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Linking telomere dynamics to evolution, life history and environmental change: perspectives, predictions and problems. 将端粒动态与进化、生活史和环境变化联系起来:观点、预测和问题。
IF 4.5 4区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-04-01 Epub Date: 2024-01-22 DOI: 10.1007/s10522-023-10081-8
Pat Monaghan

This perspectives paper considers the value of studying telomere biology outside of a biomedical context. I provide illustrative examples of the kinds of questions that evolutionary ecologists have addressed in studies of telomere dynamics in non-model species, primarily metazoan animals, and what this can contribute to our understanding of their evolution, life histories and health. I also discuss why the predicted relationships between telomere dynamics and life history traits, based on the detailed cellular studies in humans and model organisms, are not always found in studies in other species.

这篇视角论文探讨了在生物医学背景之外研究端粒生物学的价值。我举例说明了进化生态学家在研究非模式物种(主要是元祖类动物)端粒动态时所涉及的问题类型,以及这对我们理解它们的进化、生命史和健康有什么帮助。我还将讨论为什么在人类和模式生物的详细细胞研究基础上预测的端粒动态和生命史特征之间的关系并不总是能在其他物种的研究中找到。
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引用次数: 0
Telomeres and telomerase: active but complex players in life-history decisions. 端粒和端粒酶:生命史决策中活跃而复杂的角色。
IF 4.5 4区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-04-01 Epub Date: 2023-08-23 DOI: 10.1007/s10522-023-10060-z
Radmila Čapková Frydrychová, Barbora Konopová, Vratislav Peska, Miloslav Brejcha, Michala Sábová

Studies on human telomeres have established that telomeres exert a significant influence on lifespan and health of organisms. However, recent research has indicated that the original idea that telomeres affect lifespan in a universal and central manner across all eukaryotic species is an oversimplification. Indeed, findings from a variety of animal species revealed that the role of telomere biology in aging is more subtle and intricate than previously recognized. Here, we show how telomere biology varies depending on the taxon. We also show how telomere biology corresponds to basic life history traits and affects the life table of a species and investments in growth, body size, reproduction, and lifespan; telomeres are hypothesized to shape evolutionary perspectives for species in an active but complex manner. Our evaluation is based on telomere biology data from many examples from throughout the animal kingdom that vary according to the degree of organismal complexity and life history strategies.

对人类端粒的研究证实,端粒对生物体的寿命和健康有重大影响。然而,最近的研究表明,最初认为端粒以普遍和核心的方式影响所有真核生物物种的寿命的观点过于简单化了。事实上,来自各种动物物种的研究结果表明,端粒生物学在衰老中的作用比以前认识到的更加微妙和错综复杂。在这里,我们展示了端粒生物学如何因类群而异。我们还展示了端粒生物学如何与基本的生活史特征相对应,并影响物种的生命表以及在生长、体型、繁殖和寿命方面的投资;端粒被假定以一种积极而复杂的方式塑造物种的进化前景。我们的评估是基于动物王国中许多实例的端粒生物学数据,这些实例因生物体的复杂程度和生活史策略而异。
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引用次数: 0
Methods that shaped telomerase research. 影响端粒酶研究的方法。
IF 4.5 4区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-04-01 Epub Date: 2023-10-31 DOI: 10.1007/s10522-023-10073-8
Louise Bartle, Raymund J Wellinger

Telomerase, the ribonucleoprotein (RNP) responsible for telomere maintenance, has a complex life. Complex in that it is made of multiple proteins and an RNA, and complex because it undergoes many changes, and passes through different cell compartments. As such, many methods have been developed to discover telomerase components, delve deep into understanding its structure and function and to figure out how telomerase biology ultimately relates to human health and disease. While some old gold-standard methods are still key for determining telomere length and measuring telomerase activity, new technologies are providing promising new ways to gain detailed information that we have never had access to before. Therefore, we thought it timely to briefly review the methods that have revealed information about the telomerase RNP and outline some of the remaining questions that could be answered using new methodology.

