: 10.14336/AD.2024.0959
Reka Szekeres, Daniel Priksz, Mariann Bombicz, Beata Pelles-Tasko, Anna Szilagyi, Brigitta Bernat, Aniko Posa, Balazs Varga, Rudolf Gesztelyi, Sandor Somodi, Zoltan Szabo, Zoltan Szilvassy, Bela Juhasz

Although age-related deterioration of the cardiac function is a well-studied area of research, the interventions and their molecular pathways have not yet been fully identified. Since physical activity is a powerful preventive measure against cardiac aging, our study compared the effects of long-term voluntary and forced physical activity with a sedentary group, utilizing an aging rat model characterized by mitochondrial dysfunction that contributes to age-related cardiovascular diseases. Four experimental groups were created: (I) young controls (12-week-old); (II) 18-month-old aged sedentary rats; (III) aged group with free access to running wheels for 6 months; (IV) aged rats subjected to forced physical activity for 6 months. At the endpoint of the study, the aged animals were two years old. The aged sedentary rats exhibited increased Tei-index, LA/Ao and E/e' ratios as well as decreased e'/a' ratio and lengthened DecT and IVRT, higher perivascular fibrosis ratio and reduced myocardial PKG, STAT3 and Opa1 protein expression, along with decreased ATP synthase (ATPS) activity in comparison to the young controls. In terms of echocardiographic parameters and perivascular fibrosis, the forced running provided more substantial benefits than the voluntary activity demonstrated by decreased Tei-index, E/e' ratio, increased e'/a' ratio and reduced DecT and IVRT. Forced exercise was strongly associated with elevated myocardial expression of PKG, STAT3 and Opa1 proteins and, moreover, the ATPS activity was restored only in the forced running rats. In conclusion, forced but not voluntary exercise has significant protective effects on age-associated diastolic dysfunction by upregulating PKG-STAT3-Opa1 axis and thereby enhancing ATPS activity.

尽管与年龄相关的心脏功能衰退是一个研究得很透彻的领域,但干预措施及其分子途径尚未完全确定。由于体育锻炼是预防心脏衰老的有力措施,我们的研究利用了一种以线粒体功能障碍为特征的衰老大鼠模型,比较了长期自愿和强迫体育锻炼与久坐不动组的效果,线粒体功能障碍是导致与年龄相关的心血管疾病的原因之一。实验分为四组:(I) 幼年对照组(12 周大);(II) 18 个月大的老年久坐大鼠;(III) 可自由使用跑步轮 6 个月的老年组;(IV) 强迫体力活动 6 个月的老年组。研究结束时,老年动物已满两岁。与年轻对照组相比,老年久坐大鼠的Tei指数、LA/Ao和E/e'比值升高,e'/a'比值降低,DecT和IVRT延长,血管周围纤维化比值升高,心肌PKG、STAT3和Opa1蛋白表达降低,ATP合成酶(ATPS)活性降低。在超声心动图参数和血管周围纤维化方面,强制跑步比自愿活动带来的益处更大,具体表现为Tei指数、E/e'比值降低,e'/a'比值增加,DecT和IVRT降低。强迫运动与 PKG、STAT3 和 Opa1 蛋白的心肌表达升高密切相关,此外,只有在强迫跑步的大鼠中 ATPS 活性才得到恢复。总之,通过上调 PKG-STAT3-Opa1 轴,从而增强 ATPS 的活性,强迫运动(而非自愿运动)对年龄相关性舒张功能障碍具有显著的保护作用。
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引用次数: 0
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