Mechanisms of Ageing and Development最新文献_第4页

Increased mTOR signaling secondary to a human ILK missense variant inhibits nephrogenesis with decreased metabolism 继发于人类ILK错义变异的mTOR信号增加抑制代谢降低的肾发生。

IF 5.1 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-09-19 DOI: 10.1016/j.mad.2025.112115

Xiangyue Hu , Dana Kablawi , Wout F.J. Feitz , Kirsten Y. Renkema , Nine V.A.M. Knoers , Norman D. Rosenblum

Nephrogenesis is critical to mammalian kidney function throughout life. Decreased nephron formation, an embryonic process dependent on ureteric-mesenchymal tissue interactions, is a fundamental feature of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) and an antecedent to adult-onset cardiovascular and renal disease. Yet, mechanisms controlling the number of nephrons formed during embryogenesis are largely undefined. Here, we elucidated deleterious effects of increased mTOR signaling on murine nephrogenesis. A rare human genetic missense variant (ILK^T173I) in Integrin-Linked Kinase (ILK) was identified in a human CAKUT cohort. Replacement of the mouse ILK^WT allele with Ilk^T173I caused increased kidney mTOR signaling, low nephron number, and decreased ureteric branching, the latter of which was rescued by rapamycin. Transcriptomic analysis of sorted embryonic kidney cells suggested that elevated mTOR signaling is limited to non-ureteric mesenchyme, a finding that was substantiated by immunostaining in situ. Maturation of nephrogenic cells in Ilk^T173I-knock-in kidneys was decreased as demonstrated by nephrogenic-specific markers, morphologic analysis, and proliferation of nephrogenic progenitors. Metabolic profiling of non-ureteric cells demonstrated decreased oxidative ATP production. Together, our data revealed a deleterious role of excessive mTOR signaling downstream of ILK^T173I by inhibiting maturation, cell proliferation and metabolism in the nephrogenic cell lineage.

肾脏形成对哺乳动物一生的肾脏功能至关重要。肾元形成减少是一个依赖于输尿管-间质组织相互作用的胚胎过程，是先天性肾尿路异常（先天性肾尿路异常）的基本特征，也是成人发病的心血管和肾脏疾病的前兆。然而，控制胚胎发生过程中肾单位数量的机制在很大程度上是不明确的。在这里，我们阐明了mTOR信号增加对小鼠肾形成的有害影响。在人类CAKUT队列中发现了一种罕见的人类整合素连接激酶（ILK）遗传错义变异（ILKT173I）。用IlkT173I替代小鼠ILKWT等位基因导致肾脏mTOR信号增加，肾细胞数量减少，输尿管分支减少，后者可通过雷帕霉素恢复。胚胎肾细胞的转录组学分析表明，mTOR信号的升高仅限于非输尿管间质，原位免疫染色证实了这一发现。肾源特异性标志物、形态学分析和肾源性祖细胞的增殖表明，ilkt173i敲入肾脏的肾源性细胞成熟减少。非输尿管细胞的代谢谱显示氧化ATP产生减少。总之，我们的数据揭示了ILKT173I下游过量mTOR信号通过抑制肾源性细胞谱系中的成熟、细胞增殖和代谢而起的有害作用。

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引用次数: 0

Disentangling tau, glymphatic dysfunction and astrocytic activation in amyloid-positive Alzheimer's disease 淀粉样蛋白阳性阿尔茨海默病中Tau蛋白、淋巴功能障碍和星形细胞激活的分离。

IF 5.1 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-09-17 DOI: 10.1016/j.mad.2025.112113

Hsin-I. Chang , Shih-Wen Chen , Shu-Hua Huang , Shih-Wei Hsu , Chen-Chang Lee , Chung-Guei Huang , Chi-Wei Huang , Chiung-Chih Chang

