Ageing Research Reviews最新文献

{"title":"The gut microbiota dysbiosis in geriatric multimorbidity: Pharmacotherapeutic implications, pathophysiological mechanisms, and precision modulation strategies","authors":"Duo Yang ,&nbsp;Dan Ren ,&nbsp;Yu Zhang ,&nbsp;Yuanzhu Hao ,&nbsp;Yixing Yue ,&nbsp;Qian Li ,&nbsp;QingLing Fan ,&nbsp;Chao Sun ,&nbsp;Manli Cui ,&nbsp;Mingxin Zhang","doi":"10.1016/j.arr.2026.103023","DOIUrl":"10.1016/j.arr.2026.103023","url":null,"abstract":"<div><div>Aging around the world is accelerating. With that comes the intersection of geriatric multimorbidity and polypharmacy, creating a large uncertainty about the pharmacological efficacy and therapeutic consequences of medications used when multiple concurrent health issues exist. The gut microbiota coordinates the way drugs work through multiple pathways: through the way drugs are metabolised, the way they maintain immune homeostasis, and the way they regulate the epithelial barrier. For these reasons, the gut microbiota is becoming an important therapeutic target for optimizing precision medicine strategies in treating patients with geriatric multimorbidities. In this narrative review, we systematically synthesize the evidence regarding how gut dysbiosis leads to decreased efficacy of multi-drug regimens through the interplay between metabolism, immune response, and barrier function in aging patients with multimorbidities, and we evaluate targeted interventions. Furthermore, we demonstrate that current interventions (e.g., probiotics, prebiotics, fecal microbiota transplants (FMT), phage therapy, and dietary modulation) have unique benefits but are limited by inter-individual variability, safety concerns, and a lack of proven long-term efficacy. Thus, many areas of microbiota-drug interactions in older adults with multimorbidity should be explored through future research. Key areas to address are: the establishment of large, multicenter longitudinal cohorts of older adults with multimorbidity that would allow for repeated collection of microbiota profiles, medication use, and health outcomes to identify the evolving interaction between multimorbidity, microbiota, and polypharmacy; the urgent need for standardized and integrated databases of microbiome-drug interactions that harmonize data formats, provide metabolic annotations and medication identifiers in order to support reproducible cross-study validation; and the further validation and application of artificial intelligence (AI) and machine learning (ML) in clinical trials. High-dimensional data collected from cohorts and databases will enable the development of predictive algorithms to identify individual drug responses and how effective microbiota-targeted interventions will be; these algorithms must then be prospectively validated. Ultimately, these initiatives are necessary to move toward the personalized management of microbiota-drug interactions in older adults with multimorbidity, providing greater safety of polypharmacy and promoting healthy aging.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"115 ","pages":"Article 103023"},"PeriodicalIF":12.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145992313","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 m⁶A epitranscriptome: A regulatory nexus linking cellular senescence and oncogenesis","authors":"Yao Xu ,&nbsp;Xin Zhou ,&nbsp;Xiaoling Su ,&nbsp;Wenxi Xie ,&nbsp;Zhijie Huang ,&nbsp;Shan Yu ,&nbsp;Jinghua Tan ,&nbsp;Jun He ,&nbsp;Ji Zhang","doi":"10.1016/j.arr.2026.103032","DOIUrl":"10.1016/j.arr.2026.103032","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"115 ","pages":"Article 103032"},"PeriodicalIF":12.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044350","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":"Proteolysis-targeting chimera (PROTAC): A promising senolytic strategy","authors":"Gang Fan ,&nbsp;Qingping Zhang ,&nbsp;Weiming Guo ,&nbsp;Miao Liu ,&nbsp;Dong Tan ,&nbsp;Zhihan Tang ,&nbsp;Jing Yang","doi":"10.1016/j.arr.2026.103027","DOIUrl":"10.1016/j.arr.2026.103027","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"115 ","pages":"Article 103027"},"PeriodicalIF":12.