Aging and Disease最新文献

{"title":"APOE ε4 and Insulin Resistance Influence Path-Integration-Based Navigation through Distinct Large-Scale Network Mechanisms.","authors":"Karel M Lopez-Vilaret, Marina Fernandez-Alvarez, Anne Bierbrauer, Nikolai Axmacher, Jose L Cantero, Mercedes Atienza","doi":"10.14336/AD.2024.0975","DOIUrl":"https://doi.org/10.14336/AD.2024.0975","url":null,"abstract":"<p><p>Path integration (PI), which supports navigation without external spatial cues, is facilitated by grid cells in the entorhinal cortex. These cells are often impaired in individuals at risk for Alzheimer's disease (AD). However, other brain systems can compensate for this impairment, especially when spatial cues are available. From a graph-theoretical perspective, this compensatory mechanism might manifest through changes in network segregation, indicating shifts in distinct functional roles among specialized brain regions. This study explored whether similar compensatory mechanisms are active in APOE ε4 carriers and individuals with elevated insulin resistance, both susceptible to entorhinal cortex dysfunction. We applied a graph-theoretical segregation index to resting-state fMRI data from two cohorts (aged 50-75) to assess PI performance across virtual environments. Although insulin resistance did not directly impair PI performance, individuals with higher insulin resistance demonstrated better PI with less segregated brain networks, regardless of spatial cue availability. In contrast, the APOE effect was cue-dependent: ε4 heterozygotes outperformed ε3 homozygotes in the presence of local landmarks, linked to increased sensorimotor network segregation. When spatial cues were absent, ε4 carriers exhibited reduced PI performance due to lower segregation in the secondary visual network. Controlling cortical thickness and intracortical myelin variability mitigated these APOE effects on PI, with no similar adjustment made for insulin resistance. Our findings suggest that ε4 carriers depend on cortical integrity and spatial landmarks for successful navigation, while insulin-resistant individuals may rely on less efficient neural mechanisms for processing PI. These results highlight the importance of targeting insulin resistance to prevent cognitive decline, particularly in aging navigation and spatial cognition.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799045","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":"Aging Deteriorates Blood Brain Barrier Function and Polarizes Adaptive T Cell Expansion Contributing to Neurocognitive Damage in Experimental Cirrhosis.","authors":"Sebastiań Martínez-López, María Salud García-Gutiérrez, Francisco Navarrete, Isabel Gómez-Hurtado, Pedro Zapater, Enrique Ańgel, Oriol Juanola, Juan L López-Cánovas, Paula Boix, Manel C Hadid, Amaya Puig-Kröger, Manuel D Gahete, Jorge Manzanares, Esther Caparrós, Rubén Francés","doi":"10.14336/AD.2024.0932","DOIUrl":"https://doi.org/10.14336/AD.2024.0932","url":null,"abstract":"<p><p>Cirrhosis incidence is significantly increased with age and frequently complicated with neurocognitive dysfunction. We have evaluated the contribution of aging to neuroinflammation in the liver-brain axis in advanced chronic liver disease. Young (6-week-old) and old (9-month-old) mice were included in a 12-week protocol of CCl₄-induced cirrhosis. Liver damage, neuromotor and cognitive capacities, blood brain barrier integrity and function, liver and brain T cell subpopulations and ammonia levels were evaluated. Timp1 and Acta2 gene expression was upregulated in old cirrhotic mice. Increased liver damage was confirmed histologically by Sirius red staining, expression of alpha-SMA, collagen 1-alpha1 and vimentin in aged CCl₄-treated mice. Aging further compromised the neuromotor and cognition capabilities in cirrhotic animals. Stress axis components Crh and its receptor Nr3c1 gene expression levels were upregulated in the paraventricular nucleus and hippocampus of old cirrhotic mice. CCl₄-damage significantly increased ammonia levels in the liver, brain and serum of cirrhotic mice. Circulating ammonia was significantly higher in old cirrhotic mice. Significant correlations were established between brain ammonia, neuromotor capabilities and results on the object recognition tests. A decreased integrity of blood brain barrier was accompanied by astrocyte activation and increased apoptosis-linked cleaved Caspase 3 in old cirrhotic mice. Liver resident CD4⁺ T-cell subpopulations were contracted in cirrhosis, although they showed a pro-inflammatory Th17 profile. Liver and brain resident CD8⁺ T-cell subpopulations were expanded in old cirrhotic animals, along with reduced tissue cytolytic activity. CD8⁺ T cell expansion and reduced perforin levels in the brain correlated with neuromotor and cognitive dysfunction. In conclusion, aging aggravates liver fibrosis, worsens neuromotor and cognitive functions and shifts liver and brain adaptive T cell profiles compromising the BBB integrity in experimental advanced chronic liver disease. Results strengthen the impact of aging in the liver-brain axis and neuroinflammation in cirrhosis.