Ageing Research Reviews最新文献

{"title":"Ca2+/Calmodulin-dependent protein kinase II (CaMKII)-targeted drug discovery: Challenges and strategies","authors":"Xinmiao Tian ,&nbsp;Xianghui Wang ,&nbsp;Sichong Chen ,&nbsp;Xuefei Sun ,&nbsp;Dongxue Shao ,&nbsp;Kuo Zhang ,&nbsp;Qinghua Gao ,&nbsp;Liying Hao","doi":"10.1016/j.arr.2025.102886","DOIUrl":"10.1016/j.arr.2025.102886","url":null,"abstract":"<div><div>Calcium (Ca²⁺)/calmodulin (CaM)-dependent protein kinase II (CaMKII) is an emerging drug target for age-related diseases. It is a multifunctional kinase with complex activation modes, numerous isoforms, broad tissue distribution, and a dual role in health and disease. In particular, its isoforms share a high degree of conservation within the catalytic and regulatory domains, with only minor differences confined to the linker region. These characteristics of CaMKII make the development of selectively targeted inhibitors particularly challenging. Current CaMKII inhibitors can be classified into the following categories: CaM-binding site blockers (KN62, KN93); ATP-competitive inhibitors (AS105, GS-680, RA306, RA608, SMP-114, NP202, hesperadin); substrate-binding site blockers (AIP, AC3-I, CN21); and pathway-targeted novel modulators (e.g., Athycaltide-1). However, no CaMKII inhibitor has yet reached clinical approval. Nevertheless, CaMKII remains a compelling target due to its pivotal role in age-related pathologies. Several innovative approaches hold promise for overcoming current limitations, including: activating endogenous degradation of CaMKII by proteolysis-targeting chimeras (PROTACs), applying novel materials such as peptide- or nucleic acid-based agents and CRISPR-Cas9-mediated gene editing approaches, employing tissue-specific delivery systems and engineered drug molecules, and targeting disease-specific signaling pathways. Together, these strategies may pave the way for more precise and effective CaMKII-targeted interventions in aging-associated diseases.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"112 ","pages":"Article 102886"},"PeriodicalIF":12.4,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006975","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":"Deep aging clocks: AI-powered strategies for biological age estimation","authors":"Luma Srour ,&nbsp;Yosra Bejaoui ,&nbsp;James She ,&nbsp;Tanvir Alam ,&nbsp;Nady El Hajj","doi":"10.1016/j.arr.2025.102889","DOIUrl":"10.1016/j.arr.2025.102889","url":null,"abstract":"<div><div>Several strategies have emerged lately in response to the rapid increase in the aging population to enhance health and life span and manage aging challenges. Developing such strategies is imperative and requires an assessment of biological aging. Several aging clocks have recently been developed to measure biological aging and to assess the efficacy of longevity interventions. Biological age better reflects a person’s actual age and is closely associated with health outcomes and time to mortality. Traditionally, most aging clocks assume that biological changes occur linearly over time. However, age-related changes do not necessarily follow a linear trajectory. Thus, “Deep Aging Clocks” have been developed to overcome previous clocks' limitations and better capture subtle changes that occur during aging. Here, we summarize the current deep aging clocks, including epigenetics, transcriptomics, metabolomics, microbiome, and imaging based clocks for age prediction. Recent advances in artificial intelligence (AI), utilizing deep learning techniques, have significantly enhanced the prediction of biological aging, and this would help improve aging clocks and accelerate efforts to reach longer and healthier lives.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"112 ","pages":"Article 102889"},"PeriodicalIF":12.4,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144988401","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":"Regulation of PPAR-γ coactivator-1α and its implication in mitochondrial function and neurodegenerative diseases","authors":"Ashwini Prem Kumar ,&nbsp;Devaraj Thittayil Puthussery","doi":"10.1016/j.arr.2025.102887","DOIUrl":"10.1016/j.arr.2025.102887","url":null,"abstract":"<div><div>Peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α, interacts with numerous transcription factors implicated in a wide spectrum of biological responses. It has been identified as a key player in the transcriptional regulation of many mitochondrial components. The activity of PGC1-α is regulated at multiple levels, such as gene expression, transcriptional, post-transcriptional, and post-translational modification. The purpose of this review is to highlight the data supporting PGC1-α-mediated regulation by transcriptional and post-translational modification. We summarize the mechanisms involved in PGC1-α regulation by phosphorylation (AMPK, p38 MAPK, Akt, and GSK3β), acetylation (GCN5, p300, and SRCC), and ubiquitination (E3-ubiquitin ligase). Moreover, the review focuses on the multidomain structure of PGC1-α, its expression in the brain, and the importance of PGC1-α-mediated mitochondrial functions.