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146013882","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":"Single-cell aging clocks: A precision tool for dissecting and targeting the aging process","authors":"Yuduo Hao ,&nbsp;Sijia Xie ,&nbsp;Yijie Wei ,&nbsp;Xiaoshuo Sun ,&nbsp;Yu Xiao ,&nbsp;Xueqin Xie ,&nbsp;Kaiyuan Han ,&nbsp;Ting Wang ,&nbsp;Zhepeng Wang ,&nbsp;Luqiang Zhang ,&nbsp;Hao Lyu ,&nbsp;Hao Lin","doi":"10.1016/j.arr.2026.103040","DOIUrl":"10.1016/j.arr.2026.103040","url":null,"abstract":"<div><div>Biological age, an indicator of an individual’s health status, was initially measured using bulk tissue aging clocks. However, by averaging molecular signals across thousands of cells, these tools mask the cellular heterogeneity that characterizes aging. Recent single-cell aging clocks, enabled by high-resolution omics technologies, address this limitation. In this review, we provide a systematic overview of these tools, covering their computational foundations and the key biological insights they enable. These clocks have transformed “mosaic aging” from a hypothesis into a quantifiable phenomenon. They also highlight the plasticity of aging by tracking cell-type-specific age acceleration in disease and its reversal after interventions. Furthermore, they are opening new biological frontiers, including the “age reset” during embryogenesis, the role of the tissue microenvironment, and the molecular underpinnings of extreme longevity. Collectively, these findings recast aging not as passive decline but as a regulated, potentially malleable biological program. Single-cell aging clocks provide the foundational tools for developing the next generation of precision interventions aimed at extending human healthspan.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"115 ","pages":"Article 103040"},"PeriodicalIF":12.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146078333","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":"Exercise and the hallmarks of cardiovascular aging","authors":"Dan Zhong ,&nbsp;Benjamin Fernández-García ,&nbsp;Priyanka Gokulnath ,&nbsp;Kexin Lin ,&nbsp;Guoping Li ,&nbsp;Guido Kroemer ,&nbsp;Carlos López-Otín ,&nbsp;Junjie Xiao","doi":"10.1016/j.arr.2026.103030","DOIUrl":"10.1016/j.arr.2026.103030","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"115 ","pages":"Article 103030"},"PeriodicalIF":12.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044331","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 of human myofibres in the Vastus Lateralis muscle: A narrative review","authors":"Antoneta Granic ,&nbsp;Davina C.M. Simoes ,&nbsp;T. Scott Bowen ,&nbsp;Nessrin Almaghtuf ,&nbsp;Gavin Richardson ,&nbsp;Avan A. Sayer","doi":"10.1016/j.arr.2026.103022","DOIUrl":"10.1016/j.arr.2026.103022","url":null,"abstract":"<div><div>Human skeletal muscle is a complex, dynamic tissue that changes profoundly with age. It comprises heterogenous cells including long, contractile, multinucleated myofibres, broadly classified into type I (slow-twitch/oxidative) fibres and type II (fast-twitch/glycolytic) fibres, as well as a variety of mononucleated cells (e.g., immune, satellite, and endothelial cells), and the extracellular matrix (ECM). Ageing as well as sarcopenia, a muscle condition characterised by progressive loss of muscle strength and mass observed mostly in older adults, appear to disproportionately affect type II fibres. In histomorphometric studies of ageing muscle this has been described as type II myofibres loss, fibre atrophy, and redistribution of fibre types, although some inconsistent findings exist. The precise mechanisms underlying this selective vulnerability remains elusive but are likely attributable to dysregulated nutrient sensing contributing to the deregulation of muscle protein synthesis and degradation cycle, and neuromuscular junction, satellite cells, ECM and mitochondrial dysfunction. This narrative review focuses on the <em>Vastus Lateralis</em> (<em>VL</em>) muscle—a major limb muscle involved in locomotion and one of the most extensively studied human skeletal muscles—and summarises key structural and phenotypic changes that occur with ageing at the organ, tissue, and cell levels, and their relevance to sarcopenia. We also briefly discuss external influences of these changes, highlight gaps in knowledge, and suggest future directions.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"115 ","pages":"Article 103022"},"PeriodicalIF":12.