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Low-molecular-weight heparin ameliorates intestinal barrier dysfunction in aged male rats via protection of tight junction proteins. 低分子量肝素通过保护紧密连接蛋白改善老年雄性大鼠的肠屏障功能障碍
IF 4.4 4区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-11-01 Epub Date: 2024-07-06 DOI: 10.1007/s10522-024-10118-6
Shaojun Wang, Hong Yang

The intestinal barrier weakens and chronic gut inflammation occurs in old age, causing age-related illnesses. Recent research shows that low-molecular-weight heparin (LMWH), besides anticoagulation, also has anti-inflammatory and anti-apoptotic effects, protecting the intestinal barrier. This study aims to analyze the effect of LMWH on the intestinal barrier of old male rodents. This study assigned Sprague-Dawley male rats to four groups: young (3 months), young + LMWH, old (20 months), and old + LMWH. The LMWH groups received 1 mg/kg LMWH via subcutaneous injection for 7 days. Optical and transmission electron microscopy (TEM) were used to examine morphological changes in intestinal mucosa due to aging. Intestinal permeability was measured using fluorescein isothiocyanate (FITC)-dextran. ELISA kits were used to measure serum levels of IL-6 and IL-1β, while Quantitative RT-PCR detected their mRNA levels in intestinal tissues. Western blotting and immunohistochemistry (IHC) evaluated the tight junction (TJ) protein levels such as occludin, zonula occludens-1 (ZO-1), and claudin-2. Western blotting assessed the expression of the apoptosis marker cleaved caspase 3, while IHC was used to detect LGR5+ intestinal stem cells. The intestinal permeability of aged rats was significantly higher than that of young rats, indicating significant differences. With age, the protein levels of occludin and ZO-1 decreased significantly, while the level of claudin-2 increased significantly. Meanwhile, our study found that the levels of IL-1β and IL-6 increased significantly with age. LMWH intervention effectively alleviated age-related intestinal barrier dysfunction. In aged rats treated with LMWH, the expression of occludin and ZO-1 proteins in the intestine increased, while the expression of claudin-2 decreased. Furthermore, LMWH administration in aged rats resulted in a decrease in IL-1β and IL-6 levels. LMWH also reduced age-related cleaved caspase3 expression, but IHC showed no difference in LGR5+ intestinal stem cells between groups. Research suggests that LMWH could potentially be a favorable therapeutic choice for age-related diseases associated with intestinal barrier dysfunction, by protecting TJ proteins, reducing inflammation, and apoptosis.

人到老年,肠道屏障功能减弱,出现慢性肠道炎症,引发老年性疾病。最新研究表明,低分子量肝素(LMWH)除具有抗凝作用外,还具有抗炎和抗细胞凋亡作用,可保护肠道屏障。本研究旨在分析 LMWH 对老年雄性啮齿动物肠道屏障的影响。本研究将 Sprague-Dawley 雄性大鼠分为四组:幼年组(3 个月)、幼年 + LMWH 组、老年组(20 个月)和老年 + LMWH 组。LMWH 组大鼠皮下注射 1 毫克/千克 LMWH,连续注射 7 天。使用光学显微镜和透射电子显微镜(TEM)检查肠粘膜因衰老而发生的形态学变化。使用异硫氰酸荧光素(FITC)-葡聚糖测量肠道通透性。ELISA 试剂盒用于检测血清中 IL-6 和 IL-1β 的水平,定量 RT-PCR 检测肠组织中这两种物质的 mRNA 水平。免疫印迹和免疫组织化学(IHC)评估了紧密连接(TJ)蛋白水平,如闭塞素、闭塞带-1(ZO-1)和Claudin-2。Western 印迹法评估了凋亡标记物裂解的 caspase 3 的表达,而 IHC 则用于检测 LGR5+ 肠干细胞。老龄大鼠的肠道通透性明显高于年轻大鼠,表明两者存在显著差异。随着年龄的增长,occludin 和 ZO-1 蛋白水平明显下降,而 claudin-2 水平明显上升。同时,我们的研究发现,随着年龄的增长,IL-1β和IL-6的水平明显升高。LMWH干预可有效缓解与年龄相关的肠屏障功能障碍。在接受 LMWH 治疗的老年大鼠中,肠道中的 occludin 和 ZO-1 蛋白表达量增加,而 claudin-2 的表达量减少。此外,老年大鼠服用 LMWH 后,IL-1β 和 IL-6 水平下降。LMWH还降低了与年龄相关的裂解caspase3表达,但IHC显示不同组间的LGR5+肠干细胞没有差异。研究表明,通过保护TJ蛋白、减少炎症和细胞凋亡,LMWH有可能成为与肠屏障功能障碍相关的老年疾病的有利治疗选择。
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引用次数: 0
The role of phagocytic cells in aging: insights from vertebrate and invertebrate models. 吞噬细胞在衰老中的作用:脊椎动物和无脊椎动物模型的启示。
IF 4.4 4区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-21 DOI: 10.1007/s10522-024-10131-9
Brecht Driesschaert, Lucas Mergan, Cristiano Lucci, Caroline Simon, Dulce Santos, Lies De Groef, Liesbet Temmerman