</div><div>Mitochondrial dysfunction and impaired energy metabolism are key characteristics of neurodegenerative diseases like Alzheimer's, Huntington's, Parkinson's, amyotrophic lateral sclerosis, and multiple sclerosis. It is associated with reduced PGC1-α expression or activity, resulting in an imbalance in the maintenance of mitochondrial dynamics. In this backdrop, we additionally provide a comprehensive overview of the implication of PGC1-α in the pathogenesis of neurodegenerative disease. Overall, PGC1-α acts as a potential target for therapies to reduce mitochondrial dysfunction associated with neurodegenerative diseases and aid in neuroprotection.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"112 ","pages":"Article 102887"},"PeriodicalIF":12.4,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144988400","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":"Effectiveness of various exercise on neuropsychiatric symptoms among older adults with mild cognitive impairment or dementia: A systematic review and network meta-analysis","authors":"Qinghuan Kong ,&nbsp;Kexin Huang ,&nbsp;Shuang Li ,&nbsp;Xinyun Li ,&nbsp;Rui Han ,&nbsp;Haiqi Yang ,&nbsp;Yuhang Pu ,&nbsp;Li Chen ,&nbsp;Yong Jia","doi":"10.1016/j.arr.2025.102890","DOIUrl":"10.1016/j.arr.2025.102890","url":null,"abstract":"<div><h3>Objective</h3><div>To identify the comparative efficacy of exercise for reducing neuropsychiatric symptoms (NPS) among older adults with mild cognitive impairment (MCI) or dementia.</div></div><div><h3>Methods</h3><div>Ten databases were systematically searched from their inception to April 29, 2025, with the latest update in July 13, 2025. Randomized controlled trials (RCTs) and quasi-experimental studies evaluating the effectiveness of exercise on NPS in older adults with MCI or dementia were included. Risk of bias was assessed using the Risk of Bias tool (RoB 2) tool for RCTs and the Joanna Briggs Institute (JBI) critical appraisal checklists. A random-effects network meta-analysis model was employed to synthesize all available evidence. The registration number of this study is CRD420251087869.</div></div><div><h3>Results</h3><div>A total of 34 studies involving 3655 participants were included. Among them, 29 RCTs showed a low to high risk of bias, while 5 quasi-experimental studies had moderate risk. A network meta-analysis revealed that for NPS, resistance exercise (<em>SMD</em> = −1.70, <em>95 % CI</em>: −3.12 to −0.29) ranked first with 91.8 %; for cognition function, multi-component exercise (<em>SMD</em> = 1.45, <em>95 % CI</em>: −0.56 to –3.47) ranked first with 80.2 %; for quality of daily life (QoL), aerobic exercise (<em>SMD</em> = 0.37, <em>95 % CI</em>: −0.26 to –0.99) ranked first with 77.5 %; and for activities of daily living (ADL), finger exercise (<em>SMD</em> = 0.86, <em>95 % CI</em>: 0.02 to –1.71) ranked first with 89.6 %.</div></div><div><h3>Conclusions</h3><div>This network meta-analysis suggests that resistance exercise is most likely the optimal intervention for improving NPS among older adults with MCI or dementia, while finger exercise appears most effective for enhancing ADL. However, due to the limited number of studies on resistance exercise, these findings should be interpreted with caution, and further high-quality research is needed to confirm its efficacy.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"112 ","pages":"Article 102890"},"PeriodicalIF":12.