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CDK3 drives neuron loss in Alzheimer’s disease CDK3驱动阿尔茨海默病的神经元损失。
IF 19.4 Q1 CELL BIOLOGY Pub Date : 2026-01-12 DOI: 10.1038/s43587-026-01065-7
We generated a mouse model of Alzheimer’s disease (AD) that replicates neuronal loss seen in patients, which overcomes a key barrier in the field. By reinstating the function of cyclin-dependent kinase 3 (CDK3), the model reliably exhibits human-like neurodegeneration, which opens a direct path towards evaluating CDK3 as a therapeutic target.
我们建立了一个阿尔茨海默病(AD)的小鼠模型,该模型复制了在患者中看到的神经元丢失,这克服了该领域的一个关键障碍。通过恢复细胞周期蛋白依赖性激酶3 (CDK3)的功能,该模型可靠地表现出类似人类的神经变性,这为评估CDK3作为治疗靶点开辟了直接途径。
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引用次数: 0
Senotoxins target senescence via lipid binding specificity, ion imbalance and lipidome remodeling. Senotoxins通过脂质结合特异性,离子失衡和脂质组重塑靶向衰老。
IF 19.4 Q1 CELL BIOLOGY Pub Date : 2026-01-12 DOI: 10.1038/s43587-025-01030-w
Javier Moral-Sanz, Isabel Fernández-Carrasco, Valentina Ramponi, Amanda Garrido, Izhar Karbat, Pablo Cabezas-Sainz, Esperanza Rivera-de-Torre, Osama Elsallabi, Roberto Martín-Hernández, José L López-Aceituno, Nathan L Price, Laura Sanchez, Gonzalo Colmenarejo, Álvaro Martínez-Del-Pozo, Irina Vetter, Angel Cogolludo, Francisco Perez-Vizcaino, Jorge Del-Pozo, Eitan Reuveny, Manuel A Fernández-Rojo, Paul D Robbins, Rafael de Cabo, Manuel Serrano, Maria P Ikonomopoulou

Senescence is a driver of aging and a barrier to tumor progression, but its persistent accumulation drives inflammation and relapse. Thus, the success of chemotherapy could be jeopardized when senescence emerges in the tumor microenvironment. Here we identified the senolytic properties of a pore-forming toxin, sticholysin I (StnI). StnI and our engineered improved form, StnIG, selectively hampers viability of chemotherapy-induced senescent cancer cells, as well as senescent primary cells. We show that its selectivity is mediated by specific binding and lipid ratios associated with senescence, including compromised membrane bilayer asymmetry. Mechanistically, StnIG triggers sodium and calcium influx and an enduring potassium efflux in senescent cells. Calcium triggers the opening of calcium-activated potassium channels, leading to cell death by apoptosis and pyroptosis. Finally we show that StnIG synergizes with senescence-inducing chemotherapy to drive remission of solid tumors in mice. Our findings define StnI and StnIG as senotoxins with translational potential for cancer therapy.

衰老是衰老的驱动因素和肿瘤进展的屏障,但它的持续积累会导致炎症和复发。因此,当肿瘤微环境中出现衰老时,化疗的成功可能会受到损害。在这里,我们确定了一种成孔毒素,sticholysin I (StnI)的衰老特性。StnI和我们的工程改进形式StnIG,选择性地阻碍化疗诱导的衰老癌细胞和衰老原代细胞的生存能力。我们发现它的选择性是由与衰老相关的特异性结合和脂质比率介导的,包括受损的膜双层不对称性。从机制上讲,StnIG在衰老细胞中触发钠和钙的流入以及持久的钾的流出。钙触发钙活化钾通道的打开,导致细胞凋亡和焦亡。最后,我们发现StnIG与诱导衰老的化疗协同作用可驱动小鼠实体瘤的缓解。我们的研究结果将StnI和StnIG定义为具有癌症治疗转化潜力的sentoxins。
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引用次数: 0
Evaluating music interventions to treat depression in people living with dementia 评估音乐干预对痴呆症患者抑郁症的治疗效果。
IF 19.4 Q1 CELL BIOLOGY Pub Date : 2026-01-09 DOI: 10.1038/s43587-025-01055-1
Hannah Walters
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引用次数: 0
Socioeconomic reforms are needed to address disparities for the aging rural-to-urban migrant workforce in China. 中国需要进行社会经济改革,以解决农村向城市流动劳动力老龄化的差距问题。
IF 19.4 Q1 CELL BIOLOGY Pub Date : 2026-01-09 DOI: 10.1038/s43587-025-01051-5
Huaxiong Jiang
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引用次数: 0
Author Correction: Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial. 作者更正:线粒体自噬诱导剂尿素A对年龄相关免疫衰退的影响:一项随机、安慰剂对照试验。