While the main role of phagocytic scavenger cells consists of the neutralization and elimination of pathogens, they also keep the body fluids clean by taking up and breaking down waste material. Since a build-up of waste is thought to contribute to the aging process, these cells become particularly pertinent in the research field of aging. Nevertheless, a direct link between their scavenging functions and the aging process has yet to be established. Integrative approaches involving various model organisms hold promise to elucidate this potential, but are lagging behind since the diversity and evolutionary relationship of these cells across animal species remain unclear. In this perspective, we review the current knowledge associating phagocytic scavenger cells with aging in vertebrate and invertebrate animals, as well as put forward important questions for further exploration. Additionally, we highlight future challenges and propose a constructive approach for tackling them.

虽然吞噬清除细胞的主要作用是中和并消除病原体,但它们也通过吸收和分解废物来保持体液清洁。由于废物的堆积被认为会导致衰老,因此这些细胞在衰老研究领域显得尤为重要。然而,这些细胞的清除功能与衰老过程之间的直接联系尚未确立。涉及各种模式生物的综合方法有望阐明这一潜力,但由于这些细胞在动物物种间的多样性和进化关系仍不清楚,因此这种方法还很落后。在这一视角中,我们回顾了脊椎动物和无脊椎动物中吞噬清扫细胞与衰老相关的现有知识,并提出了有待进一步探索的重要问题。此外,我们还强调了未来的挑战,并提出了应对这些挑战的建设性方法。
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引用次数: 0
Mitochondria: fundamental characteristics, challenges, and impact on aging. 线粒体:基本特征、挑战和对衰老的影响。
IF 4.4 4区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-28 DOI: 10.1007/s10522-024-10132-8
Runyu Liang, Luwen Zhu, Yongyin Huang, Jia Chen, Qiang Tang

As one of the most vital organelles within biological cells, mitochondria hold an irreplaceable status and play crucial roles in various diseases. Research and therapies targeting mitochondria have achieved significant progress in numerous conditions. Throughout an organism's lifespan, mitochondrial dynamics persist continuously, and due to their inherent characteristics and various external factors, mitochondria are highly susceptible to damage. This susceptibility is particularly evident during aging, where the decline in biological function is closely intertwined with mitochondrial dysfunction. Despite being an ancient and enigmatic organelle, much remains unknown about mitochondria. Here, we will explore the past and present knowledge of mitochondria, providing a comprehensive review of their intrinsic properties and interactions with nuclear DNA, as well as the challenges and impacts they face during the aging process.

