Ageing Research Reviews最新文献

{"title":"Targeting the Nrf2/HO-1 aixs: A therapeutic strategy against regulated cell death in Alzheimer’s disease","authors":"Zhiji Wang ,&nbsp;Wenxin Feng ,&nbsp;Xiaohua Li ,&nbsp;Xia Yun ,&nbsp;Shuang Wu ,&nbsp;Lida Du ,&nbsp;Hongquan Wang","doi":"10.1016/j.arr.2026.103035","DOIUrl":"10.1016/j.arr.2026.103035","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"116 ","pages":"Article 103035"},"PeriodicalIF":12.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146095213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fanconi anaemia as a human model of accelerated epigenetic and immune ageing","authors":"Eunike Velleuer ,&nbsp;Carsten Carlberg","doi":"10.1016/j.arr.2026.103038","DOIUrl":"10.1016/j.arr.2026.103038","url":null,"abstract":"<div><div>Fanconi anaemia (FA) is a DNA-repair disorder that compresses multiple hallmarks of ageing into childhood and early adulthood. Persistent genomic instability in FA precipitates oxidative stress, inflammatory remodelling, and metabolic reprogramming, which together erode epigenetic integrity and immune competence. Here we provide evidence FA-specific DNA-repair failure is linked to mitochondrial metabolism, nutrient-sensing networks, and immune dysfunction. In this context, we discuss how these interactions accelerate epigenetic drift and cancer susceptibility. We propose FA as a human “time-lapse” model to separate the sequence and interdependence of selected ageing hallmarks, such as genome instability, epigenetic deregulation, stem cell exhaustion, and immunosenescence, which together contribute to a markedly increased risk of early cancer development. We further highlight nutrigenomic mechanisms, including vitamin <span>D</span>-dependent chromatin remodelling and redox-sensitive cofactors, that modulate epigenetic states and immune resilience. Framing FA within the broader framework of ageing biology suggests testable biomarkers and precision-prevention strategies aimed at stabilising the epigenome, delaying carcinogenesis, and prolonging healthspan.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"115 ","pages":"Article 103038"},"PeriodicalIF":12.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146078331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ageing and liver immune cells","authors":"Jarrod J. Kennedy ,&nbsp;Patrick Bertolino ,&nbsp;Sophie Lucic Fisher ,&nbsp;Meng C. Ngu ,&nbsp;Nicholas J. Hunt ,&nbsp;Peter A.G. McCourt ,&nbsp;Victoria C. Cogger ,&nbsp;David G. Le Couteur","doi":"10.1016/j.arr.2026.103039","DOIUrl":"10.1016/j.arr.2026.103039","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"115 ","pages":"Article 103039"},"PeriodicalIF":12.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146078332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA G-quadruplexes mediated protein aggregation in neurodegenerative diseases","authors":"Tu Chen Guan ,&nbsp;Li Zeng ,&nbsp;Mei Liu ,&nbsp;Yan Liu ,&nbsp;Yun-Cheng Wu ,&nbsp;Yu Guan Mu ,&nbsp;Eng King Tan ,&nbsp;Zhi Dong Zhou","doi":"10.1016/j.arr.2025.103006","DOIUrl":"10.1016/j.arr.2025.103006","url":null,"abstract":"<div><div>RNA G-quadruplexes (rG4s) are stable secondary structures formed by guanine-rich RNA sequences that have emerged as critical regulators of RNA metabolism. The rG4s are widespread in both coding and noncoding RNAs and have been implicated in regulating multiple post-transcriptional processes, including RNA stability, splicing, polyadenylation, nuclear export, localization, and translation. Recent findings reveal that rG4s play pathological roles in neurodegenerative diseases (NDs), including Alzheimer's disease (AD) and Parkinson’s disease (PD). The rG4s function in stress granule dynamics, aberrant phase separation, and the nucleation of pathological protein assemblies, which is implicated in protein co-aggregation and pathological protein aggregation in NDs. Here, we provide an integrated synthesis of how rG4s influence protein aggregation through biophysical, cellular, and molecular mechanisms, with particular emphasis on rG4-driven perturbations of phase separation and aggregation pathways. The rG4s relevant disease pathogenesis, biomarker development, and therapeutic interventions in NDs are discussed. Furthermore, we highlight emerging translational opportunities, including the potential of rG4-targeting small molecules such as 5-aminolevulinic acid (5-ALA) and other modulators, which may open new avenues for combating neurodegeneration.