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144988399","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":"Tailoring the biomarkers of Alzheimer’s disease using a gut microbiome-centric approach: Preclinical, clinical, and regulatory perspectives","authors":"Siya Sharma ,&nbsp;Bushra Bashir ,&nbsp;Kaustubh Ajit Kolekar ,&nbsp;Anuradha Acharya ,&nbsp;Mukta Gupta ,&nbsp;Radheshyam Jena ,&nbsp;Sukriti Vishwas ,&nbsp;Jaskiran Kaur ,&nbsp;Gaurav Gupta ,&nbsp;Popat S. Kumbhar ,&nbsp;Deepshikha Patle ,&nbsp;MVNL Chaitanya ,&nbsp;Monica Gulati ,&nbsp;Sachin Kumar Singh","doi":"10.1016/j.arr.2025.102888","DOIUrl":"10.1016/j.arr.2025.102888","url":null,"abstract":"<div><div>Alzheimer’s disease (AD), a progressive neurodegenerative disorder, poses significant therapeutic challenges due to its complex etiology and limited treatment options. Traditional pharmacotherapies targeting amyloid-β (Aβ) and cholinergic pathways offer modest benefits and are often associated with adverse effects. Emerging evidence implicates gut dysbiosis and the gut–brain axis in the pathogenesis and progression of AD. This review explores the multifactorial pathophysiology of AD and evaluates the therapeutic potential of gut-based interventions such as probiotics, prebiotics, synbiotics, metabiotics, postbiotics, and fecal microbiota transplantation (FMT) in mitigating disease pathology. Emphasis has also been given on role of miRNA released from FMT in management of AD. Preclinical and clinical studies demonstrate that these strategies can restore microbial homeostasis, reduce neuroinflammation, enhance gut barrier integrity, and improve cognitive outcomes. The regulatory aspects with use of probiotics based products and FMT is also highlighted. The modulation of neuroimmune, neuroendocrine, and neural pathways through microbiota-derived metabolites offers a promising avenue for AD management. Despite encouraging findings, further research is needed to address interindividual microbiome variability, delivery challenges, and the requirement for large-scale, randomized trials. Personalized gut-targeted approaches may open new horizons for the prevention and treatment of AD.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"112 ","pages":"Article 102888"},"PeriodicalIF":12.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144988402","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":"HIV infection is associated with accelerated epigenetic ageing: A systematic review","authors":"Mateusz Bożejko ,&nbsp;Brygida Knysz ,&nbsp;Anna Czernicka ,&nbsp;Ignacy Tarski ,&nbsp;Aleksandra Szymczak ,&nbsp;Małgorzata Małodobra-Mazur","doi":"10.1016/j.arr.2025.102884","DOIUrl":"10.1016/j.arr.2025.102884","url":null,"abstract":"<div><h3>Purpose</h3><div>We conducted a systematic review of studies comparing the intensity of epigenetic ageing in people living with human immunodeficiency virus (HIV) and uninfected individuals. We included studies that quantitatively examined the intensity of age-related epigenetic changes in both groups.</div></div><div><h3>Results</h3><div>We identified 25 studies meeting the inclusion criteria. The results of the vast majority (22 out of 25) of the studies included in the review indicate the presence of accelerated epigenetic ageing in people living with HIV compared to uninfected individuals. Most studies reported evidence of epigenetic age acceleration in people living with HIV, both among those not receiving antiretroviral therapy (ART) and those who were on ART treatment. However, the studies included in the review were conducted mostly on relatively small groups and using different methods. While several studies have carefully addressed confounding variables, others did not report adjustments for factors such as BMI, diabetes, HBV and HCV co-infections, or lifestyle influences, which may be especially relevant for interpreting second-generation epigenetic clocks such as GrimAge and PhenoAge.</div></div><div><h3>Conclusions</h3><div>We believe that the results of our review indicate accelerated epigenetic ageing in people living with HIV compared to uninfected individuals. There is a need for further research, which will analyse material from different tissues and take into account a number of biomarkers and the mentioned confounding factors. Studies considering the impact of individual classes of antiretroviral drugs, the age of the patient at the time of HIV diagnosis, and the timeliness of diagnosis on epigenetic ageing are particularly needed.