端粒是负责端粒维持的核糖核蛋白(RNP),具有复杂的生命。复杂性在于它由多种蛋白质和一种RNA组成,复杂性在于它经历了许多变化,并穿过不同的细胞隔室。因此,已经开发了许多方法来发现端粒酶成分,深入了解其结构和功能,并弄清楚端粒酶生物学最终如何与人类健康和疾病相关。虽然一些旧的金标准方法仍然是确定端粒长度和测量端粒酶活性的关键,但新技术正在提供我们以前从未获得过的有希望的新方法来获得详细信息。因此,我们认为现在是时候简要回顾一下已经揭示端粒酶RNP信息的方法,并概述一些可以使用新方法回答的剩余问题。
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引用次数: 0
Mitochondria and telomeres: hand in glove. 线粒体和端粒:携手合作。
IF 4.5 4区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-04-01 Epub Date: 2023-10-21 DOI: 10.1007/s10522-023-10074-7
Mélina Vaurs, Elif Beyza Dolu, Anabelle Decottignies

Born as an endosymbiont, the bacteria engulfed by the proto-eukaryotic cell more than 1.45 billion years ago progressively evolved as an important organelle with multiple interactions with the host cell. In particular, strong connections between mitochondria and the chromosome ends, the telomeres, led to propose a new theory of ageing in which dysfunctional telomeres and mitochondria are the main actors of a vicious circle reducing cell fitness and promoting cellular ageing. We review the evidences that oxidative stress and dysfunctional mitochondria damage telomeres and further discuss the interrelationship between telomere biology and mitochondria through the lens of telomerase which shuttles between the nucleus and mitochondria. Finally, we elaborate on the possible role of the mitochondrial genome on the inheritance of human telomere length through the expression of mitochondrial gene variants.

作为一种内共生体,14.5亿年前被原真核细胞吞噬的细菌逐渐进化为一种重要的细胞器,与宿主细胞有多种相互作用。特别是,线粒体和染色体末端端粒之间的紧密联系,提出了一种新的衰老理论,其中功能失调的端粒和线粒体是降低细胞健康度和促进细胞衰老的恶性循环的主要参与者。我们综述了氧化应激和线粒体功能障碍损害端粒的证据,并通过穿梭于细胞核和线粒体之间的端粒酶的透镜进一步讨论了端粒生物学与线粒体之间的相互关系。最后,我们详细阐述了线粒体基因组通过线粒体基因变体的表达在人类端粒长度遗传中的可能作用。
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引用次数: 0
Alexey Olovnikov: theoretical biology beyond the margins. 阿列克谢-奥洛夫尼科夫:超越边缘的理论生物学。
IF 4.5 4区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-04-01 Epub Date: 2023-09-07 DOI: 10.1007/s10522-023-10061-y
Ivan A Olovnikov

Alexey Olovnikov (1936-2022) is an author of the famous marginotomy hypothesis, where he recognized the DNA end replication problem and its role in cell aging. In this biographical note we celebrate the 50th anniversary of this theoretical discovery that later enjoyed a brilliant confirmation and gave rise to a new thriving field of molecular biology and gerontology. We also take a look at the evolution of ideas in Alexey Olovnikov's lifelong quest to uncover the molecular mechanisms of aging, exploring the reasons why he walked away from his initial conclusion about the key role of telomeres in aging, and built a new vast theoretical landscape that linked all stages of ontogenesis.

阿列克谢-奥洛夫尼科夫(Alexey Olovnikov,1936-2022 年)是著名的边缘切开假说(marginotomy hypothesis)的提出者,他在该假说中认识到了 DNA 末端复制问题及其在细胞衰老中的作用。在本传记中,我们将庆祝这一理论发现 50 周年,这一发现后来得到了辉煌的证实,并催生了分子生物学和老年学这一新领域的蓬勃发展。我们还将回顾阿列克谢-奥洛夫尼科夫毕生探索衰老分子机制的思想演变过程,探讨他为何放弃最初关于端粒在衰老中的关键作用的结论,并建立起一个连接本体发生各个阶段的新的庞大理论体系。
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引用次数: 0
The potential use of nanozyme in aging and age‐related diseases 纳米酶在衰老和老年相关疾病中的潜在用途
IF 4.5 4区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-03-11 DOI: 10.1007/s10522-024-10095-w
Amirsasan Gorgzadeh, Paria Arab Amiri, Saman Yasamineh, Basim Kareem Naser, Khairia abdulrahman abdulallah

