Ageing Research Reviews最新文献_第2页

IF 12.4 1区医学 Q1 CELL BIOLOGY

Ageing Research Reviews

Pub Date : 2026-01-28 DOI: 10.1016/j.arr.2026.103039

Jarrod J. Kennedy , Patrick Bertolino , Sophie Lucic Fisher , Meng C. Ngu , Nicholas J. Hunt , Peter A.G. McCourt , Victoria C. Cogger , David G. Le Couteur

Ageing is associated with a dysregulated immune system that contributes to vulnerability in older adults to infection, malignancies, autoimmune diseases, and inflammatory disorders. This immune dysfunction can be categorised into two processes: progressive decline in immune responsiveness (immunosenescence) and chronic low-grade systemic inflammation (inflammaging). These processes perpetuate a cycle wherein persistent inflammation accelerates immune cell exhaustion and senescence, while diminished immune surveillance heightens inflammation, together promoting tissue damage and age-related disease. The liver, a crucial immune organ pivotal for maintaining systemic immune tolerance, assumes an increasingly prominent role in regulating peripheral immune tolerance as age-related thymic involution diminishes central tolerance. Ageing alters the liver's immune landscape, with diverse patterns of infiltration and structural remodelling marked by the emergence of ageing-related tertiary lymphoid-associated structures (ATLAS), enriched with focal clusters of inflammatory cells. These structures and associated fibrotic niches function as hubs for pro-inflammatory and pro-fibrotic signalling. Transcriptomic studies reveal consistent upregulation of inflammatory immune pathways and pro-inflammatory cytokines across the aged liver. Immune cells are dysregulated with liver macrophages shifting toward pro-inflammatory phenotypes, NK cells showing exhaustion with reduction in frequency and impaired senescent cell clearance. T and B cells accumulate exhausted phenotypes with expanding populations of senescence-associated T cells (SATs) and age-associated B cells (ABCs), respectively. Liver sinusoidal endothelial cells (LSECs) undergo pseudo-capillarization and defenestration, creating a physical barrier that impairs clearance of tissue-adjacent T cells by hepatocytes. Taken together, age-related immune changes in liver immune cells indicate that the liver plays a central role in systemic inflammation in old age.

衰老与免疫系统失调有关，免疫系统失调导致老年人易受感染、恶性肿瘤、自身免疫性疾病和炎症性疾病的影响。这种免疫功能障碍可分为两个过程：免疫反应性的进行性下降（免疫衰老）和慢性低度全身炎症（炎症）。这些过程延续了一个循环，其中持续的炎症加速了免疫细胞的衰竭和衰老，而免疫监控的减弱则加剧了炎症，共同促进了组织损伤和与年龄相关的疾病。肝脏是维持全身免疫耐受的关键免疫器官，随着年龄相关性胸腺退化降低中枢免疫耐受，肝脏在调节外周免疫耐受方面的作用越来越突出。衰老改变了肝脏的免疫景观，以出现与衰老相关的三级淋巴相关结构（ATLAS）为特征的浸润和结构重塑的不同模式，丰富了炎症细胞的局灶簇。这些结构和相关的纤维化小生境作为促炎和促纤维化信号传导的中枢。转录组学研究显示，炎症免疫途径和促炎细胞因子在老年肝脏中一致上调。免疫细胞失调，肝巨噬细胞向促炎表型转移，NK细胞表现出衰竭，频率减少，衰老细胞清除受损。T细胞和B细胞分别随着衰老相关T细胞（SATs）和衰老相关B细胞（abc）群体的扩大而积累耗尽表型。肝窦内皮细胞（LSECs）经历假毛细血管化和脱巢，形成物理屏障，损害肝细胞对组织邻近T细胞的清除。综上所述，肝脏免疫细胞中与年龄相关的免疫变化表明，肝脏在老年人的全身性炎症中起着核心作用。

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引用次数: 0

Targeting the Nrf2/HO-1 aixs: A therapeutic strategy against regulated cell death in Alzheimer’s disease 靶向Nrf2/HO-1通道：抗阿尔茨海默病调节细胞死亡的治疗策略

IF 12.4 1区医学 Q1 CELL BIOLOGY

Ageing Research Reviews

Pub Date : 2026-01-28 DOI: 10.1016/j.arr.2026.103035

Zhiji Wang , Wenxin Feng , Xiaohua Li , Xia Yun , Shuang Wu , Lida Du , Hongquan Wang

Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque deposition, neurofibrillary tangles of hyperphosphorylated tau protein, chronic neuroinflammation, and dysregulation of multiple regulated cell death pathways. Aging, as the primary risk factor for AD, is accompanied by the accumulation of oxidative stress, which serves as a pivotal contributor to AD pathogenesis and is intricately linked to the activation of diverse cell death modalities, including ferroptosis, pyroptosis, apoptosis, and autophagy-endoplasmic reticulum stress. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) acts as a master regulator of cellular redox homeostasis. By binding to the antioxidant response element (ARE), Nrf2 orchestrates the transcriptional activation of a cytoprotective gene network, including heme oxygenase-1 (HO-1). Activation of the Nrf2/HO-1 signaling axis not only enhances cellular antioxidant defenses but also critically regulates iron metabolism, suppresses inflammatory cascades, mitigates endoplasmic reticulum stress (ERS), and modulates autophagic and apoptotic processes. This review delineates the interplay between distinct cell death modalities in AD and their convergence with age-associated oxidative stress. It provides a comprehensive analysis of the neuroprotective mechanisms mediated by the Nrf2/HO-1 pathway in counteracting ferroptosis, pyroptosis, apoptosis and autophagic endoplasmic reticulum stress dysregulation. Furthermore, we discuss the therapeutic potential of pharmacologically targeting this pathway with various bioactive compounds, highlighting promising strategies for multi-targeted intervention in AD, particularly in the context of aging.

阿尔茨海默病（AD）是一种与年龄相关的进行性神经退行性疾病，其特征是淀粉样蛋白（Aβ）斑块沉积、tau蛋白过度磷酸化的神经原纤维缠结、慢性神经炎症和多种受调节的细胞死亡途径失调。衰老是阿尔茨海默病的主要危险因素，它伴随着氧化应激的积累，氧化应激是阿尔茨海默病发病的关键因素，并与多种细胞死亡方式的激活密切相关，包括铁亡、焦亡、凋亡和自噬-内质网应激。转录因子核因子-红细胞2相关因子2（Nrf2）是细胞氧化还原稳态的主要调控因子。通过与抗氧化反应元件（ARE）结合，Nrf2协调细胞保护基因网络的转录激活，包括血红素加氧酶-1（HO-1）。Nrf2/HO-1信号轴的激活不仅可以增强细胞的抗氧化防御能力，还可以调节铁代谢，抑制炎症级联反应，减轻内质网应激（ERS），调节自噬和凋亡过程。这篇综述描述了AD中不同细胞死亡模式之间的相互作用及其与年龄相关的氧化应激的趋同。全面分析了Nrf2/HO-1通路在抑制铁凋亡、焦亡、细胞凋亡和自噬内质网应激失调中的神经保护机制。此外，我们讨论了用各种生物活性化合物从药理学上靶向这一途径的治疗潜力，强调了多靶点干预AD的有希望的策略，特别是在衰老的背景下。

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引用次数: 0

Role of lysosomal morphology in aging and age-related diseases 溶酶体形态在衰老和年龄相关疾病中的作用。

IF 12.4 1区医学 Q1 CELL BIOLOGY

Ageing Research Reviews

Pub Date : 2026-01-23 DOI: 10.1016/j.arr.2026.103033

Huimin Liu, Haiqing Tang, Shanshan Pang

Lysosomes are responsible for clearing cellular waste and facilitating material recycling, thus playing a crucial role in maintaining cellular homeostasis and even in resisting the development of various diseases. Lysosomes are highly dynamic organelles. While typically exhibiting a vesicular morphology, lysosomes can remodel into tubular structures under specific conditions; this morphological plasticity underpins their functional complexity. Aging triggers significant lysosomal morphological remodeling and functional decline, contributing to the development of age-related diseases, notably neurodegenerative disorders. Although lysosomal function has been extensively studied in age-related diseases, the mechanisms driving aging-associated morphological alterations and their pathophysiological significance remain elusive. This review synthesizes current knowledge on the regulation of lysosomal morphology and its changes and functions during aging and in age-related diseases. We propose that altered lysosomal morphology represents not merely a hallmark of aging, but also a significant determinant of lysosomal and cellular functions during aging. Targeting lysosomal morphology holds promise as an emerging strategy for counteracting functional deterioration in aged lysosomes and mitigating associated disease pathogenesis.