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"112 ","pages":"Article 102884"},"PeriodicalIF":12.4,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144913072","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":"Unravelling neuronal death mechanisms: The role of cytokines and chemokines in immune imbalance in Alzheimer’s disease progression","authors":"Sneha Kumari ,&nbsp;Rishika Dhapola ,&nbsp;Prajjwal Sharma ,&nbsp;Mohit Paidlewar ,&nbsp;Balachandar Vellingiri ,&nbsp;Bikash Medhi ,&nbsp;Dibbanti HariKrishnaReddy","doi":"10.1016/j.arr.2025.102883","DOIUrl":"10.1016/j.arr.2025.102883","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is marked by neuroinflammation, neurodegeneration and cognitive decline, with emerging evidence highlighting the critical roles of cytokines and chemokines in its pathogenesis. Regulated cell death is a highly structured and meticulously coordinated series of molecular and signalling processes involving gene expression and protein activity. This mechanism is essential for normal developmental processes and the preservation of tissue homeostasis. Abnormal regulation of inflammatory mediators contributes to or results from amyloid-β and tangle deposition, triggers oxidative stress, excitotoxicity, and neuroinflammation, leads to cell death through multiple mechanisms, including apoptosis, ferroptosis, pyroptosis, PANoptosis, etc. The pathogenetic mechanisms responsible for neuronal death and dysfunction in AD are not yet fully understood. This review seeks to compile evidence for the various modes of neuronal cell death in AD and to explore how the neuroinflammatory environment of the AD brain influences these distinct forms of cell death. Several inflammatory signalling cascades are involved in above discussed neuronal death mechanisms, such as RAGE<strong>/</strong>NF-κB, NLRP3 inflammasome, AMPK/mTOR/ULK1, cGAS-STING, RIPK1/RIPK3/MLKL<strong>,</strong> GPX4/Nrf2 and JAK-STAT pathways. Therapeutic drugs such as Magnolol, Necrostatin-1, Salidroside, Azeliragon, DNL788, Baricitinib, Sargramostim, etc. targeting neuroinflammation-associated signaling pathways, have shown efficacy in preclinical and clinical studies mitigating AD pathology. Enhancing our comprehension of neuronal death mechanisms could elucidate disease pathogenesis, offer insights for therapeutic approaches, and aid in developing modified animal models of AD.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"112 ","pages":"Article 102883"},"PeriodicalIF":12.4,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144913073","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":"Vesicle-guided mitochondria: A new perspective for brain mitochondrial transplantation","authors":"Antonella Girgenti ,&nbsp;Laura Palumbo ,&nbsp;Gokhan Burcin Kubat ,&nbsp;Ibrahim Turkel ,&nbsp;Pasquale Picone ,&nbsp;Domenico Nuzzo","doi":"10.1016/j.arr.2025.102881","DOIUrl":"10.1016/j.arr.2025.102881","url":null,"abstract":"<div><div>Mitochondrial activity is essential for the proper functioning of higher brain processes, and its impairment has been linked to a wide range of neurological disorders. Increasing evidence shows that under physiological and pathological conditions, mitochondria can be secreted into the extracellular environment to regulate various biological responses, including cellular bioenergetics. Today, the therapeutic modality known as “mitochondrial transplantation” has emerged as a cutting-edge and highly promising intervention for the promotion of cell and tissue regeneration. This innovative approach entails the replacement of dysfunctional mitochondria in the recipient organism with healthy, functional exogenous mitochondria, thereby aiming to restore cellular function and promote tissue repair and recovery. Several studies have demonstrated the beneficial effects of local or systemic administration of mitochondria on <em>in vitro</em> and <em>in vivo</em> models of brain diseases. We discuss the effect of mitochondrial transplantation in various brain diseases and highlight some critical issues. In this regard, we propose vesicles as a delivery system for both whole mitochondria and mitochondrial components to target cells in the central nervous system. Furthermore, the aim of this review is twofold: firstly, to emphasize the significance of brain mitochondrial transplantation, and secondly, to prompt the scientific community to consider the practical applications of brain mitochondrial transplantation. To this end, the text highlights the as yet unresolved issues and challenges that must be addressed and surmounted if this field is to progress. In conclusion, the authors express their support for the development of new potential therapies for mitochondrial diseases of the central nervous system.