Alzheimer’s disease (AD) features tau pathology, neurodegeneration, and cognitive decline. Dysfunction of the glymphatic system, which clears pathological proteins, and astrocytic activation may exacerbate neurodegeneration. We investigated the interplay among tau accumulation, glymphatic dysfunction, and astrocytic activation in amyloid PET-positive AD patients using diffusion tensor image analysis along the perivascular space (DTI-ALPS) as a glymphatic biomarker. Our cohort comprised 157 AD patients and 117 cognitively unimpaired controls. We measured DTI-ALPS, plasma GFAP, hippocampal volume, and cognitive scores at two time points. [F18]Florzolotau PET quantified tau burden. Regression analyses assessed associations between biomarkers and cognitive decline, and mediation analysis tested GFAP’s role in tau-driven neurodegeneration. We also compared topographical distributions of DTI-ALPS and GFAP using tau PET and gray matter images. Tau burden emerged as the strongest predictor of cognitive decline, while DTI-ALPS showed no significant cognitive association. GFAP mediated the link between tau burden and hippocampal atrophy, implicating astrocytic activation in tau-driven neurodegeneration. Regional analyses revealed GFAP associations in anterior cingulate and medial temporal areas, contrasting with DTI-ALPS patterns in parasagittal and lateral prefrontal regions. These findings underscore tau burden as the driver of cognitive decline, with astrocytic activation mediating neurodegeneration; glymphatic dysfunction minimally impacts cognition.

阿尔茨海默病（AD）以tau蛋白病理、神经变性和认知能力下降为特征。清除病理蛋白的淋巴系统功能障碍和星形细胞活化可能加剧神经退行性变。我们研究了淀粉样pet阳性AD患者中tau积累、淋巴功能障碍和星形细胞激活之间的相互作用，采用沿血管周围间隙扩散张量图像分析（DTI-ALPS）作为淋巴生物标志物。我们的队列包括157名AD患者和117名认知功能未受损的对照组。我们在两个时间点测量了DTI-ALPS、血浆GFAP、海马体积和认知评分。[F18]Florzolotau PET量化tau负荷。回归分析评估了生物标志物与认知能力下降之间的关联，中介分析测试了GFAP在tau驱动的神经变性中的作用。我们还使用tau PET和灰质图像比较了DTI-ALPS和GFAP的地形分布。Tau负担是认知能力下降的最强预测因子，而DTI-ALPS没有显示出显著的认知关联。GFAP介导了tau负荷和海马萎缩之间的联系，暗示了tau驱动的神经退行性变中星形细胞的激活。区域分析显示GFAP在前扣带区和内侧颞区存在关联，而在副矢状面区和外侧前额叶区存在DTI-ALPS模式。这些发现强调tau负担是认知能力下降的驱动因素，星形胶质细胞激活介导神经变性；淋巴功能障碍对认知的影响最小。

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引用次数: 0

Defective mitochondrial quality control in the aging of skeletal muscle 骨骼肌老化过程中线粒体质量控制缺陷。

IF 5.1 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-09-08 DOI: 10.1016/j.mad.2025.112112

Emanuele Marzetti , Riccardo Calvani , Helio José Coelho-Junior , Francesco Landi , Anna Picca

Age-related skeletal muscle decline is a major contributor to frailty, functional impairment, and loss of independence in advanced age. This process is characterized by selective atrophy of type II fibers, impaired excitation–contraction coupling, and reduced regenerative capacity. Emerging evidence implicates mitochondrial dysfunction as a central mechanism in the disruption of muscle homeostasis with age. Beyond ATP production, mitochondria orchestrate redox signaling, calcium handling, and apoptotic pathways, which are increasingly compromised in aged muscle due to chronic oxidative stress and defective quality control. High-resolution respirometry has revealed intrinsic, lifestyle-independent declines in mitochondrial respiratory capacity, while large-scale phenotyping and transcriptomic profiling have established robust associations between mitochondrial integrity, physical performance, and mobility. These findings have prompted a paradigm shift from static descriptions of mitochondrial decline toward dynamic analyses of mitochondrial signaling networks and stress adaptability. Several quality control mechanisms, including mitochondrial biogenesis, dynamics, mitophagy, and vesicle trafficking, emerge as critical regulators of myocyte integrity. Understanding how these systems deteriorate with age will be pivotal for developing therapeutic targets to preserve muscle function, mitigate sarcopenia, and extend health span.