线粒体是生物细胞内最重要的细胞器之一,具有不可替代的地位,在各种疾病中发挥着至关重要的作用。针对线粒体的研究和疗法在多种疾病中取得了重大进展。在生物体的整个生命周期中,线粒体的动态变化持续存在,由于其固有的特性和各种外部因素,线粒体极易受到损伤。这种易损性在衰老过程中尤为明显,生物功能的衰退与线粒体功能障碍密切相关。尽管线粒体是一个古老而神秘的细胞器,但人们对它仍有许多未知。在这里,我们将探讨线粒体过去和现在的知识,全面回顾线粒体的内在特性、与核 DNA 的相互作用,以及线粒体在衰老过程中面临的挑战和影响。
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引用次数: 0
Invariances in relations between aging, exposure to external hazards, and mortality reflected in life table aging rate (LAR) patterns examined through the lens of generalized Gompertz-Makeham law. 通过广义贡培兹-马凯汉姆定律的视角,研究生命表老龄化率(LAR)模式中反映的老龄化、外部危害暴露和死亡率之间关系的不变量。
IF 4.4 4区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-11-01 Epub Date: 2024-07-22 DOI: 10.1007/s10522-024-10123-9
A Golubev

According to the Gompertz law, the age-dependent change in the logarithm of mortality (life-table aging rate, LAR) is equal to the population-averaged age-independent biological aging rate (γ), and LAR would be constant if aging were the only cause of mortality increase. However, LAR is influenced by population exposures to the external hazards. If they were constant, according to the Gompertz-Makeham law (GML), LAR would be below γ at lower ages and asymptotically and monotonically approach γ with increasing age. Actually, LAR trajectories derived from data on mortality in different countries and historical periods feature systematic undulations. In the present investigation, mortality-vs.-age trajectories were modeled based on a generalized GML (gGML). Unlike the canonical GML terms, which are population-specific constants, the respective terms of the gGML are represented with some population-specific functions of age. Invariant in gGML are the modes of translation of these functions into the dependency of mortality on age: linear for population exposure to the irresistible external hazards or exponential for population-averaged ability to withstand the resistible external and internal hazards. Modeling suggests that, at earlier ages, LAR undulations are attributable to changes in population exposures to the former hazards. However, only their unrealistically high levels can produce the transient increase in LAR at about 65 to 90 years. This pervasive undulation of LAR-vs.-age trajectory is rather caused by an increment in γ. Reasons to regard gGML as a genuine natural law, which defines relations between mortality, aging and environment, are discussed.

根据贡珀茨定律,与年龄相关的死亡率对数变化(生命表老化率,LAR)等于与年龄无关的人口平均生物老化率(γ),如果老化是死亡率上升的唯一原因,则 LAR 将保持不变。然而,LAR 受人口暴露于外部危害的影响。如果它们保持不变,根据贡珀茨-马凯姆定律(GML),低年龄段的 LAR 将低于 γ,并随着年龄的增加而渐近和单调地接近 γ。实际上,根据不同国家和历史时期的死亡率数据得出的 LAR 轨迹具有系统性起伏的特点。本研究根据广义 GML(gGML)对死亡率-年龄轨迹进行建模。与典型的 GML 项(特定人口的常数)不同,gGML 的相应项用特定人口的年龄函数来表示。gGML 中不变的是这些函数转化为死亡率与年龄关系的模式:线性表示人口暴露于不可抗拒的外部危害的程度,指数表示人口平均抵御可抗拒的外部和内部危害的能力。建模表明,在较早的年龄段,LAR 的起伏是由于人口遭受前一种危害的程度发生了变化。然而,只有其不切实际的高水平才能产生 LAR 在 65 至 90 岁左右的瞬时增长。这种 LAR 随年龄变化的普遍起伏是由γ 的增加引起的。本文讨论了将 gGML 视为真正的自然法则的理由,它定义了死亡率、衰老和环境之间的关系。
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引用次数: 0
Correction: Chronic trans fatty acid consumption shortens lifespan in male Drosophila melanogaster on a high-sugar and high-fat diet. 更正:长期摄入反式脂肪酸会缩短高糖高脂饮食雄性黑腹果蝇的寿命。
IF 4.4 4区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-11-01 DOI: 10.1007/s10522-024-10116-8
Qianhua Yuan, Mengliu Luo, Yutong Xie, Wanhan Song, Ya Wang, Dazhang Deng, Shuyan Chen, Honghui Guo
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引用次数: 0
Age-related decline in the expression of BRG1, ATM and ATR are partially reversed by dietary restriction in the livers of female mice. 在雌性小鼠肝脏中,与年龄相关的 BRG1、ATM 和 ATR 表达下降可通过限制饮食得到部分逆转。
IF 4.4 4区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-11-01 Epub Date: 2024-07-06 DOI: 10.1007/s10522-024-10117-7
Pynskhem Bok Swer, Babiangshisha Kharbuli, Donkupar Syiem, Ramesh Sharma