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145928598","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 potential of prehabilitation to enhance recovery in sarcopenic and frail older kidney transplant candidates: A narrative review","authors":"Natália Tomborelli Bellafronte ,&nbsp;Guillermina Barril-Cuadrado ,&nbsp;Francesco Carli","doi":"10.1016/j.arr.2026.103021","DOIUrl":"10.1016/j.arr.2026.103021","url":null,"abstract":"<div><h3>Background</h3><div>Older adults represent the fastest-growing segment on kidney transplant (KT) waiting lists. In this population, the high prevalence of sarcopenia and frailty impairs the ability to adapt and respond to metabolic stress, contributing to poorer postoperative outcomes. Given that many adverse events occur in the early postoperative period, the optimal window for intervention is prior to surgery. Prehabilitation, defined as a structured intervention delivered before surgery, aims to enhance postoperative recovery.</div></div><div><h3>Methods</h3><div>In the context of older adults candidates to KT, we constructed a detailed narrative review on: the development of sarcopenia and frailty as a result of ageing and chronic kidney disease pathophysiologic process; sarcopenia and frail influence on post-operative outcomes, and prehabilitation as a strategy to improve recovery.</div></div><div><h3>Results</h3><div>Age-related anabolic resistance and hormonal, cellular and metabolic disarrangements resulting from the pathophysiologic process of kidney failure, aggravated by dialysis side effects, result in sarcopenia and frailty. Frail/sarcopenic older adults are more vulnerable to post-operative complications and recovery is prolonged. Published prehabilitation studies for candidates to KT mostly comprised of in-situ exercise-only interventions; prehabilitated patients demonstrated improvement of physical function as compared to baseline and just one study assessed post-operative outcomes. The limited results from these studies reflect the absence of a multimodal approach with a comprehensive and personalized medical, dietetic and psychosocial intervention in addition to exercise, necessary to accomplish success. Based on renal, ageing and surgical scientific literature, a suggested multimodal prehabilitation program is proposed.</div></div><div><h3>Conclusion</h3><div>Although the optimal structure of prehabilitation remains to be established, individualized multimodal interventions appear to hold promise for optimizing patients during the KT waiting period.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"115 ","pages":"Article 103021"},"PeriodicalIF":12.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145928597","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":"Sepsis-induced cardiomyopathy: A comprehensive review of pathogenic mechanism and therapeutic strategies","authors":"Zhang Shangzu ,&nbsp;Li Qiyang ,&nbsp;Peng Zhiyun ,&nbsp;Shan Yunan ,&nbsp;Liu Xinbang ,&nbsp;Chen Yan ,&nbsp;Zeng Zhaoshang ,&nbsp;Tang Zhongxiang ,&nbsp;Fang Bangjiang","doi":"10.1016/j.arr.2026.103025","DOIUrl":"10.1016/j.arr.2026.103025","url":null,"abstract":"<div><div>Sepsis-induced cardiomyopathy (SCM) augments the mortality of sepsis patients. SCM prevention and early monitoring are widely agreed upon, but therapeutic approaches against SCM are challenging to develop primarily due to the complexity of its pathophysiological mechanisms. The fundamental mechanisms contributing to SCM include inflammation, oxidative stress, mitochondrial dysfunction, energy metabolism disorders, disorders of calcium homeostasis, myocardial edema, and cell death. These processes are subject to complex cross-regulatory interactions, forming a pathological network centered on inflammation. Furthermore, this review summarized the efficacy and mechanisms of vasoactive drugs, other pharmacological agents, and natural products in treating SCM, emphasizing emerging therapeutic targets. Advancing the clinical management of SCM requires a shift from interventions focused on single mechanisms to the establishment of a network-based regulatory strategy centered on inflammation. This method may provide innovative solutions for treating SCM.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"115 ","pages":"Article 103025"},"PeriodicalIF":12.