与年龄相关的骨骼肌衰退是老年虚弱、功能损伤和丧失独立性的主要原因。这一过程的特点是II型纤维选择性萎缩，兴奋-收缩耦合受损，再生能力降低。新出现的证据表明，线粒体功能障碍是随着年龄增长而破坏肌肉平衡的中心机制。除了ATP产生外，线粒体还协调氧化还原信号、钙处理和凋亡途径，这些途径在衰老肌肉中由于慢性氧化应激和质量控制缺陷而日益受损。高分辨率呼吸测量揭示了线粒体呼吸能力内在的、与生活方式无关的下降，而大规模表型分析和转录组分析已经建立了线粒体完整性、身体表现和流动性之间的强大关联。这些发现促使了从线粒体衰退的静态描述向线粒体信号网络和应激适应性的动态分析的范式转变。一些质量控制机制，包括线粒体生物发生、动力学、线粒体自噬和囊泡运输，是肌细胞完整性的关键调节因素。了解这些系统如何随着年龄的增长而恶化，将是开发治疗目标的关键，以保持肌肉功能，减轻肌肉减少症，延长健康寿命。

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引用次数: 0

Histone modifications: Key players in Alzheimer's disease 组蛋白修饰：阿尔茨海默病的关键因素

IF 5.1 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-09-02 DOI: 10.1016/j.mad.2025.112102

Kun Li , Xiaolin Qiu , Qiqi Yang , Ziqiang Wang

Alzheimer’s disease (AD) is one of the most prevalent diseases in the older population. AD causes progressive cognitive and behavioral impairment, but current treatments are unable to slow or prevent the progression of this disease. Thus, identification of novel biomarkers and therapeutic targets is urgently needed. We previously described the roles of histone acetylation, crotonylation, and lactylation in the accumulation of amyloid beta and hyperphosphorylation of Tau protein, which are the hallmarks of AD. In this review, we summarize and discuss the current knowledge of the role of histone modifications in AD, with a particular emphasis on its association with characterized pathological alterations, including amyloid plaques, Tau tangles, neuroinflammation, and synaptic dysfunction. This review provides novel insights into the central role of histone modifications in AD pathogenesis and evaluates histone-modifying enzymes as potential therapeutic targets for the treatment of AD.

阿尔茨海默病（AD）是老年人群中最常见的疾病之一。阿尔茨海默病导致进行性认知和行为障碍，但目前的治疗方法无法减缓或预防这种疾病的进展。因此，迫切需要鉴定新的生物标志物和治疗靶点。我们之前描述了组蛋白乙酰化、巴豆酰化和乳酸化在淀粉样蛋白积累和Tau蛋白过度磷酸化中的作用，这些都是AD的标志。在这篇综述中，我们总结和讨论了目前关于组蛋白修饰在AD中的作用的知识，特别强调了它与特征性病理改变的关联，包括淀粉样斑块、Tau缠结、神经炎症和突触功能障碍。这篇综述为组蛋白修饰在AD发病机制中的核心作用提供了新的见解，并评估了组蛋白修饰酶作为AD治疗的潜在治疗靶点。

引用次数: 0

ABI3BP deficiency alleviates Ang II-induced VSMC senescence through the Nrf2 signalling pathway ABI3BP缺失通过NRF2信号通路缓解angii诱导的VSMC衰老

IF 5.1 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-08-30 DOI: 10.1016/j.mad.2025.112104