溶酶体负责清除细胞废物和促进物质循环，因此在维持细胞稳态甚至抵抗各种疾病的发展中起着至关重要的作用。溶酶体是高度动态的细胞器。虽然溶酶体通常表现为囊泡形态，但在特定条件下，溶酶体可以重塑成管状结构；这种形态的可塑性支撑了它们功能的复杂性。衰老引发显著的溶酶体形态重塑和功能下降，促进年龄相关疾病的发展，特别是神经退行性疾病。尽管溶酶体功能在年龄相关疾病中已被广泛研究，但驱动衰老相关形态学改变的机制及其病理生理意义仍然难以捉摸。本文综述了溶酶体形态的调控及其在衰老和年龄相关疾病中的变化和功能。我们认为，溶酶体形态的改变不仅是衰老的标志，也是衰老过程中溶酶体和细胞功能的重要决定因素。靶向溶酶体形态有望成为对抗衰老溶酶体功能恶化和减轻相关疾病发病机制的新兴策略。

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引用次数: 0

Oligodendrocytes at the crossroads: Central players and interactive partners in white matter aging 十字路口的少突胶质细胞：白质老化的核心参与者和互动伙伴。

IF 12.4 1区医学 Q1 CELL BIOLOGY

Ageing Research Reviews

Pub Date : 2026-01-23 DOI: 10.1016/j.arr.2026.103034

Xinxin Zhang , Peiyao Yu , Yicheng Chen , Yanzhi Xu , Ruofei Xu , Xinyu Yang , Shichao Lv , Hongcai Shang , Yue Hu

White matter degeneration in aging drives cognitive and motor decline. Oligodendrocytes (OLs) and their precursors are central to this process. Their intrinsic aging, marked by differentiation failure, metabolic and mitochondrial deficits, and transcriptional epigenetic dysregulation, causes myelin thinning and axonal support loss. Degeneration is amplified by dysfunctional crosstalk: microglia clear debris poorly and turn inflammatory; astrocytes disrupt lipid balance and secrete inflammatory signals; vascular defects impair metabolic supply; and T cell infiltration injures OLs. We review therapies targeting OL lineage, glial networks, vascular health, and lifestyle. Positioning OLs as integrative hubs of white matter integrity offers new strategies to maintain brain function during aging.

衰老过程中的白质退化导致认知和运动能力下降。少突胶质细胞（OLs）及其前体是这一过程的核心。它们的内在衰老，以分化失败、代谢和线粒体缺陷以及转录表观遗传失调为特征，导致髓磷脂变薄和轴突支持丧失。功能失调的串扰放大了变性：小胶质细胞难以清除碎片并转为炎症；星形胶质细胞破坏脂质平衡并分泌炎症信号；血管缺损损害代谢供应；T细胞浸润损伤ol。我们回顾了针对OL谱系、神经胶质网络、血管健康和生活方式的治疗方法。将ol定位为白质完整性的综合枢纽提供了在衰老过程中维持大脑功能的新策略。

引用次数: 0

exBAClock: A comprehensive database of published clocks for age quantification and age-related diseases exBAClock：年龄量化和年龄相关疾病出版时钟的综合数据库

IF 12.4 1区医学 Q1 CELL BIOLOGY

Ageing Research Reviews

Pub Date : 2026-01-22 DOI: 10.1016/j.arr.2026.103031

Anastasiya Kobelyatskaya , Anastasiya Novoselova , Ksenia Bylinskaya , Nikolai Nemirovich-Danchenko , Mikhail Ivanchenko , Claudio Franceschi , Alexey Moskalev

Biological age, as opposed to chronological age, quantifies the body's functional state and rate of aging. Despite the absence of a universal formula for its determination, panels of biomarkers that change consistently with age are used to construct predictive aging clocks. These models enable the identification of accelerated aging and are valuable as surrogate endpoints in clinical trials. The proliferation of published aging clocks has created a challenge: data is fragmented across numerous publications, making manual extraction and analysis highly labor-intensive. To consolidate this information, we present exBAClock, a comprehensive, web-based database for exploring aging clocks (https://akob.shinyapps.io/exbaclock/). exBAClock integrates multiple functional modules, featuring structured tables on clocks (over 100 formulas from 95 publications), their predictors, and their associations with diseases, mortality, lifestyle, and clinical trials (about 270 more articles).

