Aging and Disease最新文献

{"title":"Acute Myocardial Infarction and Ischemic Stroke as Systemic Accelerators of Atherosclerotic Plaque Inflammation and Vulnerability.","authors":"Jiang-Ming Yu, Yu-Xiao Liu, Qin Li, Jia-Bin Zong, Tuersun Aili, Xin-Ran Zhao, Bo Hu, Jie-Hong Wu","doi":"10.14336/AD.2026.1495","DOIUrl":"https://doi.org/10.14336/AD.2026.1495","url":null,"abstract":"<p><p>Acute ischemic cardio-cerebrovascular events are critical clinical emergencies characterized by sudden interruption of arterial blood supply to the myocardium or cerebral tissue, predominantly presenting as acute myocardial infarction and ischemic stroke. Individuals affected by these events exhibit a significantly elevated risk of recurrence, particularly during the critical timeframe spanning the initial weeks to months following the primary incident. Accumulating evidence reveals that, in the aftermath of acute ischemic events, endothelial senescence and sustained endothelial dysfunction are mediated by trained immunity, alongside signaling cascades activated by exosome-derived ligands and neutrophil extracellular trap (NET)-derived cell-free DNA-most notably encompassing the Notch1 pathway and the high mobility group box 1-receptor for advanced glycation end products (HMGB1-RAGE) axis. Furthermore, neuroendocrine responses coupled with glucose metabolic dysregulation contribute to systemic inflammation and promote atherosclerotic progression. Current preclinical models highlight the therapeutic efficacy of multifaceted interventions, ranging from targeted interventions and immunomodulation to chemokine-receptor blockade. Consequently, this review elucidates the underlying mechanisms promoting post-ischemic plaque destabilization and systematically evaluates therapeutic strategies designed to minimize recurrence and optimize long-term patient outcomes.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extreme Longevity Areas: Redefining the Need for A Transparent and Standardized Framework.","authors":"José María Faílde Garrido, María Dolores Dapía Conde, Alberto Ruano-Ravina, Mónica Pérez-Ríos, Guadalupe García","doi":"10.14336/AD.2026.0673","DOIUrl":"https://doi.org/10.14336/AD.2026.0673","url":null,"abstract":"<p><p>The concept of extreme longevity areas, geographically circumscribed areas with an extremely high prevalence of centenarians compared with surrounding regions, has attracted increasing scientific and public attention in recent decades. The Extreme Longevity Index (ELI), based on birth-cohort survival, is the main operational metric currently used to identify such areas. However, its application remains highly heterogeneous, and no standardized and transparent framework exists for the robust and reproducible characterization of extreme longevity patterns. In this commentary, we identify key methodological limitations in current approaches and argue for the need to strengthen the conceptual basis of this field. These limitations include insufficiently defined population denominators, variability in the handling of migrations, inconsistent spatial analytical approaches, lack of agreed thresholds for defining extreme values, limited specification of appropriate observation periods, and variable standards of registry quality and age validation. We further argue that a more robust approach should incorporate mechanisms for periodic reassessment, broader demographic profiling beyond centenarians alone, and clearer definitions of territorial continuity. In the absence of such methodological standardization, the validity and comparability of reported extreme longevity areas remain uncertain, including the calculations used to characterize previously described regions. Establishing a coherent and transparent framework is therefore necessary to strengthen the scientific foundations of this field.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ubiquitin-Dependent Protein Quality Control in Polyglutamine Diseases.","authors":"Matthew V Prifti, Kristin Richardson, Sokol V Todi","doi":"10.14336/AD.2026.0887","DOIUrl":"https://doi.org/10.14336/AD.2026.0887","url":null,"abstract":"<p><p>Polyglutamine diseases comprise a family of nine age-dependent disorders caused by CAG triplet-repeat expansions that produce misfolded proteins with elongated glutamine tracts. Although these diseases share proteotoxic stress and engagement of protein quality control pathways as responses to their presence and disruptive activities, they differ in protein context, normal function, localization, interactomes and selective vulnerability. Here, we review how expanded polyglutamine proteins engage ubiquitin-dependent protein quality control across Huntington's disease, dentatorubral-pallidoluysian atrophy, spinal and bulbar muscular atrophy, and spinocerebellar ataxias 1, 2, 3, 6, 7 and 17. Rather than treating protein quality control as a uniform response, we emphasize pathway selectivity. A central theme arises across these diseases: mutant polyglutamine proteins are recognized by ubiquitin-related machinery, but recognition does not necessarily produce productive degradation. Instead, disease-specific outcomes are shaped by tissue context, subcellular localization, aggregate state, disease protein fragmentation, normal protein function, compensatory pathway activation and local proteostasis capacity over time. The information synthesized in this review may help the field develop a more comparative and granular understanding of processes and pathways that are shared or divergent among polyglutamine diseases and may also inform more targeted therapeutic strategies for this family of incurable disorders.