Aiqiu Mao , Qiang Tu , Huaqiang Xie , Xiaoying Wang , Yuhan Liu , Yan Ding , Zheng Cao

Vascular aging is a critical independent risk factor for cardiovascular disease (CVD), yet its precise molecular mechanisms remain poorly understood. In this study, we generated an ABI3BP knockout mouse to investigate the role of ABI3BP deficiency in angiotensin II (Ang II)-induced vascular aging. The results demonstrated that ABI3BP was highly expressed in AngII-induced senescent vascular smooth muscle cell (VSMC) and vascular tissues, with significantly increased expression also observed in the blood vessels of naturally aged mice. Downregulation of ABI3BP expression using siRNA significantly inhibited Ang II-induced senescence of VSMC. ABI3BP knockout ameliorated Ang II-induced vascular aging in mice, reduced the secretion of senescence-associated inflammatory factors IL-6 and TNF-α, alleviated senescence-induced accumulation of collagen in the vascular media and thickening of the vascular intima, and effectively suppressed Ang II-induced elevation of blood pressure. Further investigations revealed that these protective effects might be mediated through enhanced expression of Nrf2 and its downstream anti-aging factors. Silencing Nrf2 with siRNA attenuated the protective effects of ABI3BP downregulation on vascular aging. Overall, these findings demonstrate that ABI3BP downregulation inhibits VSMC senescence by enhancing the activity of the Nrf2-mediated antioxidant defense pathway, thereby attenuating the progression of vascular aging.

血管老化是心血管疾病（CVD）的一个重要独立危险因素，但其确切的分子机制尚不清楚。在这项研究中，我们制造了一只ABI3BP敲除小鼠来研究ABI3BP缺乏在血管紧张素II （AngII）诱导的血管衰老中的作用。结果表明，ABI3BP在血管素诱导的衰老血管平滑肌细胞（VSMC）和血管组织中高表达，在自然衰老小鼠血管中的表达也显著增加。利用siRNA下调ABI3BP表达可显著抑制血管内皮细胞诱导的衰老。敲除ABI3BP可改善小鼠血管血管老化，减少衰老相关炎症因子IL-6和TNF-α的分泌，减轻衰老诱导的血管介质胶原堆积和血管内膜增厚，有效抑制血管内皮引起的血压升高。进一步的研究表明，这些保护作用可能是通过Nrf2及其下游抗衰老因子的表达增强介导的。用siRNA沉默Nrf2可减弱ABI3BP下调对血管衰老的保护作用。综上所述，这些研究结果表明，ABI3BP下调通过增强nrf2介导的抗氧化防御通路的活性来抑制VSMC衰老，从而减缓血管衰老的进程。

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引用次数: 0

DKK3, regulated by FOXF1-EZH2 axis, takes action on tubular epithelial cells senescence to trigger glomerular endothelial cells ferroptosis involving in renal fibrosis DKK3受FOXF1-EZH2轴调控，作用于小管上皮细胞衰老，触发肾小球内皮细胞铁上沉，参与肾纤维化。

IF 5.1 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-08-28 DOI: 10.1016/j.mad.2025.112103

Huiling Cao , Yanxia Chen , Jinjing Huang, Weiping Tu, Ben Ke, Xiangdong Fang

Chronic kidney disease (CKD) can be accelerated by renal fibrosis. Dickkopf-3 (DKK3) plays a role in regulating renal fibrosis, while tubular cell senescence contributes to fibrosis development. Here, the role and mechanism of DKK3 on senescence and renal fibrosis were evaluated. We demonstrated that in CKD patients and Unilateral Ureteral Obstruction (UUO) mice, downregulation of FOXF1 and upregulation of DDK3 was observed, of which expression patterns exhibited negative association. Reinforced FOXF1 protected against H₂O₂-triggered tubular cell damage, fibrosis, and senescence, which was reversed by DKK3 overexpression. In UUO mice, FOXF1 depletion worsened renal fibrosis and senescence. Mechanistically, FOXF1 was identified to be a transcriptional activator of EZH2 to mediated epigenetic silence of DKK3 via H3K27me3 levels. Moreover, exosomal DKK3 from tubular cells controlled Endothelial to Mesenchymal Transition, oxidative stress and ferroptosis in MRGECs. Overall, our data reveal that the FOXF1-EZH2-DKK3 axis controls tubular cell senescence. Exosome-borne DKK3 influences lipid peroxidation in glomerular endothelial cells, inducing ferroptosis and advancing renal fibrosis, which provides new therapeutic targets for CKD treatment.

