Aging and Disease最新文献

{"title":"The Expanding Burden of Neurodegenerative Diseases: An Unmet Medical and Social Need.","authors":"Shu Wang, Yin Jiang, Anchao Yang, Fangang Meng, Jianguo Zhang","doi":"10.14336/AD.2024.1071","DOIUrl":"https://doi.org/10.14336/AD.2024.1071","url":null,"abstract":"<p><p>Neurodegenerative diseases, particularly Alzheimer's disease and other dementias as well as Parkinson's disease, are emerging as profoundly significant challenges and burdens to global health, a trend highlighted by the most recent Global Burden of Disease (GBD) 2021 studies. This growing impact is closely linked to the demographic shift toward an aging population and the potential long-term repercussions of the COVID-19 pandemic, both of which have intensified the prevalence and severity of these conditions. In this review, we explore several critical aspects of this complex issue, including the increasing global burden of neurodegenerative diseases, unmet medical and social needs within current care systems, the unique and amplified challenges posed by the COVID-19 pandemic, and potential strategies for enhancing healthcare policy and practice. We underscore the urgent need for cohesive, multidisciplinary approaches across medical, research, and policy domains to effectively address the increasing burden of neurodegenerative diseases, thereby improving the quality of life for patients and their caregivers.</p>","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":"142685799","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":"Circulating Ketone Bodies, Pyruvate, and Citrate and Risk of Cognitive Decline, Structural Brain Abnormalities, and Dementia.","authors":"Laia Gutierrez-Tordera, Kristine F Moseholm, Marta Trius-Soler, Mònica Bulló, Annette Fitzpatrick, Margery A Connelly, Oscar L Lopez, Majken K Jensen, Marta Guasch-Ferré, Kenneth J Mukamal","doi":"10.14336/AD.2024.0754","DOIUrl":"https://doi.org/10.14336/AD.2024.0754","url":null,"abstract":"<p><p>The relationship between key energy metabolites and brain health is not well understood. We investigated the association between circulating ketone bodies, pyruvate, and citrate with cognitive decline, structural brain characteristics, and risk of dementia. We measured ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone), pyruvate, and citrate species using NMR in plasma samples from 1,850 older adults in the Cardiovascular Health Study collected in 1989-90 or 1992-93. Cognitive decline was assessed using the modified Mini-Mental State Examination and the Digit Symbol Substitution Test. Dementia was adjudicated by a committee of experts through comprehensive evaluations including cognitive tests, medical records, and interviews with the next of kin. Dementia-related mortality was confirmed by a committee using death certificates and other clinical data from hospitalization. Multivariable linear mixed models were used to assess 9-year cognitive decline, while multivariable Cox regression models evaluated 6-year dementia incidence and 22-year dementia-related mortality. White matter lesions and ventricular size were measured using MRI in 1992-94 and were analyzed using multivariable linear regression models. Higher plasma levels of ketones, particularly β-hydroxybutyrate, were associated with faster cognitive decline (β, -0.10; 95% CI, -0.15 to -0.05; P_adj&;lt.001) and dementia-related mortality (HR per SD, 1.29; 95% CI, 1.07 to 1.56; P_adj=0.023). Higher pyruvate concentrations were associated with slower cognitive decline, smaller ventricular size, lower dementia risk (HR per SD, 0.87; 95% CI, 0.77 to 0.97; P=0.013; P_adj=0.073), and lower dementia mortality. Higher citrate levels were associated with less cognitive decline and lower dementia risk. In adults aged 65 years and older, circulating ketone bodies are associated with faster cognitive decline and higher dementia mortality, while pyruvate and citrate are associated with lower dementia risk.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685775","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":"Plasma Neurodegenerative Biomarkers in Cognitively Preserved Nonagenarians.","authors":"Estrella Gómez-Tortosa, Pablo Agüero-Rabes, Alicia Ruiz-González, Sonia Wagner, Raquel Téllez, Ignacio Mahillo, Andrea Ruiz-Calvo, María José Sainz, Anna Lena Nystrom, Lucía Cremades-Jimeno, Teodoro Del Ser, Pascual Sánchez-Juan","doi":"10.14336/AD.2024.1260","DOIUrl":"https://doi.org/10.14336/AD.2024.1260","url":null,"abstract":"<p><p>Plasma biomarkers represent promising tools for the screening and diagnosis of patients with neurodegenerative conditions. However, it is crucial to account for the effects of aging on biomarker profiles, especially in the oldest segments of the population. Additionally, biomarkers in this sample can offer in vivo insights into the physiological mechanisms underlying brain aging while concomitantly supporting cognitive preservation. In this study we analyzed plasma Alzheimer's disease (AD) core biomarkers, neurofilament light chain (NfL), and