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The IGF/IGFR System During Chronic Liver Disease: Role in Neurocognitive Complications and Aging.","authors":"Ani Gasparyan, Esther Caparrós, Rubén Francés","doi":"10.14336/AD.2026.0576","DOIUrl":"https://doi.org/10.14336/AD.2026.0576","url":null,"abstract":"<p><p>Aging is associated with a significant functional impairment of different organs, including liver, and it increases sensitivity to the development of liver-related complications. In fact, advanced chronic liver disease is higher in aged populations and is associated with worse prognosis. These patients frequently show a dysfunctional liver-brain axis and exhibit mild neurocognitive dysfunction, which significantly impairs quality of life. The insulin-like growth factor system is the major endocrine system regulating energy and substrate metabolism, participating also in growth, proliferation and regulation of tissue-specific cell differentiation. Several studies have shown that the IGF1-IGF1R system is significantly altered in CLD contributing to CD4+ T cell activation and differentiation toward Th17, a main driver of the inflammatory microenvironment and liver tissue damage present in these patients. Recent studies highlight the involvement of Th17 cells in cognitive impairment. These cells can breach the blood-brain barrier and exacerbate brain injury in various neurological disorders. Neuroinflammation is also linked to the insulin-like growth factor system, as IGF is involved in the protein synthesis necessary for the growth and survival of different cell populations of the brain, such as neurons, astrocytes and microglia. Thus, an altered IGF/IGFR system is involved in cognitive decline and memory, and several studies have revealed its implication in aging and cell senescence. This narrative review summarizes the participation of the IGF/IGFR system in chronic liver disease, focusing on its multifactorial role on the liver-brain axis and its contribution to inflammatory and neurocognitive complications developed during aging in these patients.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Pathology-Trained Lipid Aging Clock Reveals Accelerated Aging and Prognostic Sphingolipid Signatures in Pancreatic Disease.","authors":"Maximilian Unfried, Amaury Cazenave-Gassiot, Evelyne Bischof, Michal Holcapek, Morten Scheibye-Knudsen, Markus R Wenk, Jan Gruber, Brian K Kennedy","doi":"10.14336/AD.2026.0300","DOIUrl":"https://doi.org/10.14336/AD.2026.0300","url":null,"abstract":"<p><p>Altered lipid metabolism is increasingly recognized as a feature of aging and age-related disease, including cancer. Here, we present a lipid-based biological aging clock developed from serum lipidomics data of 443 patients with pancreatic ductal adenocarcinoma (PDAC). Using penalized Cox proportional hazards models, we derived a risk-equivalent Lipid Age and Lipid Age Acceleration (LAA) metric and evaluated its relationship to survival, healthy aging, and pancreatitis. Despite being trained exclusively on a pathological PDAC cohort, the lipid clock predicted chronological age in healthy individuals with high accuracy (Pearson r=0.86; median absolute error = 3.46 years), indicating that pathological cohorts can retain biologically meaningful aging signals. Both PDAC patients and, in exploratory analyses, pancreatitis patients exhibited accelerated lipid aging relative to healthy individuals, with mean LAA values of 5.57 and 2.71 years, respectively. Increased continuous LAA was significantly associated with worse overall and progression-free survival and remained predictive of overall mortality even after adjusting for standard clinical cancer measures, staging, and the conventional tumor marker CA19-9 (HR=1.09 per 1-year increase, p<0.005). Specific individual lipid species, particularly sphingolipids, carried independent prognostic value. Lipid age acceleration was associated with pancreatic disease and with lipidomic patterns consistent with systemic aging-associated and inflammatory remodeling independent of traditional oncological risk parameters. Because the model was developed and evaluated within a single parent dataset and analytical platform, external validation in independent cohorts will be needed to establish broader generalizability.