BRG1 (Brahma-related gene 1) is a member of the SWI/SNF (switch/sucrose nonfermentable) chromatin remodeling complex which utilizes the energy from ATP hydrolysis for its activity. In addition to its role of regulating the expression of a vast array of genes, BRG1 mediates DNA repair upon genotoxic stress and regulates senescence. During organismal ageing, there is accumulation of unrepaired/unrepairable DNA damage due to progressive breakdown of the DNA repair machinery. The present study investigates the expression level of BRG1 as a function of age in the liver of 5- and 21-month-old female mice. It also explores the impact of dietary restriction on BRG1 expression in the old (21-month) mice. Salient findings of the study are: Real-time PCR and Western blot analyses reveal that BRG1 levels are higher in 5-month-old mice but decrease significantly with age. Dietary restriction increases BRG1 expression in the 21-month-old mice, nearly restoring it to the level observed in the younger group. Similar expression patterns are observed for DNA damage response genes ATM (Ataxia Telangiectasia Mutated) and ATR (Ataxia Telangiectasia and Rad3-related) with the advancement in age and which appears to be modulated by dietary restriction. BRG1 transcriptionally regulates ATM as a function of age and dietary restriction. These results suggest that BRG1, ATM and ATR are downregulated as mice age, and dietary restriction can restore their expression. This implies that dietary restriction may play a crucial role in regulating BRG1 and related gene expression, potentially maintaining liver repair and metabolic processes as mice age.

BRG1(梵天相关基因 1)是 SWI/SNF(开关/蔗糖不发酵)染色质重塑复合体的成员,它利用 ATP 水解产生的能量进行活动。除了调节大量基因的表达外,BRG1 还能在基因毒性应激时介导 DNA 修复,并调节衰老。在机体衰老过程中,由于 DNA 修复机制逐渐崩溃,未修复/可修复的 DNA 损伤不断积累。本研究调查了 5 个月大和 21 个月大雌性小鼠肝脏中 BRG1 的表达水平与年龄的关系。研究还探讨了饮食限制对老龄(21 个月)小鼠 BRG1 表达的影响。研究的主要发现有实时 PCR 和 Western 印迹分析表明,5 个月大小鼠的 BRG1 水平较高,但随着年龄的增长会显著降低。饮食限制会增加 21 个月大小鼠的 BRG1 表达量,几乎恢复到较小鼠组的水平。随着年龄的增长,DNA损伤反应基因ATM(Ataxia Telangiectasia Mutated)和ATR(Ataxia Telangiectasia and Rad3-related)也出现了类似的表达模式,并且似乎受到饮食限制的调节。BRG1对ATM的转录调节与年龄和饮食限制有关。这些结果表明,随着小鼠年龄的增长,BRG1、ATM 和 ATR 的表达会降低,而饮食限制可以恢复它们的表达。这意味着饮食限制可能在调节BRG1及相关基因表达方面起着至关重要的作用,有可能随着小鼠年龄的增长而维持肝脏修复和代谢过程。
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引用次数: 0
Isotschimgine promotes lifespan, healthspan and neuroprotection of Caenorhabditis elegans via the activation of nuclear hormone receptors. 异噻嗪通过激活核激素受体促进秀丽隐杆线虫的寿命、健康和神经保护。
IF 4.4 4区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-10-29 DOI: 10.1007/s10522-024-10142-6
Hang Shi, Xiaoyan Gao, Jing Yu, Lijun Zhang, Bingbing Fan, Ying Liu, Xinyi Wang, Shengjie Fan, Cheng Huang