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145928599","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":"Effects of six traditional Chinese mind-body exercise therapies on vascular health and cardiac function in middle-aged and elderly hypertensive patients: A network meta-analysis of 48 randomized controlled trials","authors":"Yanli Han ,&nbsp;Weihao Sun ,&nbsp;Jian Han ,&nbsp;Suxia Li ,&nbsp;Yue Zhou","doi":"10.1016/j.arr.2025.103007","DOIUrl":"10.1016/j.arr.2025.103007","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Hypertension is a significant risk factor for cardiovascular disease on a global scale, particularly among middle-aged and elderly individuals. Hypertension is not only associated with cardiovascular disease, including heart disease and stroke, but also leads to vascular endothelial dysfunction and decreased cardiac function. Among non-pharmacological intervention modalities, traditional Chinese mind-body exercise therapy can regulate blood pressure, induce psychological relaxation and improve cardiovascular health through gentle exercise with respiratory regulation. However, further verification is required to confirm the specific effects of this therapy.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Relevant randomized controlled trials (RCTs) published after 2000 were searched and screened in Chinese and English databases. A systematic review and frequency network meta-analysis (NMA) were used to assess the effects of six traditional Chinese mind-body exercise therapies, Taichi, Baduanjin, Liuzijue, Shuxinpingxuegong, Qigong, and Daoyinyangshengshu, on blood pressure (systolic blood pressure, diastolic blood pressure), vascular endothelial function secretion factors (nitric oxide, endothelin-1) and cardiac function (heart rate, cardiac output, stroke volume, cardiac index, ejection fraction). The risk of bias was independently assessed using the RoB tool, and the quality of evidence for outcome indicators was evaluated using the Confidence in Network Meta-Analysis (CINeMA) online tool.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;A total of 48 RCTs (4184 patients) were included in this study, of which 77.6 % were assessed as having a low risk of bias. Of the various exercise interventions, Taichi was the most commonly used, accounting for 51.02 % of cases, while Baduanjin was the second most prevalent, representing 26.53 % of cases. The mean duration of a single exercise session for patients was 48.8 min, with most intervention cycles exceeding 12 weeks and an average frequency of 3.9 sessions per week. The NMA results revealed that Taichi was most effective in reducing systolic blood pressure (SMD = -1.10, 95 % CI [-1.23, -0.98]), improving cardiac output (SMD = 1.31, 95 % CI [0.42, 2.20]), and enhancing cardiac index (SMD = 0.43, 95 % CI [0.02, 0.84]) among middle-aged and elderly patients. Baduanjin exercise was found to be the most effective in reducing heart rate (SMD = -1.60, 95 % CI [-2.01, -1.18]), increasing nitric oxide levels (SMD = 0.96, 95 % CI [0.58, 1.33]), and decreasing endothelin-1 concentrations (SMD = -0.91, 95 % CI [-1.29, −0.52]). Daoyinyangshengshu was the most effective in improving diastolic blood pressure (SMD = -1.26, 95 % CI [-1.65, -0.87]) and elevating stroke volume (SMD = 0.93, 95 % CI [0.47, 1.38]). Liuzijue was the most effective in improving ejection fraction (SMD = 3.30, 95 % CI [1.73, 4.88]).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;Taichi, Baduanjin and Daoyinyangshengshu are the most suitable ex","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"115 ","pages":"Article 103007"},"PeriodicalIF":12.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145879657","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":"Evaluating senescence-targeted approaches in Alzheimer’s Disease: What we know and what lies ahead","authors":"Pratik Prashant Doshi ,&nbsp;Sakshee Hemant Desale ,&nbsp;Aarti Ashok Khutale ,&nbsp;Sarvesh Sabarathinam ,&nbsp;Swathi Suresh","doi":"10.1016/j.arr.2026.103029","DOIUrl":"10.1016/j.arr.2026.103029","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"115 ","pages":"Article 103029"},"PeriodicalIF":12.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146020914","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}