glial fibrillary acid protein (GFAP) using the Single Molecule Array (SIMOA) platform in 75 cognitively preserved nonagenarians, and compared with baseline samples of 153 volunteers who were cognitively unimpaired (CU) during six years (classified in ≤ 70, and 71 to 85 years of age), and with 108 AD patients. Nonagenarians almost lack the APOEε4 allele, and had significantly higher Aß40, Aß42, p-tau181, NfL, and GFAP, along with a significantly lower Aß42/40 ratio (P&;lt0.001) compared with the two CU groups. NfL and GFAP tripled concentrations in nonagenarians. No differences were noted in any plasma biomarker between the younger and older CU groups. Biomarkers correlated strongly with age only when analyzing together CU controls and nonagenarians. Compared with AD cases, nonagenarians showed lower p-tau181 (P=0.001), higher total tau (P=0.02), and much higher Aß40, Aß42 and NfL levels (P&;lt0.001). The levels of GFAP in nonagenarians were similar to those observed in AD patients. In conclusion, cognitively preserved nonagenarians do not develop the AD biomarker signature and exhibit higher levels of Aß42. However, their threefold increase in NfL and GFAP supports their aging brains are somehow resilient to neurodegeneration. These data support caution in the prognosis of clinical dementia based on NfL and GFAP values. Overall, plasma biomarkers in CU individuals remained quite stable till the eighties.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685707","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":"Bidirectional Crosstalk between the Heart and Brain in Alzheimer's Disease.","authors":"Zhitian Wang, Lv Zhou, Na Zhao, Zhijun Zhang, Junjian Zhang, Qing-Guo Ren","doi":"10.14336/AD.2024.1132","DOIUrl":"https://doi.org/10.14336/AD.2024.1132","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disorder condition linked to various systemic comorbidities. Numerous studies have shown bidirectional crosstalk between the heart and the brain, but the specifics of how these interactions occur in AD are poorly understood. This narrative review summarizes the clinical evidence for a firm link between AD and cardiovascular health and discusses the bidirectional roles of AD and the cardiovascular system. AD pathogenic proteins, AD risk genes, neurohormones, the autonomic nervous system, and neurotransmitters may affect cardiovascular health, and cardiac-derived proteins, neurohormones, vascular function, inflammation, and other potential specific molecules or neural pathways may also influence AD pathology and cognitive function. Additionally, we propose potential AD intervention strategies based on the heart-brain axis to provide novel insights into AD prevention and treatment.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685772","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":"Advancements in Targeting Macrophage Senescence for Age-Associated Conditions.","authors":"Jingwei Xiao, Hung Sing Li, Senthil Kumaran Satyanarayanan, Shu Lai Leung, Qiuju Yuan, Yaofeng Wang, Dajiang Qin, Suki Man Yan Lee","doi":"10.14336/AD.2024.0720","DOIUrl":"https://doi.org/10.14336/AD.2024.0720","url":null,"abstract":"<p><p>Macrophages, a critical subset of innate immune cells, play a pivotal role in cytokine production during disease progression, tissue injury, and pathogen invasion. Their intricate involvement in the manifestation of chronic low-grade inflammation associated with the aging process is widely acknowledged. Notably, in aged tissues, macrophages exhibit an altered phenotype characterized by an augmented synthesis of pro-inflammatory cytokines and chemokines, a profile intimately associated with a phenomenon known as inflammaging. Macrophages possess the capacity to undergo cellular senescence, a state of permanent growth arrest, in response to diverse stressors, including aging. Senescent macrophages secrete an array of pro-inflammatory molecules, growth factors, and matrix metalloproteinases, collectively referred to as the Senescence-Associated Secretory Phenotype (SASP). The SASP exacerbates the state of chronic inflammation observed in aging tissues. Thus, disruptions in macrophage function and signaling pathways due to aging result in escalated production of inflammatory mediators, perpetuating inflammaging. Recent research has uncovered novel mechanisms centred around innate immune signaling and mitochondrial dysfunction in macrophages, highlighting their crucial role in the development of inflammaging and associated pathological conditions. This review delves into the latest scientific findings on these emerging mechanisms in macrophage senescence related to aging and explores the prospects of targeting macrophages to address age- associated conditions effectively.