Isotschimgine (ITG) is a bornane-type monoterpenoid derivative naturally occurring in genus Ferula plants and propolis. Its effects on aging and the underlying mechanisms are not yet well understood. This study employed Caenorhabditis elegans (C. elegans) as a model organism to evaluate the potential of ITG in extending lifespan, enhancing healthspan, and promoting neuroprotection, while exploring the underlying mechanisms involved. The results showed that ITG extended the lifespan and healthspan of C. elegans, significantly enhanced stress resistance and detoxification functions. Studies on mutants and qPCR data indicated that ITG-mediated lifespan extension was modulated by the insulin/IGF-1 signaling pathway and nuclear hormone receptors. Furthermore, ITG markedly increased stress-responsive genes, including daf-16 and its downstream genes sod-3 and hsp-16.2, as well as NHR downstream detoxification-related genes cyp35a1, cyp35b3, cyp35c1, gst-4, pgp-3 and pgp-13. Additionally, ITG alleviated β-amyloid-induced paralysis and behavioral dysfunction in transgenic C. elegans strains. The neuroprotective efficacy of ITG was weakened by RNAi knockdown of nuclear hormone receptors daf-12 and nhr-8. Overall, our study identifies ITG as a potential compound for promoting longevity and neuroprotection, mediated through nuclear hormone receptors.

异苦参碱(ITG)是一种天然存在于阿魏属植物和蜂胶中的生番烷类单萜衍生物。它对衰老的影响及其内在机制尚不十分清楚。本研究以秀丽隐杆线虫(C. elegans)为模式生物,评估 ITG 在延长寿命、延长健康寿命和促进神经保护方面的潜力,同时探索其潜在机制。研究结果表明,ITG能延长秀丽隐杆线虫的寿命和健康寿命,显著增强其抗应激能力和解毒功能。对突变体的研究和qPCR数据表明,ITG介导的寿命延长受胰岛素/IGF-1信号通路和核激素受体的调控。此外,ITG明显增加了应激反应基因,包括daf-16及其下游基因sod-3和hsp-16.2,以及NHR下游解毒相关基因cyp35a1、cyp35b3、cyp35c1、gst-4、pgp-3和pgp-13。此外,ITG 还能缓解β-淀粉样蛋白诱导的转基因优雅小鼠瘫痪和行为功能障碍。核激素受体daf-12和nhr-8的RNAi敲除削弱了ITG的神经保护功效。总之,我们的研究发现 ITG 是一种通过核激素受体介导的促进长寿和神经保护的潜在化合物。
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引用次数: 0
The evolution of ageing: classic theories and emerging ideas. 老龄化的演变:经典理论与新兴观点。
IF 4.4 4区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-10-29 DOI: 10.1007/s10522-024-10143-5
Mark T Mc Auley

Ageing is generally regarded as a non-adaptive by-product of evolution. Based on this premise three classic evolutionary theories of ageing have been proposed. These theories have dominated the literature for several decades. Despite their individual nuances, the common thread which unites them is that they posit that ageing results from a decline in the intensity of natural selection with chronological age. Empirical evidence has been identified which supports each theory. However, a consensus remains to be fully established as to which theory best accounts for the evolution of ageing. A consequence of this uncertainty are counter arguments which advocate for alternative theoretical frameworks, such as those which propose an adaptive origin for ageing, senescence, or death. Given this backdrop, this review has several aims. Firstly, to briefly discuss the classic evolutionary theories. Secondly, to evaluate how evolutionary forces beyond a monotonic decrease in natural selection can affect the evolution of ageing. Thirdly, to examine alternatives to the classic theories. Finally, to introduce a pluralistic interpretation of the evolution of ageing. The basis of this pluralistic theoretical framework is the recognition that certain evolutionary ideas will be more appropriate depending on the organism, its ecological context, and its life history.