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"115 ","pages":"Article 103006"},"PeriodicalIF":12.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145879686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanotechnology-based advancements in Parkinson's therapy: Exploring animal models and clinical insights in neurodegenerative disorders","authors":"Dnyandev G. Gadhave ,&nbsp;Varsha V. Kale ,&nbsp;Aishwarya P. Kade ,&nbsp;Onkar R. Jadhav ,&nbsp;Vrashabh V. Sugandhi ,&nbsp;Vishal B. Babar ,&nbsp;Shubham Khot ,&nbsp;Chandrakant R. Kokare ,&nbsp;Keshav Raj Paudel","doi":"10.1016/j.arr.2026.103026","DOIUrl":"10.1016/j.arr.2026.103026","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a chronic neurological disorder characterized by loss of body movement control due to dopamine abnormalities. PD leads to various pathological symptoms, including muscle stiffness, bradykinesia, tremors, and postural disturbances. As a severe disease, PD caused approximately 329,000 deaths worldwide in 2019. However, PD treatment is very challenging; thus, alternative therapeutic strategies are in high demand. The primary therapeutic hurdle in PD therapy is the blood-brain barrier (BBB). This biological barrier further protects against dangerous foreign substances and drugs in the brain, which limits therapeutic action in PD. Currently, there are several approved medications for PD therapy, although the majority only address associated symptoms. Unfortunately, because of related adverse effects, existing treatments have not been able to slow the severity of PD. This illness is initiated and progresses by specific pathogenic mechanisms like α-synuclein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. As a result, a patient with PD has a limited chance of surviving roughly about 14.5 years. Therefore, to better understand and improve the overall survival rate, it is necessary to understand the different pathogenic processes behind the progress of PD. However, in the current and past decade, nanotechnology has rapidly expanded into the field of treatment and diagnosis of mental illnesses. Therefore, the review underscored recent insights into PD pathogenesis, neuropathogenic mechanisms, advancements in theragnostic and therapeutic strategies, nanotherapeutics, current clinical trial updates, and emerging PD therapeutic development. That has aided scientists in developing alternative approaches to deal with the drawbacks of PD's conventional therapies.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"115 ","pages":"Article 103026"},"PeriodicalIF":12.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145979433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of lysosomal morphology in aging and age-related diseases","authors":"Huimin Liu,&nbsp;Haiqing Tang,&nbsp;Shanshan Pang","doi":"10.1016/j.arr.2026.103033","DOIUrl":"10.1016/j.arr.2026.103033","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"115 ","pages":"Article 103033"},"PeriodicalIF":12.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146047512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The epigenetic rejuvenation promise: Partial reprogramming as a therapeutic strategy for aging and disease","authors":"Yuan-Yuan Li ,&nbsp;Franklin R. Tay","doi":"10.1016/j.arr.2026.103009","DOIUrl":"10.1016/j.arr.2026.103009","url":null,"abstract":"<div><div>Reprogramming of somatic cells into induced pluripotent stem cells through the introduction of transcription factors Oct3/4, Sox2, Klf4, and c-Myc (OSKM) represents a landmark advance in regenerative biology. Building on this foundation, partial reprogramming can help reset epigenetic age. It further opens opportunities to treat degenerative diseases without the tumorigenic risks associated with full pluripotency. The review advances the field in three ways: it links lineage-preserving partial reprogramming to quantifiable rejuvenation endpoints; defines mesenchymal drift as an age- and disease-associated trajectory amenable to reversal; and maps strategies beyond OSKM, including small-molecule programs and CRISPR-based control circuits. Convergent phenotypes are surveyed in nervous, metabolic, musculoskeletal, and craniofacial systems, with emphasis on improved tissue repair and regeneration. A translational checklist is proposed that emphasizes schedule, delivery, and safety pharmacology to guide rigorous preclinical studies and de-risk early clinical entry points for partial reprogramming therapies.