IF 19.4 Q1 CELL BIOLOGY Pub Date : 2026-01-05 DOI: 10.1038/s43587-025-01060-4
Dominic Denk, Anurag Singh, Herbert G Kasler, Davide D'Amico, Julia Rey, Lucía Alcober-Boquet, Johanna M Gorol, Christoph Steup, Ritesh Tiwari, Ryan Kwok, Rafael J Argüello, Julie Faitg, Kathrin Sprinzl, Stefan Zeuzem, Valentina Nekljudova, Sibylle Loibl, Eric Verdin, Chris Rinsch, Florian R Greten
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引用次数: 0
Brain neuron-derived WDFY1 induces bone loss. 脑神经元源性WDFY1诱导骨质流失。
IF 19.4 Q1 CELL BIOLOGY Pub Date : 2026-01-05 DOI: 10.1038/s43587-025-01032-8
Chun-Yuan Chen, Zun Wang, Chun-Gu Hong, Yi-Juan Tan, Yan-Xin Duan, Yi Luo, Xin Wang, Hai-Jin Zeng, Jing-Yao Luo, Teng-Fei Wan, Hao Yin, Xi-Xi Liu, Hao Zhu, Yong Zhou, Zheng-Guang Wang, Ze-Hui He, Xin-Yue Hu, Guo-Wen Hu, Hai-Li Lang, Zhen-Xing Wang, Jia Cao, Shan-Shan Rao, Hui Xie

Brain health is closely linked to bone homeostasis. Skeletal aging is characterized by inadequate bone formation and marrow adiposity, but whether the brain contributes to this imbalance remains unknown. This study shows that aged brain neurons, mainly those in the hippocampus and cerebral cortex, produce excess WD repeat and FYVE domain containing 1 (WDFY1) protein and transfer it to the bone via extracellular vesicles (EVs), leading to bone-fat imbalance and osteoporosis. Increasing brain Wdfy1 expression causes premature skeletal aging. Conversely, suppressing Wdfy1 in the whole brain, hippocampus or neurons, genetically deleting neuronal Wdfy1, and selectively inhibiting neuronal EV release all improve bone health. Mechanistically, WDFY1 binds to the retromer complex to promote the endosome-to-Golgi recycling of cathepsin D and peroxiredoxin 2, thus inhibiting osteogenesis and augmenting adipogenesis. This study identifies the role of aged brain neuronal EVs as an important messenger in triggering bone-fat imbalance by transferring WDFY1 to bone.

大脑健康与骨骼稳态密切相关。骨骼老化的特征是骨骼形成不足和骨髓肥胖,但大脑是否有助于这种不平衡仍然未知。本研究表明,老化的大脑神经元,主要是海马和大脑皮层的神经元,产生过量的WD重复和含有1的FYVE结构域(WDFY1)蛋白,并通过细胞外囊泡(EVs)将其转移到骨骼中,导致骨脂失衡和骨质疏松。大脑Wdfy1表达增加导致骨骼过早老化。相反,抑制全脑、海马或神经元中的Wdfy1,基因删除神经元Wdfy1,选择性抑制神经元EV释放,都能改善骨骼健康。机制上,WDFY1与逆转录复合物结合,促进组织蛋白酶D和过氧化物还氧蛋白2的内体到高尔基体的再循环,从而抑制成骨和增加脂肪生成。本研究确定了衰老的脑神经元ev通过将WDFY1转移到骨骼中,作为触发骨脂失衡的重要信使的作用。
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引用次数: 0
Rejuvenating the aging gut by targeting senescence 通过靶向衰老使衰老的肠道恢复活力。
IF 19.4 Q1 CELL BIOLOGY Pub Date : 2026-01-02 DOI: 10.1038/s43587-025-01045-3
Marina Kolesnichenko
Aging erodes the regenerative capacity of the gut, which weakens barrier function and repair. Eskiocak, Gewolb, Shah, Rouse, Chowdhury and colleagues show that senescent epithelial cells accumulate and drive this decline. Selective elimination of cells that express the senescence-associated surface marker uPAR using senolytic chimeric antigen receptor T cells restores stem cell function and rejuvenates the aged mouse gut.
衰老会侵蚀肠道的再生能力,从而削弱屏障功能和修复能力。Eskiocak, Gewolb, Shah, Rouse, Chowdhury和他们的同事表明,衰老的上皮细胞积累并推动了这种衰退。使用抗衰老嵌合抗原受体T细胞选择性消除表达衰老相关表面标记物uPAR的细胞可恢复干细胞功能并使衰老小鼠肠道恢复活力。
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引用次数: 0
Squishing, squeezing and stretching age hematopoietic stem cells 挤压、挤压和拉伸使造血干细胞衰老。
IF 19.4 Q1 CELL BIOLOGY Pub Date : 2026-01-02 DOI: 10.1038/s43587-025-01044-4
Chih-Ling Wang, Mary Mohrin
Two recent studies, from Shang et al. and Mejía-Ramírez et al., identify complementary mechanical mechanisms that regulate hematopoietic stem cell aging: external shear stress and internal nuclear envelope tension. These forces represent an evolutionary tradeoff between immediate immune defense and long-term stem cell maintenance.