The effects of an increasingly elderly population are among the most far-reaching in 21st-century society. The growing healthcare expense is mainly attributable to the increased incidence of chronic illnesses that accompany longer life expectancies. Different ideas have been put up to explain aging, but it is widely accepted that oxidative damage to proteins, lipids, and nucleic acids contributes to the aging process. Increases in life expectancy in all contemporary industrialized cultures are accompanied by sharp increases in the prevalence of age-related diseases such as cardiovascular and neurological conditions, type 2 diabetes, osteoporosis, and cancer. Therefore, academic and public health authorities should prioritize the development of therapies to increase health span. Nanozyme (NZ)-like activity in nanomaterials has been identified as promising anti-aging nanomedicines. More than that, nanomaterials displaying catalytic activities have evolved as artificial enzymes with high structural stability, variable catalytic activity, and functional diversity for use in a wide range of biological settings, including those dealing with age-related disorders. Due to their inherent enzyme-mimicking qualities, enzymes have attracted significant interest in treating diseases associated with reactive oxygen species (ROS). The effects of NZs on aging and age-related disorders are summarized in this article. Finally, prospects and threats to enzyme research and use in aging and age-related disorders are offered.

Graphical Abstract

老年人口日益增多对 21 世纪社会的影响最为深远。医疗费用不断增长的主要原因是,随着预期寿命的延长,慢性病的发病率也在增加。人们提出了不同的观点来解释衰老,但普遍认为蛋白质、脂类和核酸的氧化损伤是衰老过程的原因。在所有当代工业化文化中,预期寿命延长的同时,与年龄有关的疾病,如心血管和神经系统疾病、2 型糖尿病、骨质疏松症和癌症的发病率也急剧上升。因此,学术界和公共卫生部门应优先开发延长健康寿命的疗法。纳米材料中的纳米酶(NZ)类活性已被确认为有前途的抗衰老纳米药物。不仅如此,具有催化活性的纳米材料已发展成为具有高结构稳定性、可变催化活性和功能多样性的人工酶,可用于各种生物环境,包括与年龄有关的疾病。由于具有模仿酶的固有特性,酶在治疗与活性氧(ROS)有关的疾病方面引起了极大的兴趣。本文概述了 NZs 对衰老和老年相关疾病的影响。最后,提出了在衰老和与年龄有关的疾病中研究和使用酶的前景和威胁。
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引用次数: 0
The SGLT2 inhibitor empagliflozin inhibits skeletal muscle fibrosis in naturally aging male mice through the AMPKα/MMP9/TGF-β1/Smad pathway SGLT2抑制剂empagliflozin通过AMPKα/MMP9/TGF-β1/Smad途径抑制自然衰老雄性小鼠的骨骼肌纤维化
IF 4.5 4区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-02-26 DOI: 10.1007/s10522-024-10093-y

Abstact

With advancing age, the incidence of sarcopenia increases, eventually leading to a cascade of adverse events. However, there is currently a lack of effective pharmacological treatment for sarcopenia. Sodium-glucose co-transporter 2 inhibitor (SGLT2i) empagliflozin demonstrates anti-fibrotic capabilities in various organs. This study aims to determine whether empagliflozin can improve skeletal muscle fibrosis induced by sarcopenia in naturally aging mice. A natural aging model was established by feeding male mice from 13 months of age to 19 months of age. A fibrosis model was created by stimulating skeletal muscle fibroblasts with TGF-β1. The Forelimb grip strength test assessed skeletal muscle function, and expression levels of COL1A1, COL3A1, and α-SMA were analyzed by western blot, qPCR, and immunohistochemistry. Additionally, levels of AMPKα/MMP9/TGFβ1/Smad signaling pathways were examined. In naturally aging mice, skeletal muscle function declines, expression of muscle fibrosis markers increases, AMPKα expression is downregulated, and MMP9/TGFβ1/Smad signaling pathways are upregulated. However, treatment with empagliflozin reverses this phenomenon. At the cellular level, empagliflozin exhibits similar anti-fibrotic effects, and these effects are attenuated by Compound C and siAMPKα. Empagliflozin exhibits anti-fibrotic effects, possibly associated with the AMPK/MMP9/TGFβ1/Smad signaling pathways.