慢性肾脏疾病（CKD）可因肾脏纤维化而加速。Dickkopf-3 （DKK3）在调节肾纤维化中起作用，而小管细胞衰老有助于纤维化的发生。本文探讨了DKK3在衰老和肾纤维化中的作用及机制。我们发现，在CKD患者和单侧输尿管梗阻（UUO）小鼠中，FOXF1下调，DDK3上调，两者的表达模式呈负相关。增强FOXF1可防止h2o2引发的小管细胞损伤、纤维化和衰老，这一作用可通过DKK3过表达逆转。在UUO小鼠中，FOXF1缺失加重了肾脏纤维化和衰老。机制上，FOXF1被鉴定为EZH2的转录激活因子，通过H3K27me3水平介导DKK3的表观遗传沉默。此外，来自小管细胞的外泌体DKK3在mrgec中控制内皮细胞向间充质细胞的转化、氧化应激和铁凋亡。总之，我们的数据显示FOXF1-EZH2-DKK3轴控制着管状细胞的衰老。外泌体携带的DKK3影响肾小球内皮细胞的脂质过氧化，诱导铁凋亡，促进肾纤维化，为CKD的治疗提供了新的靶点。

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引用次数: 0

Mechanism of FTO-mediated m6A demethylation regulation of YAP1 in nucleus pulposus cell senescence fto介导的m6A去甲基化调控YAP1在髓核细胞衰老中的机制

IF 5.1 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-08-26 DOI: 10.1016/j.mad.2025.112101

Rui Sun , Xiao-Tao Wu , Hang Shi , Feng Wang , Jia-Wei Gao , Pei-Yang Wang , Zheng-Yuan Xu , Wen-Wu Gan , Yun-Tao Wang , Cong Zhang

Nucleus pulposus (NP) cell senescence is a critical factor in the progression of intervertebral disc degeneration (IVDD). Our analysis demonstrates that FTO and YAP1 expression levels are significantly diminished in degenerative NP tissues from both human and rat models, which correlates with increased m6A modification of YAP1 transcripts. To investigate the underlying mechanisms, we utilized IL-1β to induce senescence in cultured NP cells. Our findings reveal that FTO knockdown leads to a decrease in YAP1 levels while simultaneously increasing senescence markers. In contrast, the overexpression of YAP1 alleviates the senescence phenotype in FTO-deficient cells, underscoring the protective role of YAP1 in NP cells. This study proposes a novel regulatory pathway in which FTO modulates YAP1 through m6A demethylation, suggesting potential therapeutic targets for mitigating NP cell senescence and IVDD.

髓核（NP）细胞衰老是椎间盘退变（IVDD）进展的关键因素。我们的分析表明，在人和大鼠模型的退行性NP组织中，FTO和YAP1的表达水平显著降低，这与YAP1转录物的m6A修饰增加有关。为了研究其潜在的机制，我们利用IL-1β诱导培养的NP细胞衰老。我们的研究结果表明，FTO敲低导致YAP1水平下降，同时增加衰老标志物。相反，YAP1过表达可缓解fto缺陷细胞的衰老表型，说明YAP1对NP细胞具有保护作用。本研究提出了FTO通过m6A去甲基化调控YAP1的新调控途径，为缓解NP细胞衰老和IVDD提供了潜在的治疗靶点。