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799043","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":"Histone Methylation, Energy Metabolism, and Alzheimer's Disease.","authors":"Jiaqi Fu, Li An","doi":"10.14336/AD.2024.0899","DOIUrl":"https://doi.org/10.14336/AD.2024.0899","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is an insidious, progressive, and irreversible neurodegenerative disease characterized by the deposition of extracellular amyloid β-protein (Aβ) to form senile plaques and abnormal phosphorylation of intracellular tau protein to form neuronal fiber tangles. The pathogenesis of AD is complex, and there are several hypotheses, primarily including the Aβ cascade hypothesis, the neurofibrillary tangle hypothesis, the inflammatory hypothesis, and the cholinergic hypothesis. It has been suggested that the dysregulation of multiple energy metabolic pathways, especially mitochondria metabolism, may be related to the severity of AD pathology and disease symptoms in the brain. The modification of histone (lysine) methylation, an actively regulated and reversible process, is closely related to energy metabolism and plays a crucial role in AD development. In summary, histone methylation, energy metabolism, and AD restricted and regulated each other. Here, we review the advances in the correlation between histone methylation, energy metabolism, and AD. This can provide further insights into the mechanisms underlying AD pathogenesis and its control.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799054","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 Organ-Joint Axes in Osteoarthritis: Significant Pathogenesis and Therapeutic Targets.","authors":"Dinglong Yang, Yujing Chen, Junfei Guo, Xin Xu, Mingyi Yang, Jiale Xie, Ke Xu, Peng Xu","doi":"10.14336/AD.2024.1223","DOIUrl":"https://doi.org/10.14336/AD.2024.1223","url":null,"abstract":"<p><p>Osteoarthritis (OA), a prevalent age-related disease, is increasingly recognized as a multifactorial condition. This comprehensive review provides a multifaceted perspective on the organ-joint crosstalk contributing to OA, transcending the traditional focus on local joint pathology. Based on current research, we discussed the brain-joint, gut-joint, muscle-joint interactions in the etiology and progression of OA. In brain-joint axis, the neuroendocrine regulation, circadian rhythms, and leptin signaling influence joint tissues. We also discussed the role of prostaglandin E2 in skeletal interoception and its potential as a therapeutic target. The gut-joint axis is underscored by the impact of gut microbiota dysbiosis on systemic inflammation and metabolic disorders, both of which are implicated in OA pathogenesis. Furthermore, age-related sarcopenia, characterized by muscle mass and strength loss, is identified as a significant risk factor. Sarcopenia may contribute to OA progression through compromised mechanical support, systemic inflammation, and muscle-derived myokines. Finally, we synthesize the evidence supporting the modulation of circadian rhythm, skeletal interoception, gut microbiome, and muscle mass as innovative strategies for OA management. The organ-joint crosstalk is integral to the complex pathogenesis of OA, highlighting the multifactorial nature of OA and the potential for targeted therapeutic interventions. By integrating these multidimensional perspectives, we aim to enhance our understanding of OA pathogenesis and explore potential pharmacological targets.