停用 随着年龄的增长,肌肉疏松症的发病率也会增加,最终导致一系列不良反应。然而,目前还缺乏治疗肌肉疏松症的有效药物。钠-葡萄糖协同转运体 2 抑制剂(SGLT2i)empagliflozin 在多个器官中显示出抗纤维化能力。本研究旨在确定empagliflozin能否改善自然衰老小鼠因肌肉疏松症诱发的骨骼肌纤维化。通过喂养 13 个月至 19 个月大的雄性小鼠,建立了自然衰老模型。通过用 TGF-β1 刺激骨骼肌成纤维细胞建立了纤维化模型。前肢握力测试评估了骨骼肌功能,并通过Western印迹、qPCR和免疫组化分析了COL1A1、COL3A1和α-SMA的表达水平。此外,还检测了 AMPKα/MMP9/TGFβ1/Smad 信号通路的水平。在自然衰老的小鼠中,骨骼肌功能下降,肌肉纤维化标志物表达增加,AMPKα表达下调,MMP9/TGFβ1/Smad信号通路上调。然而,使用empagliflozin治疗可逆转这一现象。在细胞水平,empagliflozin表现出类似的抗纤维化作用,而化合物C和siAMPKα会减弱这些作用。Empagliflozin 的抗纤维化作用可能与 AMPK/MMP9/TGFβ1/Smad 信号通路有关。
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引用次数: 0
A CRISPR base editing approach for the functional assessment of telomere biology disorder-related genes in human health and aging 用 CRISPR 碱基编辑方法对人类健康和衰老过程中端粒生物学紊乱相关基因进行功能评估
IF 4.5 4区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-02-04 DOI: 10.1007/s10522-024-10094-x
Gustavo Borges, Yahya Benslimane, Lea Harrington

Telomere Biology Disorders (TBDs) are a group of rare diseases characterized by the presence of short and/or dysfunctional telomeres. They comprise a group of bone marrow failure syndromes, idiopathic pulmonary fibrosis, and liver disease, among other diseases. Genetic alterations (variants) in the genes responsible for telomere homeostasis have been linked to TBDs. Despite the number of variants already identified as pathogenic, an even more significant number must be better understood. The study of TBDs is challenging since identifying these variants is difficult due to their rareness, it is hard to predict their impact on the disease onset, and there are not enough samples to study. Most of our knowledge about pathogenic variants comes from assessing telomerase activity from patients and their relatives affected by a TBD. However, we still lack a cell-based model to identify new variants and to study the long-term impact of such variants on the genes involved in TBDs. Herein, we present a cell-based model using CRISPR base editing to mutagenize the endogenous alleles of 21 genes involved in telomere biology. We identified key residues in the genes encoding 17 different proteins impacting cell growth. We provide functional evidence for variants of uncertain significance in patients with TBDs. We also identified variants resistant to telomerase inhibition that, similar to cells expressing wild-type telomerase, exhibited increased tumorigenic potential using an in vitro tumour growth assay. We believe that such cell-based approaches will significantly advance our understanding of the biology of TBDs and may contribute to the development of new therapies for this group of diseases.

