Neuropathic pain (NP) creates a severe pathological condition that primarily affects elderly people because of their accumulated neurobiological changes that make them more susceptible to persistent pain. The aging process leads to multiple mechanisms that combine neurodegeneration with immunosenescence and mitochondrial dysfunction with impaired autophagy and glial priming, and ion channel dysregulation to create a nociceptive environment. This review examines how mitochondrial breakdown and dysfunctional autophagy, and ion channel disturbances with glial cell activation form a interconnected system which makes older people more prone to NP. The review also examines how the neuro–immune–metabolic and gut–brain axis maintain persistent pain across the lifespan while discussing its cellular pathology. Preclinical research shows that aged models develop more severe NP symptoms, yet clinical evidence reveals distinct diagnostic and therapeutic challenges that affect older adults. The review presents current treatment strategies which include mitochondrial protectants and autophagy enhancers together with immunomodulators and microbiome-based interventions, and gene therapies to develop appropriate multimodal therapies for different age group. Further, it combines mechanistic knowledge with translational viewpoints to demonstrate the immediate requirement for treating NP as a geroscience challenge to develop better pain management strategies for older adults.
{"title":"Aging and neuropathic pain: Mitochondria-to-glia cascade, system mechanisms, and therapeutic strategies","authors":"Shreyasi Majumdar , Puneet K. Samaiya , Sukesh Kumar Gupta , Sairam Krishnamurthy , Santosh Kumar Prajapati","doi":"10.1016/j.arr.2026.103042","DOIUrl":"10.1016/j.arr.2026.103042","url":null,"abstract":"<div><div>Neuropathic pain (NP) creates a severe pathological condition that primarily affects elderly people because of their accumulated neurobiological changes that make them more susceptible to persistent pain. The aging process leads to multiple mechanisms that combine neurodegeneration with immunosenescence and mitochondrial dysfunction with impaired autophagy and glial priming, and ion channel dysregulation to create a nociceptive environment. This review examines how mitochondrial breakdown and dysfunctional autophagy, and ion channel disturbances with glial cell activation form a interconnected system which makes older people more prone to NP. The review also examines how the neuro–immune–metabolic and gut–brain axis maintain persistent pain across the lifespan while discussing its cellular pathology. Preclinical research shows that aged models develop more severe NP symptoms, yet clinical evidence reveals distinct diagnostic and therapeutic challenges that affect older adults. The review presents current treatment strategies which include mitochondrial protectants and autophagy enhancers together with immunomodulators and microbiome-based interventions, and gene therapies to develop appropriate multimodal therapies for different age group. Further, it combines mechanistic knowledge with translational viewpoints to demonstrate the immediate requirement for treating NP as a geroscience challenge to develop better pain management strategies for older adults.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"116 ","pages":"Article 103042"},"PeriodicalIF":12.4,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098528","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}
Pub Date : 2026-01-29DOI: 10.1016/j.arr.2026.103038
Eunike Velleuer , Carsten Carlberg
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 D-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.
{"title":"Fanconi anaemia as a human model of accelerated epigenetic and immune ageing","authors":"Eunike Velleuer , 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":"2026-01-29","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}
Pub Date : 2026-01-29DOI: 10.1016/j.arr.2026.103040
Yuduo Hao , Sijia Xie , Yijie Wei , Xiaoshuo Sun , Yu Xiao , Xueqin Xie , Kaiyuan Han , Ting Wang , Zhepeng Wang , Luqiang Zhang , Hao Lyu , Hao Lin
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.
{"title":"Single-cell aging clocks: A precision tool for dissecting and targeting the aging process","authors":"Yuduo Hao , Sijia Xie , Yijie Wei , Xiaoshuo Sun , Yu Xiao , Xueqin Xie , Kaiyuan Han , Ting Wang , Zhepeng Wang , Luqiang Zhang , Hao Lyu , 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":"2026-01-29","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}
Pub Date : 2026-01-28DOI: 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.
{"title":"Ageing and liver immune cells","authors":"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","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":"2026-01-28","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}
Pub Date : 2026-01-23DOI: 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.
{"title":"Role of lysosomal morphology in aging and age-related diseases","authors":"Huimin Liu, Haiqing Tang, 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":"2026-01-23","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}
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.
{"title":"Oligodendrocytes at the crossroads: Central players and interactive partners in white matter aging","authors":"Xinxin Zhang , Peiyao Yu , Yicheng Chen , Yanzhi Xu , Ruofei Xu , Xinyu Yang , Shichao Lv , Hongcai Shang , Yue Hu","doi":"10.1016/j.arr.2026.103034","DOIUrl":"10.1016/j.arr.2026.103034","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"115 ","pages":"Article 103034"},"PeriodicalIF":12.4,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146047488","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}
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).
{"title":"exBAClock: A comprehensive database of published clocks for age quantification and age-related diseases","authors":"Anastasiya Kobelyatskaya , Anastasiya Novoselova , Ksenia Bylinskaya , Nikolai Nemirovich-Danchenko , Mikhail Ivanchenko , Claudio Franceschi , 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":"2026-01-22","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}
Pub Date : 2026-01-22DOI: 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。
{"title":"The m⁶A epitranscriptome: A regulatory nexus linking cellular senescence and oncogenesis","authors":"Yao Xu , Xin Zhou , Xiaoling Su , Wenxi Xie , Zhijie Huang , Shan Yu , Jinghua Tan , Jun He , 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":"2026-01-22","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}
Pub Date : 2026-01-22DOI: 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.
{"title":"Exercise and the hallmarks of cardiovascular aging","authors":"Dan Zhong , Benjamin Fernández-García , Priyanka Gokulnath , Kexin Lin , Guoping Li , Guido Kroemer , Carlos López-Otín , 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":"2026-01-22","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}
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。
{"title":"Evaluating senescence-targeted approaches in Alzheimer’s Disease: What we know and what lies ahead","authors":"Pratik Prashant Doshi , Sakshee Hemant Desale , Aarti Ashok Khutale , Sarvesh Sabarathinam , 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":"2026-01-19","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}
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