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799089","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":"Exercise Types: Physical Activity Mitigates Cardiac Aging and Enhances Mitochondrial Function via PKG-STAT3-Opa1 Axis.","authors":"Reka Szekeres, Daniel Priksz, Mariann Bombicz, Beata Pelles-Tasko, Anna Szilagyi, Brigitta Bernat, Aniko Posa, Balazs Varga, Rudolf Gesztelyi, Sandor Somodi, Zoltan Szabo, Zoltan Szilvassy, Bela Juhasz","doi":"10.14336/AD.2024.0959","DOIUrl":"https://doi.org/10.14336/AD.2024.0959","url":null,"abstract":"<p><p>Although age-related deterioration of the cardiac function is a well-studied area of research, the interventions and their molecular pathways have not yet been fully identified. Since physical activity is a powerful preventive measure against cardiac aging, our study compared the effects of long-term voluntary and forced physical activity with a sedentary group, utilizing an aging rat model characterized by mitochondrial dysfunction that contributes to age-related cardiovascular diseases. Four experimental groups were created: (I) young controls (12-week-old); (II) 18-month-old aged sedentary rats; (III) aged group with free access to running wheels for 6 months; (IV) aged rats subjected to forced physical activity for 6 months. At the endpoint of the study, the aged animals were two years old. The aged sedentary rats exhibited increased Tei-index, LA/Ao and E/e' ratios as well as decreased e'/a' ratio and lengthened DecT and IVRT, higher perivascular fibrosis ratio and reduced myocardial PKG, STAT3 and Opa1 protein expression, along with decreased ATP synthase (ATPS) activity in comparison to the young controls. In terms of echocardiographic parameters and perivascular fibrosis, the forced running provided more substantial benefits than the voluntary activity demonstrated by decreased Tei-index, E/e' ratio, increased e'/a' ratio and reduced DecT and IVRT. Forced exercise was strongly associated with elevated myocardial expression of PKG, STAT3 and Opa1 proteins and, moreover, the ATPS activity was restored only in the forced running rats. In conclusion, forced but not voluntary exercise has significant protective effects on age-associated diastolic dysfunction by upregulating PKG-STAT3-Opa1 axis and thereby enhancing ATPS activity.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685681","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":"Mechanisms of the Mitochondrial Unfolded Protein Response in Caenorhabditis elegans and Mammals and Its Roles in Striated Muscles.","authors":"Tongxiao Luan, Song Hu, Weihong Nie, Jia Liu, Li Jia, Shan Wang, Jing Zhou, Nina An, Yuting Duan, Aohua Wang, Mengru Xu, Yongjun Mao","doi":"10.14336/AD.2024.1019","DOIUrl":"https://doi.org/10.14336/AD.2024.1019","url":null,"abstract":"<p><p>Throughout the course of evolution, organisms and cells have evolved a suite of mechanisms to manage persistent stimuli, thereby preserving cellular and organismal homeostasis. Upon detecting stress signals, cells activate a transcriptional response termed the mitochondrial unfolded protein response (UPR^mt). This response is crucial for maintaining protein homeostasis, facilitating mitochondrial function recovery, promoting cell survival, and ultimately influencing lifespan. Striated muscles play a pivotal role in oxygen supply, movement, and metabolism. The aging of these muscles can lead to heart failure, arrhythmias, and sarcopenia, significantly impacting quality of life and lifespan. Given the intimate connection between UPR^mt and striated muscle aging, UPR^mt emerges as a potential therapeutic target for mitigating the effects of striated muscle aging. In this review, we delve into the role of UPR^mt in striated muscle aging, drawing upon the extant molecular regulatory mechanisms of UPR^mt. This exploration may enhance our understanding of the underlying mechanisms of striated muscle aging and aid in the identification of potential drug targets.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685685","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":"Normal Bone Matrix Mineralization but Altered Growth Plate Morphology in the Lmna^G609G/G609G Mouse Model of Progeria.","authors":"Stéphane Blouin, Markus A Hartmann, Nadja Fratzl-Zelman, Phaedra Messmer, Daniel Whisenant, Michael R Erdos, Francis S Collins, Maria Eriksson, Charlotte Strandgren, Wayne A Cabral, Thomas Dechat","doi":"10.14336/AD.2024.1094","DOIUrl":"https://doi.org/10.14336/AD.2024.1094","url":null,"abstract":"<p><p>Hutchison-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by a mutation in LMNA, the gene encoding A-type lamins, leading to premature aging with severely reduced life span. HGPS is characterized by growth deficiency, subcutaneous fat and muscle issue, wrinkled skin, alopecia, and atherosclerosis. Patients also develop a bone phenotype with reduced bone mineral density, osteolysis and striking demineralization of long bones. To further clarify the tissue modifications in HGPS, we characterized bone mineralization in the Lmna^G609G/G609G progeria mouse model. Femurs from 8-week-old mice and