与实足年龄相反，生物年龄量化了身体的功能状态和衰老速度。尽管没有一个通用的公式来确定它，但随着年龄的变化而变化的生物标志物小组被用来构建预测衰老时钟。这些模型能够识别加速衰老，并且在临床试验中作为替代终点是有价值的。已发表的老化时钟的激增带来了一个挑战：数据分散在众多出版物中，使得人工提取和分析变得非常劳动密集型。为了巩固这一信息，我们提出了exBAClock，一个全面的，基于网络的数据库，用于探索老化时钟（https://akob.shinyapps.io/exbaclock/）。exBAClock集成了多个功能模块，具有结构化时钟表（来自95个出版物的100多个公式），它们的预测因子，以及它们与疾病，死亡率，生活方式和临床试验的关联（约270多篇文章）。

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引用次数: 0

The m⁶A epitranscriptome: A regulatory nexus linking cellular senescence and oncogenesis 细胞衰老与肿瘤发生之间的调控关系。

IF 12.4 1区医学 Q1 CELL BIOLOGY

Ageing Research Reviews

Pub Date : 2026-01-22 DOI: 10.1016/j.arr.2026.103032

Yao Xu , Xin Zhou , Xiaoling Su , Wenxi Xie , Zhijie Huang , Shan Yu , Jinghua Tan , Jun He , Ji Zhang

N⁶-methyladenosine (m⁶A) orchestrates RNA fate decisions through a dynamic interplay of writers, erasers, and readers, modulating splicing, stability, and translation. This review unveils how m⁶A fine-tunes senescence-associated pathways (p53/p21, p16-RB) with cancer-context-dependent duality-either as a tumor suppressor or promoter of progression/resistance. Leveraging single-cell and spatial omics, we dissect m⁶A’s spatiotemporal heterogeneity in tumor-immune ecosystems. We consolidate diagnostic/prognostic biomarker advances and critically evaluate emerging therapeutics (small-molecule inhibitors, allosteric modulators, nanodelivery systems), addressing clinical barriers like selectivity and safety. Finally, we propose precision strategies targeting m⁶A-senescence networks for combined anti-cancer/anti-aging interventions.

N⁶-甲基腺苷（m⁶A）通过写入者、擦除者和读取者的动态相互作用，调节剪接、稳定性和翻译，协调RNA命运的决定。这篇综述揭示了m26 A如何微调衰老相关通路（p53/p21, p16-RB）与癌症背景依赖性的二元性，无论是作为肿瘤抑制因子还是作为进展/耐药的促进因子。利用单细胞和空间组学，我们剖析了肿瘤免疫生态系统中m 26 A的时空异质性。我们整合诊断/预后生物标志物的进展，并严格评估新兴治疗方法（小分子抑制剂、变张力调节剂、纳米递送系统），解决临床障碍，如选择性和安全性。最后，我们提出了针对m26 -a -衰老网络的精确策略，用于联合抗癌/抗衰老干预。

引用次数: 0

Exercise and the hallmarks of cardiovascular aging 运动和心血管老化的标志。

IF 12.4 1区医学 Q1 CELL BIOLOGY

Ageing Research Reviews

Pub Date : 2026-01-22 DOI: 10.1016/j.arr.2026.103030

Dan Zhong , Benjamin Fernández-García , Priyanka Gokulnath , Kexin Lin , Guoping Li , Guido Kroemer , Carlos López-Otín , Junjie Xiao