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Context-Dependent Roles of p53 in Cellular Senescence and Fibrosis.","authors":"Asish K Ghosh, Karim Ullah, Cian O'Donnell, Rishi Arora","doi":"10.14336/AD.2026.0543","DOIUrl":"https://doi.org/10.14336/AD.2026.0543","url":null,"abstract":"<p><p>Cellular senescence is an irreversible growth arrest state and a hallmark of organismal aging. While induction of cellular senescence in healthy organs is undesirable, senescence of specific cell types can be beneficial in certain pathological milieus. For instance, the senescence of activated myofibroblasts helps to limit excessive collagen deposition and preserving tissue homeostasis. Senescent cells express signature gene products, including cell cycle regulators and senescence-associated secretory phenotype (SASP), which includes proinflammatory cytokines, growth factors, and protease inhibitors. Among the senescence regulators, the tumor suppressor p53 plays a pivotal role in suppression of fibrogenesis by dual action: through transcriptional repression of matrix protein genes, and through activation of the cellular senescence pathway in matrix-producing myofibroblasts. Because p53 activation suppresses collagen synthesis, it offers a promising treatment for most fibrotic diseases. However, sustained activation of p53 stress-response in healthy cells may accelerate cellular senescence and aging by promoting the release of SASP. Therefore, the magnitude and timing of p53 activation are critical factors that determine whether its effects are beneficial or detrimental in a given pathological milieu. Here, we discuss the fascinating dual trajectory of p53: its role in driving cellular senescence that contributes to aging, and its capacity to limit the progression of fibrogenesis, a major driver of age-related morbidity and mortality worldwide.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Motor System Neurodegeneration in Aging and Synucleinopathies: Circuit Vulnerability and Neuroimaging Biomarkers.","authors":"Jiaqi Wen, Xiaojun Xu, Yulin Ge","doi":"10.14336/AD.2026.0457","DOIUrl":"https://doi.org/10.14336/AD.2026.0457","url":null,"abstract":"<p><p>Aging is the primary risk factor for synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), and independently contributes to motor dysfunction. This review summarizes motor system degeneration in aging and disease, focusing on the primary motor cortex (M1), its white matter tracts, and the nigrostriatal system. In healthy aging, M1 exhibits cortical thinning, myelin loss, reduced perfusion, and iron deposition. The motor cortex-derived corticospinal and corticostriatal pathways undergo microstructural decline, often linked to vascular factors. The substantia nigra (SN) demonstrates selective neuronal loss, oxidative stress, iron deposition, and synaptic reduction, contributing to motor impairment. In synucleinopathies, these age-related vulnerabilities are exacerbated by disease-specific pathology. In PD, progressive dopaminergic neuron loss in the SN is a core feature, detectable with advanced magnetic resonance imaging (MRI) markers of iron, neuromelanin, and microstructure. PD pathophysiology extends beyond the nigrostriatal system, involving M1 dysfunction and widespread white matter abnormalities linked to motor deficits and cognitive impairment. DLB is characterized by widespread involvement of cortex (especially posterior), limbic, basal ganglia, brainstem, and cholinergic system, accounting for its early cognitive impairment, neuropsychiatric, motor, and autonomic symptoms. In contrast, MSA is characterized by oligodendroglial α-synuclein inclusions, causing multi-system degeneration, with characteristic atrophy and microstructural disruption in the putamen, pons, and cerebellum that aid differential diagnosis. Multiparametric MRI offers in vivo insights into structural, microstructural, hemodynamic, metabolic, and pathological changes underlying motor dysfunction in aging and neurodegenerative disorders. Understanding the convergence of age-related motor neuron degeneration and disease-specific pathology is essential for elucidating disease mechanisms, identifying early biomarkers, and developing targeted therapies in synucleinopathies.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148885998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Glymphatic and Meningeal Lymphatic Systems: Gatekeepers of Brain Health in Aging and Neurodegeneration.","authors":"Tayyab Iqbal, Sana Tabassum, Muhammad Imran, Shilong Tang, Pengyu Xiao, Ting Wei, Dilizhawaer Hailaiti, Ping Fan, Weitian Lu, Haiyu Li, Juan Huang","doi":"10.14336/AD.2026.0009","DOIUrl":"https://doi.org/10.14336/AD.2026.0009","url":null,"abstract":"<p><p>The discovery of the glymphatic system and of meningeal lymphatic vessels has substantially revised our understanding of how the central nervous system clears waste and maintains neuroimmune homeostasis. Acting in series, these two pathways remove interstitial solutes, metabolic