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"115 ","pages":"Article 103009"},"PeriodicalIF":12.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding synaptic imbalance in neurodegenerative diseases: From pathological analysis to targeted intervention","authors":"Xiong Li ,&nbsp;Rui Wan ,&nbsp;Yang Zhao ,&nbsp;Yumeng Wu,&nbsp;Xuehua Chen,&nbsp;Qianqian Li,&nbsp;Chengliang Luo","doi":"10.1016/j.arr.2026.103028","DOIUrl":"10.1016/j.arr.2026.103028","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"115 ","pages":"Article 103028"},"PeriodicalIF":12.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145999965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"exBAClock: A comprehensive database of published clocks for age quantification and age-related diseases","authors":"Anastasiya Kobelyatskaya ,&nbsp;Anastasiya Novoselova ,&nbsp;Ksenia Bylinskaya ,&nbsp;Nikolai Nemirovich-Danchenko ,&nbsp;Mikhail Ivanchenko ,&nbsp;Claudio Franceschi ,&nbsp;Alexey Moskalev","doi":"10.1016/j.arr.2026.103031","DOIUrl":"10.1016/j.arr.2026.103031","url":null,"abstract":"<div><div>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 (<span><span>https://akob.shinyapps.io/exbaclock/</span><svg><path></path></svg></span>). 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).</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"115 ","pages":"Article 103031"},"PeriodicalIF":12.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146023344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The social microbiome of older people","authors":"Andrea Ticinesi ,&nbsp;Giovanni Zuliani ,&nbsp;Riccardo Spaggiari ,&nbsp;Stefano Volpato ,&nbsp;Stefania Maggi ,&nbsp;Claudio Franceschi","doi":"10.1016/j.arr.2025.103008","DOIUrl":"10.1016/j.arr.2025.103008","url":null,"abstract":"<div><div>The human gut microbiome (GM) is increasingly recognized as one of the main systems influencing the aging trajectory. Age-related dysbiosis, with imbalance between symbionts and pathobionts, can in fact fuel chronic inflammation (inflammaging) and promote frailty. In older individuals, GM composition is characterized by marked inter-individual variability and consistently influenced by environmental exposures. Studies conducted in animals and closed human communities suggest that social contacts are associated with horizontal transmission of commensal bacteria, enhancing biodiversity and preventing dysbiosis. Recent studies also suggest transmission of intestinal commensal bacteria from animals to humans sharing the same household. Bacterial populations residing on environmental surfaces may also have an influence on GM composition. In this framework, impoverishment of social relationships in older individuals may not be only associated with cognitive and emotional disengagement, but also with unfavorable changes in GM composition, driven by isolation and top-down neuromodulation of intestinal function. In fact, studies conducted during forced social distancing in the COVID-19 pandemic suggest GM changes pointing towards dysbiosis. Therefore, the detrimental consequences of social isolation for health outcomes of older individuals, including frailty progression towards disability, could be at least partly mediated by GM dysbiosis. Conversely, interventions aimed at restoring sociality, including animal-assisted activities, could expose older individuals to a range of novel bacterial species helping to counteract GM dysbiosis. This perspective article critically discusses the concept of social microbiome, its possible relevance for maintenance of good health in human beings, and its implications for the care of older patients.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"115 ","pages":"Article 103008"},"PeriodicalIF":12.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}