引用次数: 0

Electrical brain activity in Centenarians: Neurophysiological EEG markers in resilient brain ageing 百岁老人的脑电活动：弹性脑老化的神经生理EEG标记。

IF 5.1 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-08-09 DOI: 10.1016/j.mad.2025.112100

Fabrizio Vecchio , Chiara Pappalettera , Alessia Cacciotti , Federico Frasca , Gabriella Marcon , Paolo Maria Rossini

Centenarians are an increasing population, in particular in high income countries. Studying cognitively intact Centenarians’ brain becomes fundamental to understand physiological ageing and how it diverges from pathological one. Resting state EEG were recorded using 27 channels in more than 130 subjects (referred to Young, Adults, Elderly, Centenarians and Alzheimer Disease patients), and the power spectral density (PSD) was computed. The paper demonstrates that Centenarians electrical brain activity is more similar to Elderly’s than expected, despite approximately 30 years of age gap, provided they are cognitively intact. Centenarians EEG signal was expected to progressively approach AD one, but surprisingly they seem to slow-down their ageing and maintain non-pathological and resilient EEG patterns, particularly in Alpha bands: occipital region Centenarians PSD has lower values than Young and Adults but not than Elderly, and higher values than AD. These interesting results suggests that Centenarians brain needs to be investigated to extrapolate its characteristics and try to replicate its mechanisms for a widespread healthy ageing.

百岁老人人数不断增加，特别是在高收入国家。研究认知完整的百岁老人的大脑对于理解生理衰老及其与病理性衰老的区别至关重要。记录青年、成人、老年、百岁老人和阿尔茨海默病患者共130例，27个通道静息状态脑电图，计算功率谱密度（PSD）。这篇论文表明，在认知完整的情况下，百岁老人的脑电活动与老年人的脑电活动比预期的更相似，尽管大约有30岁的年龄差距。预期百岁老人的脑电图信号逐渐接近AD 1，但令人惊讶的是，他们似乎减缓了他们的衰老并保持非病理性和弹性的脑电图模式，特别是在Alpha波段：枕区百岁老人的PSD值低于年轻人和成年人，但不高于老年人，高于AD。这些有趣的结果表明，需要对百岁老人的大脑进行研究，以推断其特征，并试图复制其机制，以实现普遍的健康老龄化。

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引用次数: 0

Circulating microRNAs and cross sectional and longitudinal measurements of physical functioning and frailty: An explorative study in older twins 循环microrna和身体功能和虚弱的横断面和纵向测量：一项对大龄双胞胎的探索性研究。

IF 5.3 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-07-16 DOI: 10.1016/j.mad.2025.112099

Rossella La Grotta , Cecilie Agergaard Sørensen , Asmus Cosmos Skovgaard , Mikael Thinggaard , Serena Dato , Giuseppina Rose , Jonas Mengel-From , Mette Soerensen

During aging, physical functioning declines, and disability and frailty increase; phenotypes which are bidirectionally linked. MicroRNAs (miRNAs) are epigenetic regulators of various physiological processes and suggested aging biomarkers. Here we investigate the association between circulating plasma miRNAs and hand grip strength, chair stand, (Rockwood) frailty, and activity of daily living (ADL) in 86 monozygotic twins (73–88 years). In cross-sectional analysis, both individual and twin-pair level analyses were performed, the latter controlling genetic confounding. The majority (74–100 %) of miRNAs identified in the individual-level analysis were validated by twin-pair-level analysis, with 14 miRNAs showing significance (p < 0.05) in both. Longitudinal analysis (up to eight years of follow-up) yielded more significant results (75–93 miRNAs), indicating that miRNAs might be more accurate in predicting functional decline over time. Of these miRNAs, seven showed consistent directions of effects across phenotypes. For all analyses, most (65–79 %) of the observed effect sizes were negative, reflecting reduced functionality with increased miRNA levels. Enrichment analyses revealed pathways of gene expression (incl. p53- and FOXO-mediated transcription), signal transduction, the immune system, metabolism of RNA, among others. Of specific miRNAs, miR-1274a demonstrated negative association in both cross-sectional and longitudinal investigations of ADL. These findings support miRNAs as biomarkers of age-related functional decline.