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"112 ","pages":"Article 102881"},"PeriodicalIF":12.4,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144913071","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":"Enhancing cognition: The power of neuroplasticity","authors":"Iqra Mukhtar,&nbsp;Kanwal Iftikhar","doi":"10.1016/j.arr.2025.102882","DOIUrl":"10.1016/j.arr.2025.102882","url":null,"abstract":"<div><div>Cognitive enhancement and neuroplasticity are interconnected terms. Neuroplasticity is an intrinsic brain capability that enables it to adapt and learn throughout life. It involves significant reorganization of neural circuits which is evident not only during normal human development but also occurs following early injury. As aging exerts a detrimental effect on various bodily systems, the extent of neuroplasticity also declines considerably. Recent evidences emphasize that cognitive enhancement can lead to positive neuroplastic changes. Moreover, neuroplastic mechanisms can be harnessed for therapeutic purposes in clinical populations in an effective manner. This approach can also pave a way for cognitive reserve and healthy aging, facilitating the protection against age-associated cognitive impairment and development of neurodegenerative disorders. However, there is an urgent need for more rigorous scientific methods to assess the effectiveness of these interventions, which is crucial for progressing in this area. In this review we aim to illuminate the promising potential of plastic processes in the nervous system. The integrated approach, combining neuromodulatory techniques such as brain stimulation with cognitive enhancement methods, is intriguing and could offer a new avenue for enhancing cognitive functions. Overall, this paper lays the groundwork for further exploration and emphasizes the importance of developing effective interventions that leverage the brain's capacity for change. Future research must refine the methodologies used to measure outcomes, ensure generalization and practical applicability, and develop strategies for implementation in real-world settings. This will ultimately enhance our understanding of how to optimize cognitive health throughout the lifespan.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"112 ","pages":"Article 102882"},"PeriodicalIF":12.4,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144916990","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":"Biomolecular phase separation of microtubule-associated protein tau and its role in the genesis of brain disorders","authors":"Aurgha Kamal Bhandari ,&nbsp;Aman Singh Dhami ,&nbsp;Rishi Thanvanthan Hemanthkumar ,&nbsp;Nishant Mishra ,&nbsp;Beula Joslyn ,&nbsp;Sindhujit Roy ,&nbsp;Jaisri Srinivasan ,&nbsp;Kailash Prasad Prajapati ,&nbsp;Karunakar Kar ,&nbsp;Bibin Gnanadhason Anand","doi":"10.1016/j.arr.2025.102879","DOIUrl":"10.1016/j.arr.2025.102879","url":null,"abstract":"<div><div>Microtubule-associated protein tau (MAP) is a crucial component for cellular cytoskeleton stability. However, upon hyperphosphorylation, these tau proteins detach from microtubules, leading to the genesis of clumpy fibrillar-rich β or paired helical filamental structures known as amyloids. Such deposits predispose a multitude of fatal disorders, including Alzheimer’s Disease. The initial event behind such genesis is still a mystery. Today, numerous research studies try to untangle the initial events that lead to the formation of homogeneous and heterogeneous multicomponent plaques in AD, which remain elusive. Since tauopathies are linked to neurodegeneration and the tau tangles damage the neurons and glia, the question of what events trigger the phosphorylation of tau, leading to the molecular crowding of tau repeats, remains largely unknown. Such molecular crowding or initial events before primary nucleation are driven by liquid-liquid phase separation (LLPS), where tau or tau, along with various biomolecules forming dynamic interaction networks leading to the formation of homotypic and heterotypic condensates, ultimately result in co-existing phases before transitioning to nucleation. This review has explored the fundamental principles of LLPS in tau, aiming to establish a link between tau condensates and their pathogenic forms followed by the factors that modulate its phase transition. Our review hopes to provide the scientific community with a strong foundation to build upon, to understand the importance and gravity of studying tau phase separation and the new opportunities it hides within itself.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"113 ","pages":"Article 102879"},"PeriodicalIF":12.4,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144982072","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}