衰老一般被认为是进化的非适应性副产品。基于这一前提,人们提出了三种经典的老龄化进化理论。几十年来,这些理论一直在文献中占据主导地位。尽管这些理论各有细微差别,但它们的共同点是都认为衰老是自然选择的强度随年龄增长而下降的结果。每种理论都有支持的经验证据。然而,对于哪种理论最能解释老龄化的演变,目前还没有完全达成共识。这种不确定性的一个后果是出现了主张采用其他理论框架的反驳论点,例如那些提出老化、衰老或死亡是适应性起源的理论。在此背景下,本综述有几个目的。首先,简要讨论经典的进化理论。其次,评估自然选择单调减少之外的进化力量如何影响衰老的进化。第三,研究经典理论的替代方案。最后,介绍老龄化进化的多元解释。这一多元理论框架的基础是认识到,根据生物体、其生态环境和生命史的不同,某些进化观点会更加合适。
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引用次数: 0
High-quality dietary protein (essential amino acids matched to reproductive needs) partially breaks the lifespan and reproduction trade-off in lubber grasshoppers. 优质膳食蛋白质(与繁殖需求相匹配的必需氨基酸)部分打破了蚱蜢寿命与繁殖之间的平衡。
IF 4.4 4区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-10-29 DOI: 10.1007/s10522-024-10144-4
Emma Kordek, Amaya Yip, Alicia Horton, Hope Sohn, Nicholas Strasser, Maya Makhtin, John Hatle

Finding interventions to break the trade-off between reproduction and lifespan can provide insight into physiological limitations of animals. Effects of dietary protein quality on the trade-off are currently unclear, but clarity could lead to better designed diets that match animal needs. Dietary amino acid blends matching yolk proteins support reproduction and extend lifespan in fruit flies. To test if this is conserved across species, we matched dietary amino acids to vitellogenin to test reproduction and lifespan in adult females of the lubber grasshopper. Specifically, we compared varying degrees of protein quality by manipulating dietary essential amino acids. We identified a high-quality protein diet (amino acids matched to vitellogenin, or reproductive needs) that increased reproduction and matched lifespan in comparison to diets that differed only in the ratios of essential amino acids (i.e., were isocaloric and isonitrogenous). All these diets had longer lifespan but lower reproductive output than fully fed controls. In a separate experiment, full reproduction was possible on the high-quality artificial diet when offered at a 78% higher protein quantity and with a larger lettuce supplement (~ 17% of ad libitum). Additionally, we observed that as dietary protein quality was decreased (i.e., diets were less matched to vitellogenin), reproduction was reduced, and lifespan was extended in the more extreme scenarios. Taken together, these results indicate that the balance of dietary essential amino acids plays an important role in the lifespan and reproduction trade-off, while more work needs to be conducted to find the optimal diet mix for this species.

寻找干预措施来打破繁殖与寿命之间的权衡,可以让人们深入了解动物的生理限制。膳食蛋白质质量对权衡的影响目前尚不清楚,但清楚后可以更好地设计符合动物需求的膳食。与卵黄蛋白相匹配的膳食氨基酸混合物可支持果蝇的繁殖并延长其寿命。为了测试这一点在不同物种间是否一致,我们将膳食氨基酸与卵黄素相匹配,以测试蚱蜢成年雌性的繁殖和寿命。具体来说,我们通过调节膳食必需氨基酸来比较不同程度的蛋白质质量。我们确定了一种优质蛋白质日粮(氨基酸与卵黄素或生殖需求相匹配),与仅在必需氨基酸比例上存在差异(即等热量和等氮量)的日粮相比,这种日粮可提高繁殖率并延长寿命。与完全喂养的对照组相比,所有这些日粮的寿命都更长,但繁殖量却更低。在另一项实验中,优质人工日粮的蛋白质含量比普通日粮高出 78%,并且添加了更多的莴苣(约为自由摄入量的 17%),可实现完全繁殖。此外,我们还观察到,随着日粮蛋白质质量的降低(即日粮与卵黄素的匹配度降低),繁殖率降低,而在更极端的情况下,寿命延长。总之,这些结果表明,日粮中必需氨基酸的平衡在寿命和繁殖的权衡中起着重要作用,同时还需要开展更多的工作来找到该物种的最佳日粮组合。
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引用次数: 0
A novel (-)-(2S)-7,4'-dihydroxyflavanone compound for treating age-related diabetes mellitus through immunoinformatics-guided activation of CISD3. 一种新型(-)-(2S)-7,4'-二羟基黄烷酮化合物,可通过免疫制剂引导激活 CISD3 治疗老年性糖尿病。
IF 4.4 4区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-10-29 DOI: 10.1007/s10522-024-10147-1
Abdur-Rehman Munir, Saad Ilyas Baig, Muhammad Asif Razzaq, Fatima Rauf, Yasir Ali, Syed Muhammad Abdullah Azam