humeri from 15-week-old mice were analyzed using quantitative backscattered electron imaging to assess bone mineralization density distribution, osteocyte lacunae sections and structural bone histomorphometry. Tissue sections were stained with Giemsa and Goldner trichrome for histologic evaluation. Bone tissue from Lmna^+/+ and Lmna^G609G/G609G mice had similar mineral content at 3 different bone sites with specific tissue ages. The osteocyte lacunae features were not statistically different, but more empty lacunae were found in Lmna^G609G/G609G at both animal ages. Bone histomorphometry and histology demonstrated decreased bone volume per tissue volume in primary (8W: -23%, p=0.001; 15W: -38%, p=0.002) and secondary spongiosa (8W: -36%, p=0.001; 15W: -49 %, ns), as well as growth plate dysplasia with thinner unmineralized resting and proliferative zones in the Lmna^G609G/G609G mice versus controls (8W: -18%, p=0.006; 15W: -25%, p=0.001). Overall, the Lmna^G609G/G609G mouse develops chondrodysplasia with reduced trabecular bone volume. Mineral content findings at several tissue sites and ages suggest that bone dysplasia results from impaired bone formation with normal bone turnover.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685702","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 Impact of Aging on Neurological Diseases in the Elderly: Molecular Mechanisms and Therapeutic Perspectives.","authors":"Dan Zhou, Yumeng Lin, Zhongyu Han, Zhuyun Zhang, Le Lin, Shichong Lin, Qianke Yang","doi":"10.14336/AD.2024.1085","DOIUrl":"https://doi.org/10.14336/AD.2024.1085","url":null,"abstract":"<p><p>With the progression of global aging, neurological diseases in elderly individuals have aroused widespread interest among researchers. Imbalances in the homeostasis of neuronal microenvironments, including neural progenitor cells and microglia, are the leading cause of worsening neurodegenerative diseases. The aging of various glial cells can further lead to abnormal functions in the central nervous system (CNS). Recent studies have shown that aging plays a vital role in a variety of degenerative diseases, including Huntington's disease (HD). In this manuscript, we describe the molecular mechanisms of aging, the cellular constitution of the neural microenvironment and the progression of aging in various neurodegenerative diseases, providing new targets and perspectives for the clinical treatment of various neurodegenerative diseases.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685801","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":"Differential Roles of Astrocytic CSF1 in Alzheimer's Disease and Cerebral Amyloid Angiopathy: Insights from Transcriptomic Analysis.","authors":"Chunyuan Li, Yashuang Chen, Shiqi Luo, Yan Yang, Xinnan Liu, Sijie Li, Wei Ge, Cong Han","doi":"10.14336/AD.2024.10530","DOIUrl":"https://doi.org/10.14336/AD.2024.10530","url":null,"abstract":"<p><p>Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) are neurodegenerative disorders characterized by the pathological deposition of amyloid-beta (Aβ) in the brain. Although both conditions share common pathogenic pathways, they exhibit distinct cellular manifestations and disease progression. This study focused on the differential expression and role of astrocytic colony-stimulating factor 1 (CSF1) in these diseases. Through transcriptomic analysis of 248 brain tissue samples from the hippocampal-entorhinal system of 50 individuals, we identified a significant increase in CSF1 expression in the CA4 subfield of AD patients, contrasting with a marked decrease in CAA. Functional investigations revealed that astrocytes with elevated CSF1 levels displayed neurotoxicity associated with AD-like pathology, while reduced CSF1 expression in astrocytes was linked to vascular damage characteristic of CAA. These findings suggest that CSF1 plays divergent roles in AD and CAA, contributing to their distinct pathological profiles. Our study highlights the potential of targeting astrocytic CSF1 expression as both a differential diagnostic marker and a therapeutic approach in managing these overlapping yet distinct neurological conditions.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685778","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":"Spiritual Rejuvenation: An Alternative Way to Healthy Aging.","authors":"Dalmacito A Cordero","doi":"10.14336/AD.2024.1375","DOIUrl":"https://doi.org/10.14336/AD.2024.1375","url":null,"abstract":"","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685797","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}