Cardiovascular diseases (CVDs), including hypertension, heart failure, atherosclerosis and myocardial infarction, remain the leading cause of morbidity and mortality worldwide. Aging is a predominant risk factor for CVD. Cardiovascular aging is characterized by progressive structural changes at the cellular level and functional decline within the cardiovascular system, ultimately contributing to the onset and progression of CVD. These changes include alterations in left ventricular (LV) systolic and diastolic function, an increased incidence of sinus node dysfunction, myocardial hypertrophy, arterial stiffness, and fibrosis. Therefore, understanding the molecular mechanisms underlying cardiovascular aging and identifying interventions that can slow or mitigate its progression holds significant promise for CVD prevention and treatment. Numerous epidemiological and experimental studies have consistently demonstrated that physical activity or exercise training exerts protective effects against cardiovascular aging. However, the molecular mediators and underlying mechanisms of these benefits are not completely understood. Therefore, further investigation is warranted to elucidate these mechanisms, given their potential as novel therapeutic targets. In this review, we comprehensively synthesize molecular, preclinical, clinical, and epidemiological evidence to underscore the positive effects of exercise on cardiovascular aging. This review systematically investigates how exercise modulates the key biological hallmarks of cardiovascular aging, including deterioration of protein homeostasis (proteostasis), genomic instability, epigenetic disturbances, mitochondrial dysfunction, cellular senescence, chronic inflammation, and dysregulated neurohormonal signaling. The mechanistic insights of exercise-induced adaptations presented in this review may provide a valuable foundation for future investigations, paving the design of tailored exercise regimens aimed at mitigating the progression of cardiovascular aging.

心血管疾病（cvd），包括高血压、心力衰竭、动脉粥样硬化和心肌梗死，仍然是全世界发病率和死亡率的主要原因。衰老是心血管疾病的主要危险因素。心血管衰老的特征是细胞水平的进行性结构改变和心血管系统功能下降，最终导致心血管疾病的发生和发展。这些变化包括左心室收缩和舒张功能的改变，窦房结功能障碍的发生率增加，心肌肥大，动脉僵硬和纤维化。因此，了解心血管老化的分子机制，并确定可以减缓或减轻其进展的干预措施，对心血管疾病的预防和治疗具有重要意义。大量流行病学和实验研究一致表明，体育活动或运动训练对心血管衰老具有保护作用。然而，这些益处的分子介质和潜在机制尚不完全清楚。因此，考虑到它们作为新的治疗靶点的潜力，有必要进一步研究以阐明这些机制。在这篇综述中，我们综合了分子、临床前、临床和流行病学证据来强调运动对心血管衰老的积极作用。这篇综述系统地研究了运动如何调节心血管衰老的关键生物学标志，包括蛋白质稳态（proteostasis）的恶化、基因组不稳定、表观遗传干扰、线粒体功能障碍、细胞衰老、慢性炎症和神经激素信号失调。本综述中提出的运动诱导适应的机制见解可能为未来的研究提供有价值的基础，为设计量身定制的运动方案铺平道路，旨在减缓心血管衰老的进展。

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引用次数: 0

Evaluating senescence-targeted approaches in Alzheimer’s Disease: What we know and what lies ahead 评估阿尔茨海默病的衰老靶向方法：我们所知道的和未来的方向。

IF 12.4 1区医学 Q1 CELL BIOLOGY

Ageing Research Reviews

Pub Date : 2026-01-19 DOI: 10.1016/j.arr.2026.103029

Pratik Prashant Doshi , Sakshee Hemant Desale , Aarti Ashok Khutale , Sarvesh Sabarathinam , Swathi Suresh

Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disease, which represents the most prevalent dementia worldwide. Although amyloid-β (Aβ) and tau pathology have been the classic focus of treatment, accumulating evidence indicates that ageing-associated cellular senescence plays a central role in AD pathogenesis. Senescent neurons, astrocytes, microglia and endothelial cells accumulate in the ageing and Alzheimer’s brain and adopt a senescence-associated secretory phenotype characterized by sustained release of pro-inflammatory and neurotoxic factors. This chronic inflammatory milieu promotes neurodegeneration, disrupts the synaptic activity and is involved in cognitive deficit. Senolytics, which selectively eliminate senescent cells, have demonstrated benefit in multiple preclinical models of AD, including decreased neuroinflammation, improvement in neuronal function and cognitive performance. Several senolytic agents, such as dasatinib, quercetin, fisetin and navitoclax, hit anti-apoptotic modalities that support the survival of senescent cells. Early-phase human studies suggest the feasibility of senescence-targeted interventions and indicate that senescence-associated molecular changes may compromise blood–brain barrier integrity. Consistently, preclinical studies demonstrate partial restoration of barrier function following senolytic therapy; however, clinical translation remains limited and at an early stage. Major challenges include the identification of senolytic agents with effective central nervous system penetration, the determination of optimal dosing regimens and treatment schedules, generation of robust long-term safety profile in human population, and the development of predictive biomarkers to guide patient selection and clinical study design. As senolytics and senomorphic strategies continue to evolve, they hold promise as complementary approaches to existing anti-amyloid and anti-tau therapies by offering a multi-mechanistic approach toward AD modification. This review synthesizes current evidence on cellular senescence in AD, outlines the mechanistic rationale for senescence-targeted therapies, summarizes available clinical data, while providing future directions for integrating senolytics into AD management.