最近来自Shang等人和Mejía-Ramírez等人的两项研究发现了调节造血干细胞衰老的互补机械机制:外部剪切应力和内部核膜张力。这些力量代表了即时免疫防御和长期干细胞维护之间的进化权衡。
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引用次数: 0
Shear stress governs hematopoietic stem cell fate to promote inflammation-induced aging 剪切应力控制造血干细胞的命运,促进炎症诱导的衰老。
IF 19.4 Q1 CELL BIOLOGY Pub Date : 2026-01-02 DOI: 10.1038/s43587-025-01039-1
Tongyao Shang, Li Zhao, Shibo Ying, Lida Su, Yue Yang, Jiadong Liu, Yingying Wang, Jipeng Xue, Cheng Cheng, Yixin Wu, Shiyao Chen, Hongmei Dong, Xuequn Chen, Hailin Ma, Qi Zhang, Tingbo Liang, Wei Yang, Ye Feng, Marong Fang, Xinjiang Lu
Hematopoietic stem cells (HSCs) reside in the bone marrow in a quiescent state, but can be mobilized into the blood in response to inflammation, cytokine stimulation, nervous activity or hypoxia. Chronic inflammation, a hallmark of aging, accelerates HSC aging by promoting myeloid-biased differentiation and reducing self-renewal capacity, yet the role of mechanical stimulation in regulating these processes remains poorly understood. Here, we found that PIEZO1 senses shear stress in blood flow to induce HSC proliferation and myelopoiesis. We show that shear stress induces PIEZO1-mediated ion currents and Ca2+ influx in both mouse and human HSCs, with downstream effects on proliferation and myeloid differentiation mediated via JAM3 and CAPN2 pathways. GsMTx4, a PIEZO1 antagonist, attenuated inflammation-induced aging in mice by inhibiting HSC activation. These findings link the mechanical sensor PIEZO1 to HSC proliferation and myeloid differentiation via multi-tiered signaling, highlighting its role in accelerating inflammation-induced aging. Shang, Zhao, Ying and colleagues report that the mechanosensor PIEZO1 senses blood shear stress in hematopoietic stem cells, driving proliferation and myeloid bias. This axis links mechanical force to inflammation-induced aging, and PIEZO1 emerges as a potential therapeutic target.
造血干细胞(Hematopoietic stem cells, hsc)以静止状态存在于骨髓中,但在炎症、细胞因子刺激、神经活动或缺氧的反应下,可以被动员到血液中。慢性炎症是衰老的标志,通过促进髓细胞偏向分化和降低自我更新能力来加速HSC衰老,然而机械刺激在调节这些过程中的作用仍然知之甚少。在这里,我们发现PIEZO1感知血流中的剪切应力,从而诱导HSC增殖和骨髓形成。我们发现剪切应力在小鼠和人造血干细胞中诱导piezo1介导的离子电流和Ca2+内流,并通过JAM3和CAPN2途径介导增殖和骨髓分化的下游影响。GsMTx4是一种PIEZO1拮抗剂,通过抑制HSC激活来减轻小鼠炎症诱导的衰老。这些发现将机械传感器PIEZO1通过多层信号传导与HSC增殖和髓细胞分化联系起来,突出了其在加速炎症诱导衰老中的作用。
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引用次数: 0
Linking single-cell multiomics with GWAS to reveal key regulators of disease risk 将单细胞多组学与GWAS联系起来,揭示疾病风险的关键调节因子。
IF 19.4 Q1 CELL BIOLOGY Pub Date : 2026-01-02 DOI: 10.1038/s43587-025-01047-1
We developed scMORE (single-cell multiomics regulon enrichment), a computational framework that integrates single-cell multiomics with genome-wide association study summary statistics to identify transcription factor–chromatin–gene regulatory networks (eRegulons) that underlie complex diseases. Applying scMORE to 31 traits (including Parkinson’s disease), we investigated immune- and aging-associated eRegulons, and revealed how genetic variants shape cell-type-specific regulatory programs.
我们开发了scMORE(单细胞多组学调控富集),这是一个将单细胞多组学与全基因组关联研究汇总统计相结合的计算框架,用于鉴定复杂疾病背后的转录因子-染色质-基因调控网络(eRegulons)。将scMORE应用于31个特征(包括帕金森病),我们研究了免疫和衰老相关的eRegulons,并揭示了遗传变异如何塑造细胞类型特异性调控程序。
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期刊
Nature aging
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