随着年龄的增长，身体功能下降，残疾和虚弱增加；表现型是双向联系的。MicroRNAs （miRNAs）是多种生理过程的表观遗传调控因子和衰老生物标志物。在这里，我们研究了86对同卵双胞胎（73-88岁）的循环血浆mirna与手部握力、椅子站立、（Rockwood）虚弱和日常生活活动（ADL）之间的关系。在横断面分析中，进行了个体和双胞胎水平的分析，后者控制遗传混淆。大多数（74-100%）在个体水平分析中鉴定的mirna通过双对水平分析进行验证，其中14个mirna具有显著性(p

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引用次数: 0

Genome-wide RNAi analysis in adult Caenorhabditis elegans unveils genes controlling age-related fat accumulation 成年秀丽隐杆线虫全基因组RNAi分析揭示了控制年龄相关脂肪积累的基因。

IF 5.3 3区医学 Q2 CELL BIOLOGY

Mechanisms of Ageing and Development

Pub Date : 2025-07-03 DOI: 10.1016/j.mad.2025.112089

Chunxia Qin , Zicheng Liu , Duo Duan , Lianfeng Wu

Fat accumulation with aging occurs in adults across species, yet its underlying mechanisms remain poorly understood, partly due to limited number of studiesspecifically targeting adulthood. Here, we present the first genome-wide analysis of age-associated fat accumulation during adulthood in Caenorhabditis elegans. Unprecedently, our adult-specific RNAi screen identified a limited subset of genes influencing adult fat dynamics, contrasting with the extensive gene sets uncovered in prior developmental RNAi screens. This disparity suggests a unique genetic architecture governing age-related lipid deposition. Central to this network is the evolutionarily conserved transcription factor DAF-16/FoxO, which progressively accumulates in nuclei during aging. Genetic ablation of daf-16 abolished adult fat accumulation, while its adult-specific knockdown reduced adiposity without compromising healthspan or longevity, highlighting its therapeutic potential. Critically, knockdown of the top hits, pals-17 and rege-1, markedly attenuated the nuclear localization of DAF-16 and failed to reduce the adult fat content daf-16-deficient animals, establishing DAF-16 as their essential effector. Overall, our work uncouples developmental and adult lipid regulatory mechanisms and highlights potential targets for understanding and managing adult-onset obesity.

随着年龄的增长，脂肪积累在不同物种的成年人中都存在，但其机制仍然知之甚少，部分原因是专门针对成年人的研究有限。在这里，我们提出了秀丽隐杆线虫成年期年龄相关脂肪积累的第一个全基因组分析。前所未有的是，我们的成人特异性RNAi筛选鉴定了影响成人脂肪动力学的有限基因子集，与先前发育性RNAi筛选发现的广泛基因集形成对比。这种差异表明一种独特的遗传结构控制着与年龄相关的脂质沉积。这个网络的核心是进化上保守的转录因子DAF-16/FoxO，它在衰老过程中逐渐在细胞核中积累。基因消融daf-16可消除成人脂肪积累，而成人特异性敲除可减少肥胖，而不影响健康寿命或寿命，突出了其治疗潜力。至关重要的是，敲除顶端基因pal -17和rege-1显著减弱了DAF-16的核定位，但未能降低DAF-16缺陷动物的成年脂肪含量，这表明DAF-16是它们的主要效应物。总的来说，我们的工作将发育和成人脂质调节机制分开，并强调了理解和管理成人发病肥胖的潜在目标。

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引用次数: 0