阿尔茨海默病（AD）是一种进行性和不可逆的神经退行性疾病，是世界上最常见的痴呆症。尽管淀粉样蛋白-β (a β)和tau病理一直是治疗的经典焦点，但越来越多的证据表明，衰老相关的细胞衰老在AD的发病机制中起着核心作用。衰老的神经元、星形胶质细胞、小胶质细胞和内皮细胞在衰老和阿尔茨海默病的大脑中积累，并采取衰老相关的分泌表型，其特征是促炎因子和神经毒性因子的持续释放。这种慢性炎症环境促进神经退行性变，破坏突触活动，并与认知缺陷有关。抗衰老药物选择性地消除衰老细胞，已在多种阿尔茨海默病的临床前模型中显示出益处，包括减少神经炎症，改善神经元功能和认知表现。一些抗衰老药物，如达沙替尼、槲皮素、非西汀和纳维托克，可以发挥抗凋亡作用，支持衰老细胞的存活。早期人体研究表明，针对衰老的干预措施是可行的，并表明衰老相关的分子变化可能会损害血脑屏障的完整性。一致地，临床前研究表明，在抗衰老治疗后，屏障功能部分恢复；然而，临床翻译仍然有限，处于早期阶段。主要的挑战包括识别有效穿透中枢神经系统的抗衰老药物，确定最佳的给药方案和治疗方案，在人群中产生强大的长期安全性，以及开发预测性生物标志物来指导患者选择和临床研究设计。随着senolytics和同形策略的不断发展，它们有望作为现有抗淀粉样蛋白和抗tau治疗的补充方法，为AD的修饰提供多机制的方法。本文综述了目前关于阿尔茨海默病细胞衰老的证据，概述了衰老靶向治疗的机制原理，总结了现有的临床数据，同时提供了将衰老药物整合到阿尔茨海默病治疗中的未来方向。

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引用次数: 0

Proteolysis-targeting chimera (PROTAC): A promising senolytic strategy 靶向蛋白水解嵌合体（PROTAC）：一种有前途的抗衰老策略。

IF 12.4 1区医学 Q1 CELL BIOLOGY

Ageing Research Reviews

Pub Date : 2026-01-18 DOI: 10.1016/j.arr.2026.103027

Gang Fan , Qingping Zhang , Weiming Guo , Miao Liu , Dong Tan , Zhihan Tang , Jing Yang

Senescent cells (SCs) accumulate with aging and contribute to the development of age-related pathologies. These cells evade apoptosis through upregulation of senescent cell anti-apoptotic pathways (SCAPs), making their selective elimination, a strategy termed senolysis, a promising therapeutic avenue. Proteolysis-targeting chimeras (PROTACs) represent an emerging class of bifunctional molecules that exploit the ubiquitin-proteasome system to degrade specific target proteins. By concurrently binding to a protein of interest and an E3 ubiquitin ligase, PROTACs catalyze the degradation of SCAP components, offering a novel pharmacological approach to clear SCs. This review summarizes the principles and recent advances in PROTAC technology, with a focus on its application as a senolytic strategy. We highlight how PROTACs can overcome limitations of conventional inhibitors, such as targeting “undruggable” SCAP proteins, and provide a comparative analysis of major PROTAC classes targeting BCL-2 family members, p53, BRD4, SA-β-gal, and other emerging senescence regulators. Furthermore, we also discuss the aging-specific biological and translational challenges, including altered proteasomal activity, pharmacokinetics, tissue microenvironment, and immune clearance, which must be addressed to advance PROTAC senolytics toward clinical use in age-related diseases.