The iron-sulfur domain (CISD) proteins of CDGSH are classified into three classes: CISD1, CISD2, and CISD3. During premature ageing, mutations that affect these proteins, namely their binding sites, could result in reduced protein production and an inability to preserve cellular integrity. Consequently, this leads to the development of conditions such as diabetes. Notably, CISD3 plays a crucial role in the management of age-related disorders such as Wolfram syndrome, which is often referred to as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). Computational analyses have predicted that CISD3 regulates the redox state, safeguards the endoplasmic reticulum and mitochondria, and maintains intracellular calcium levels. CISD3, a member of a recently discovered gene family associated with the CDGSH iron protein apoptotic compensatory response, fulfils a crucial function in mitigating the effects of accelerated ageing. The compound "(-)-(2S)-7,4'-Dihydroxyflavanone" has been discovered by computational drug design as a possible activator of CISD3. It shows potential therapeutic benefits in ameliorating metabolic dysfunction and enhancing glucose regulation. The ligand binds to the binding pocket of the CISD3 protein, increasing the stability of the protein and enhancing its functionality. The current research investigates the binding processes of the molecule in various structures and its anticipated effects on these tissues, therefore providing valuable insights into the mitigation of age-related diabetes and metabolic dysfunction. The projected tripling of the worldwide population of individuals aged 50 and above by 2050 necessitates the urgent development of immunoinformatics-based approaches, including pharmaceutical therapies that target CISD3, to prevent age-related pathologies. The stimulation of CISD3, namely by compounds such as "(-)-(2S)-7,4'-Dihydroxyflavanone", has the potential to counteract telomere shortening and improve metabolic pathways.

CDGSH 的铁硫结构域(CISD)蛋白分为三类:CISD1、CISD2 和 CISD3。在过早衰老的过程中,影响这些蛋白质(即它们的结合位点)的突变会导致蛋白质生成减少,无法保持细胞的完整性。因此,会导致糖尿病等疾病的发生。值得注意的是,CISD3 在治疗沃尔夫拉姆综合征等与年龄有关的疾病中发挥着至关重要的作用,这种综合征通常被称为 DIDMOAD(糖尿病、糖尿病、视神经萎缩和耳聋)。计算分析预测,CISD3 可调节氧化还原状态,保护内质网和线粒体,并维持细胞内的钙水平。CISD3 是最近发现的与 CDGSH 铁蛋白凋亡补偿反应有关的基因家族的成员,在减轻加速衰老的影响方面发挥着至关重要的作用。通过计算药物设计发现的化合物"(-)-(2S)-7,4'-二羟基黄烷酮 "可能是 CISD3 的激活剂。它在改善代谢功能障碍和加强葡萄糖调节方面显示出潜在的治疗效果。该配体可与 CISD3 蛋白的结合袋结合,从而提高蛋白质的稳定性并增强其功能。目前的研究调查了该分子在各种结构中的结合过程及其对这些组织的预期影响,从而为缓解与年龄有关的糖尿病和代谢功能障碍提供了宝贵的见解。预计到 2050 年,全球 50 岁及以上人口将增加三倍,因此迫切需要开发基于免疫信息学的方法,包括针对 CISD3 的药物疗法,以预防与年龄有关的病症。(-)-(2S)-7,4'-二羟基黄烷酮 "等化合物对 CISD3 的刺激有可能抵消端粒缩短并改善代谢途径。
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