端粒生物学疾病(TBDs)是一组以端粒过短和/或端粒功能障碍为特征的罕见疾病。它们包括一组骨髓衰竭综合征、特发性肺纤维化和肝病等疾病。负责端粒平衡的基因中的遗传变异(变体)与TBDs有关。尽管有许多变体已被确定为致病基因,但仍有更多的变体需要更好地了解。对 TBDs 的研究具有挑战性,因为这些变异因其罕见性而难以确定,很难预测它们对疾病发病的影响,而且也没有足够的样本可供研究。我们对致病变异的了解大多来自于对TBD患者及其亲属端粒酶活性的评估。然而,我们仍然缺乏一个基于细胞的模型来识别新的变异体,并研究这些变异体对TBDs相关基因的长期影响。在这里,我们提出了一种基于细胞的模型,利用 CRISPR 碱基编辑技术诱变参与端粒生物学的 21 个基因的内源等位基因。我们确定了编码 17 种不同蛋白质的基因中影响细胞生长的关键残基。我们为 TBDs 患者中意义不明的变异提供了功能性证据。我们还发现了对端粒酶抑制具有抗性的变体,这些变体与表达野生型端粒酶的细胞类似,在体外肿瘤生长试验中表现出更高的致瘤潜力。我们相信,这种基于细胞的方法将极大地推动我们对TBDs生物学的了解,并可能有助于开发治疗这类疾病的新疗法。
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引用次数: 0
Fisetin, a potential skin rejuvenation drug that eliminates senescent cells in the dermis. Fisetin,一种潜在的皮肤再生药物,可以消除真皮中的衰老细胞。
IF 4.5 4区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-02-01 Epub Date: 2023-09-22 DOI: 10.1007/s10522-023-10064-9
Kento Takaya, Toru Asou, Kazuo Kishi

Accumulation of senescent fibroblasts, chronic inflammation, and collagen remodeling due to aging-related secretory phenotypes have been hypothesized to cause age-related skin aging, which results in wrinkles and loss of skin elasticity, thus compromising appearance attractiveness. However, the rejuvenating effects of removing senescent cells from the human skin and the efficacy of related therapeutic agents remain unclear. Here, we investigated the effects of fisetin, a potential anti-aging component found in various edible fruits and vegetables, on senescent human dermal fibroblasts (HDFs) and aging human skin. Senescence was induced in primary HDFs using long-term passaging and treatment with ionizing radiation, and cell viability was assessed after treatment with fisetin and a control component. A mouse/human chimeric model was established by subcutaneously transplanting whole skin grafts from aged individuals into nude mice, which were treated intraperitoneally with fisetin or control a component for 30 d. Skin samples were obtained and subjected to senescence-associated-beta-galactosidase staining; the extent of aging was evaluated using western blotting, reverse transcription-quantitative PCR, and histological analysis. Fisetin selectively eliminated senescent dermal fibroblasts in both senescence-induced cellular models; this effect is attributable to cell death induction by caspases 3, 8, and 9-mediated endogenous and exogenous apoptosis. Fisetin-treated senescent human skin grafts showed increased collagen density and decreased senescence-associated secretory phenotypes (SASP), including matrix metalloproteinases and interleukins. No apparent adverse events were observed. Thus, fisetin could improve skin aging through selective removal of senescent dermal fibroblasts and SASP inhibition, indicating its potential as an effective novel therapeutic agent for combating skin aging.

衰老成纤维细胞的积累、慢性炎症和衰老相关分泌表型引起的胶原重塑被认为会导致与年龄相关的皮肤衰老,从而导致皱纹和皮肤弹性丧失,从而损害外观吸引力。然而,从人类皮肤中去除衰老细胞的再生作用和相关治疗剂的疗效尚不清楚。在这里,我们研究了在各种可食用水果和蔬菜中发现的一种潜在的抗衰老成分非西汀对衰老的人类真皮成纤维细胞(HDFs)和衰老的人类皮肤的影响。使用长期传代和电离辐射处理在原发性HDFs中诱导衰老,并在用非西汀和对照组分处理后评估细胞活力。通过将来自老年人的整个皮肤移植物皮下移植到裸鼠中来建立小鼠/人嵌合模型,裸鼠用非西汀或对照A组分腹膜内处理30d。获得皮肤样品并进行衰老相关的β-半乳糖苷酶染色;使用蛋白质印迹、逆转录定量PCR和组织学分析来评估衰老程度。在两种衰老诱导的细胞模型中,Fisetin选择性地消除衰老的真皮成纤维细胞;这种作用可归因于胱天蛋白酶3、8和9介导的内源性和外源性细胞凋亡诱导的细胞死亡。Fisetin处理的衰老人类皮肤移植物显示出胶原密度增加和衰老相关分泌表型(SASP)降低,包括基质金属蛋白酶和白细胞介素。未观察到明显的不良事件。因此,非西汀可以通过选择性去除衰老的真皮成纤维细胞和抑制SASP来改善皮肤衰老,这表明它有潜力成为一种有效的新型治疗剂来对抗皮肤衰老。
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引用次数: 0
AMPK signaling inhibits the differentiation of myofibroblasts: impact on age-related tissue fibrosis and degeneration. AMPK信号抑制肌成纤维细胞分化:对年龄相关组织纤维化和变性的影响。
IF 4.5 4区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-02-01 Epub Date: 2023-11-02 DOI: 10.1007/s10522-023-10072-9
Antero Salminen