衰老细胞（SCs）随着年龄的增长而积累，并有助于年龄相关病理的发展。这些细胞通过上调衰老细胞抗凋亡通路（SCAPs）逃避凋亡，使其选择性消除，一种称为senolysis的策略，是一种有前途的治疗途径。靶向蛋白水解嵌合体（Proteolysis-targeting chimeras, PROTACs）是一类新兴的双功能分子，它们利用泛素-蛋白酶体系统来降解特定的靶蛋白。通过同时结合感兴趣的蛋白和E3泛素连接酶，PROTACs催化SCAP成分的降解，为清除sc提供了一种新的药理方法。本文综述了PROTAC技术的原理和最新进展，重点介绍了其作为一种抗衰老策略的应用。我们强调了PROTAC如何克服传统抑制剂的局限性，例如靶向“不可药物”的SCAP蛋白，并提供了针对BCL-2家族成员、p53、BRD4、SA-β-gal和其他新兴衰老调节因子的主要PROTAC类的比较分析。此外，我们还讨论了衰老特异性的生物学和翻译挑战，包括改变的蛋白酶体活性、药代动力学、组织微环境和免疫清除，必须解决这些问题，以推进PROTAC抗衰老药物在年龄相关疾病的临床应用。

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引用次数: 0

Decoding synaptic imbalance in neurodegenerative diseases: From pathological analysis to targeted intervention 神经退行性疾病突触失衡的解码：从病理分析到针对性干预。

IF 12.4 1区医学 Q1 CELL BIOLOGY

Ageing Research Reviews

Pub Date : 2026-01-16 DOI: 10.1016/j.arr.2026.103028

Xiong Li , Rui Wan , Yang Zhao , Yumeng Wu, Xuehua Chen, Qianqian Li, Chengliang Luo

Synapses serve as the central functional components mediating information transmission, integration, and storage within the central nervous system (CNS). Their functionality depends on the synergistic interplay of the presynaptic membrane, synaptic cleft, and postsynaptic membrane–three structures that collectively sustain neurotransmitter secretion, postsynaptic signaling, and synaptic plasticity. Of note, synaptic impairment represents an early, shared pathological hallmark across aging and age-related neurodegenerative disorders like Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic lateral sclerosis (ALS). This damage emerges prior to the demise of neuronal cell bodies and the manifestation of clinical symptoms, with its location and severity directly shaping disease phenotypes. Importantly, such synaptic dysfunction is closely linked to the pathological proteins specific to each disorder. This review comprehensively synthesizes current research advances regarding synaptic impairment in age-related neurodegenerative diseases. It elaborates on the location-specific pathological features of synaptic damage in AD, PD, HD, and ALS, with particular emphasis on their associations with disease-related pathological markers. Additionally, the work unpacks five core mechanisms driving synaptic dysfunction: the toxic effects of pathological proteins, dysregulated synaptic protein homeostasis, excitotoxicity coupled with disrupted calcium balance, oxidative stress and inflammatory responses, and deficiencies in neurotrophic factors. Ultimately, it summarizes potential biomarkers and targeted intervention strategies, aiming to provide a systematic reference for mechanistic investigations, early diagnosis, and clinical management of neurodegenerative diseases.

突触是中枢神经系统（CNS）中介导信息传递、整合和存储的中枢功能成分。它们的功能依赖于突触前膜、突触间隙和突触后膜的协同相互作用，这三种结构共同维持神经递质分泌、突触后信号传导和突触可塑性。值得注意的是，突触损伤是衰老和与年龄相关的神经退行性疾病（如阿尔茨海默病（AD）、帕金森病（PD）、亨廷顿病（HD）和肌萎缩性侧索硬化症（ALS））的早期共同病理标志。这种损伤出现在神经元细胞体死亡和临床症状出现之前，其位置和严重程度直接决定了疾病的表型。重要的是，这种突触功能障碍与每种疾病特有的病理蛋白密切相关。本文综述了与年龄相关的神经退行性疾病中突触损伤的最新研究进展。它详细阐述了AD、PD、HD和ALS的突触损伤的位置特异性病理特征，特别强调了它们与疾病相关病理标志物的关联。此外，这项工作揭示了驱动突触功能障碍的五个核心机制：病理蛋白的毒性作用，突触蛋白稳态失调，兴奋毒性与钙平衡破坏相结合，氧化应激和炎症反应，以及神经营养因子缺乏。最后，总结潜在的生物标志物和靶向干预策略，旨在为神经退行性疾病的机制调查、早期诊断和临床管理提供系统的参考。

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引用次数: 0