by-products, and neurotoxic proteins such as tau and amyloid-β from the brain parenchyma and deliver them to the peripheral lymphatic system. Converging experimental and clinical evidence indicates that both pathways decline with age, and that impaired clearance contributes to the onset and progression of Alzheimer's disease, Parkinson's disease, and stroke, although the direction of causality in these associations is not yet fully resolved. In this review, we summarize current knowledge of the anatomy and physiology of the glymphatic and meningeal lymphatic systems; examine the molecular and cellular mechanisms by which their function deteriorates with age; appraise the imaging modalities and fluid biomarkers used to assess them; and evaluate the therapeutic strategies being developed to restore them. A clearer understanding of this clearance pathways may open new avenues for the treatment of age-related neurodegenerative disease.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148885982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myo-Inositol Dampens Apathetic Symptoms in Aged Mice and Is Associated with Sex-Specific Synapse Remodelling.","authors":"Chiara D'Amelio, Francesca Natale, Sara Autelitano, Nicola Locci, Ida Nifo Sarrapochiello, Nicoletta Garofalo, Marco Rinaudo, Salvatore Fusco, Claudio Grassi","doi":"10.14336/AD.2026.0255","DOIUrl":"https://doi.org/10.14336/AD.2026.0255","url":null,"abstract":"<p><p>Late-life depression is associated with reduced treatment efficacy and age-related impairments in synaptic plasticity and stress responsiveness. Myo-inositol, an endogenous regulator of phosphoinositide signalling, has been proposed as candidate treatment for mood disorders, but its effects in age-related mood disorders remain unclear. Here, we investigated the impact of chronic myo-inositol supplementation on depressive behaviour and synaptic markers in aged male and female mice. Aged mice displayed reduced self-care behaviour in the sucrose splash test compared to young adults. Myo-inositol supplementation restored grooming behaviour in both sexes, an effect maintained following exposure to unpredictable chronic mild stress and independent of locomotor activity. Molecular analyses revealed sex-specific synaptic adaptations, with myo-inositol enhancing postsynaptic density protein 95 (PSD-95) levels in aged males, while increasing phosphorylation of the AMPA receptor subunit GluA1 at serine 845 and TARP expression in females. These findings demonstrate that myo-inositol dampens age-related apathetic alterations and is associated with sex-specific synaptic mechanisms, supporting its potential as a therapeutic strategy for late-life depression.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endocrine Factors in Sarcopenia: Lifestyle-Based Approaches with Nutrition, Exercise, and Circadian Health.","authors":"Sihyung Lee, Choon Young Kim","doi":"10.14336/AD.2026.0483","DOIUrl":"https://doi.org/10.14336/AD.2026.0483","url":null,"abstract":"<p><p>Sarcopenia, the age-related skeletal muscle disorder characterized by declines in muscle mass, strength, and physical performance, has significant health consequences and represents a major global public health challenge. Age-related endocrine and peripheral anabolic-catabolic dysregulation plays a central role in sarcopenia development, and lifestyle factors interact with hormonal regulation to influence skeletal muscle homeostasis. In older adults, reduced hormone secretion capacity, receptor responsiveness, and peripheral metabolism impair hormonal systems, including the somatotropic, gonadal, adrenal, and thyroid axes, as well as insulin and peripheral mediators, such as adipokines, myokines, and inflammatory cytokines. These alterations promote anabolic resistance, a catabolic environment, and metabolic dysfunction, contributing to sarcopenia. Age-related changes in appetite, nutrient utilization, and food choice impair anabolic efficiency and metabolic homeostasis. Declines in physical activity and neuromuscular efficiency disrupt multiple signaling pathways required to maintain muscle mass, and psychosocial factors may increase the risk of a vicious cycle of inactivity. Alterations in the suprachiasmatic nucleus (SCN) and inconsistent behavioral zeitgebers disrupt physiological rhythms. These lifestyle domains influence skeletal muscle homeostasis independently and interact bidirectionally through shared endocrine pathways. Current pharmacological approaches remain adjunctive, limited to confirmed endocrine deficiencies. The coordinated optimization of nutrition, exercise, and circadian health, with attention to regularity and timing, may offer complementary benefits exceeding single-domain interventions. A stage-specific and individually tailored approach supported by multidimensional monitoring and digital technologies is recommended for effective sarcopenia prevention and management.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}