Disruption of the extracellular matrix (ECM) and an accumulation of fibrotic lesions within tissues are two of the distinctive hallmarks of the aging process. Tissue fibroblasts are mesenchymal cells which display an impressive plasticity in the regulation of ECM integrity and thus on tissue homeostasis. Single-cell transcriptome studies have revealed that tissue fibroblasts exhibit a remarkable heterogeneity with aging and in age-related diseases. Excessive stress and inflammatory insults induce the differentiation of fibroblasts into myofibroblasts which are fusiform contractile cells and abundantly secrete the components of the ECM and proteolytic enzymes as well as many inflammatory mediators. Detrimental stresses can also induce the transdifferentiation of certain mesenchymal and myeloid cells into myofibroblasts. Interestingly, many age-related stresses, such as oxidative and endoplasmic reticulum stresses, ECM stiffness, inflammatory mediators, telomere shortening, and several alarmins from damaged cells are potent inducers of myofibroblast differentiation. Intriguingly, there is convincing evidence that the signaling pathways stimulated by the AMP-activated protein kinase (AMPK) are potent inhibitors of myofibroblast differentiation and accordingly AMPK signaling reduces fibrotic lesions within tissues, e.g., in age-related cardiac and pulmonary fibrosis. AMPK signaling is not only an important regulator of energy metabolism but it is also able to control cell fate determination and many functions of the immune system. It is known that AMPK signaling can delay the aging process via an integrated signaling network. AMPK signaling inhibits myofibroblast differentiation, e.g., by suppressing signaling through the TGF-β, NF-κB, STAT3, and YAP/TAZ pathways. It seems that AMPK signaling can alleviate age-related tissue fibrosis and degeneration by inhibiting the differentiation of myofibroblasts.

细胞外基质(ECM)的破坏和组织内纤维化病变的积聚是衰老过程的两个显著特征。组织成纤维细胞是间充质细胞,在ECM完整性的调节中表现出令人印象深刻的可塑性,从而影响组织稳态。单细胞转录组研究表明,组织成纤维细胞在衰老和与年龄相关的疾病中表现出显著的异质性。过度的压力和炎症损伤诱导成纤维细胞分化为肌成纤维细胞,肌成纤维纤维细胞是梭形收缩细胞,大量分泌ECM和蛋白水解酶的成分以及许多炎症介质。破坏性应激也可以诱导某些间充质细胞和骨髓细胞转分化为肌成纤维细胞。有趣的是,许多与年龄相关的应激,如氧化应激和内质网应激、ECM硬度、炎症介质、端粒缩短和损伤细胞的一些危言耸听,都是肌成纤维细胞分化的有效诱导剂。有趣的是,有令人信服的证据表明,AMP活化蛋白激酶(AMPK)刺激的信号通路是肌成纤维细胞分化的有效抑制剂,因此AMPK信号减少了组织内的纤维化病变,例如,在年龄相关的心脏和肺纤维化中。AMPK信号传导不仅是能量代谢的重要调节因子,而且能够控制细胞命运的决定和免疫系统的许多功能。众所周知,AMPK信令可以通过集成信令网络延迟老化过程。AMPK信号传导抑制肌成纤维细胞分化,例如通过抑制TGF-β、NF-κB、STAT3和YAP/TAZ途径的信号传导。AMPK信号传导似乎可以通过抑制肌成纤维细胞的分化来减轻与年龄相关的组织纤维化和变性。
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引用次数: 0
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Biogerontology
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