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581097","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":"Enhancing Efficiency with an AI-Augmented Clinician in Neurology.","authors":"Krish Kapadia, Sanskriti Ruwali, Tanvi Malav, Sridhar Seshadri, Abraham Seidmann, Daniel Z Press, Vijaya B Kolachalama","doi":"10.14336/AD.2024.1249","DOIUrl":"https://doi.org/10.14336/AD.2024.1249","url":null,"abstract":"<p><p>Integrating artificial intelligence (AI) technologies into neurology promises increased patient access, engagement, and quality of care, as well as improved quality of work life for clinicians. While most studies have focused on comparing AI models to expert performance, we argue for a more practical approach: demonstrating how AI can augment clinical practice. This article presents a framework for pragmatic AI augmentation, addressing the shortage in neurology practices, exploring the potential of AI in opportunistic screening, and encouraging the concept of AI serving as a \"co-pilot\" in neurology. We discuss recommendations for future studies designed to emphasize human-computer collaboration, ensuring AI enhances rather than replaces clinical expertise.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581027","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":"Impairment of the trans-Golgi-Lysosomal Pathway Accelerates Dopaminergic Neuronal Senescence in LRRK2^R1627P Rats.","authors":"Qiumei Yang, Shimin Pang, Chunsong Zhao, Yanyan Wang, Jing Lu, Zhenyu Yue, Piu Chan","doi":"10.14336/AD.2024.0883","DOIUrl":"https://doi.org/10.14336/AD.2024.0883","url":null,"abstract":"<p><p>Leucine-rich repeat kinase 2 (LRRK2)-R1628P mutation has been shown to be one of the common risk factors for Parkinson's disease (PD) in Asian populations, but the mechanism by which R1628P mutations cause neuronal dysfunction remains unknown. We used LRRK2^R1627P knock-in rats (human LRRK2-R1628P corresponds to rat LRRK2-R1627P) to investigate the R1627P mutation on function of dopaminergic neurons (DANs) and their susceptibility to the environmental toxin Lipopolysaccharide (LPS) during aging. LRRK2^R1627P rats showed no significant loss of DANs, dopamine and its metabolites, or motor dysfunction; however, spontaneous exploration and olfactory discrimination reduced, and dendritic spines of DANs showed degeneration. We found decreased p^Thr73-Rab10 located on the trans-Golgi, disrupted Golgi structure and lipofuscin accumulation in aged LRRK2^R1627P rat DANs, and the protein related to trans-Golgi complex and regulating lysosome function were significantly reduced. Although the neuroinflammation of brain was not obvious in the aging process, we confirmed a decrease in the ratio of CD4⁺/CD8⁺ and B cells, an increase in inflammatory factors (TLR4, NFKB, TNF-α) in the periphery. Furthermore, we demonstrated that the R1627P mutation caused the abnormal accumulation of α-Syn in the aged rat intestine. LPS exacerbated pathological α-Syn aggregation in the small intestine of LRRK2 transgenic rats and spread to the brain via the gut-brain axis. This led to microgliosis in the substantia nigra, creating a pro-inflammatory environment and inducing DANs degeneration. Gut-brain axis disruption may be a key determinant of progression to R1628P-PD in R1628P carriers. This insight has important clinical implications and highlights the importance of monitoring and addressing gut-brain axis integrity in individuals with LRRK2 mutations.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581174","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":"Comment on: \"Senolytic Treatment Improve Small Intestine Regeneration in Aging\".","authors":"Hirofumi Rokutan","doi":"10.14336/AD.2024.1262","DOIUrl":"https://doi.org/10.14336/AD.2024.1262","url":null,"abstract":"","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581006","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":"Modulation of Mitochondrial Dynamics by the Angiotensin System in Dopaminergic Neurons and Microglia.","authors":"Aloia Quijano, Ana I Rodriguez-Perez, María Alicia Costa-Besada, Andrea Lopez-Lopez, María J Guerra, Jose Luis Labandeira-Garcia, Rita Valenzuela","doi":"10.14336/AD.2024.0981","DOIUrl":"https://doi.org/10.14336/AD.2024.0981","url":null,"abstract":"<p><p>Renin-angiotensin system (RAS) dysfunctions have been associated to life-spam, and aging-related diseases, including neurodegenerative diseases, such as Parkinson's disease, and the neuroinflammatory associated processes. Mitochondrial dysfunctions play a major role in aging-related diseases, including dopaminergic neurodegeneration and neuroinflammation. However, the mechanisms of RAS/mitochondria interactions remain to be clarified. In the present work, we studied the role of major RAS components in the mitochondrial dynamics in dopaminergic neurons and microglia using in vitro and in vivo models. In dopaminergic neurons, we observed that activation of the RAS pro-oxidative/pro-inflammatory axis (Angiotensin II/Angiotensin type-1 receptor, AT1/NADPH oxidase complex) produces a dysregulation of mitochondrial dynamics towards mitochondrial fission, via Drp1 phosphorylation at Ser616 and translocation to mitochondria. However, activation of the RAS antioxidative/anti-inflammatory axis, using Angiotensin 1-7, counteracts this effect. RAS components also modulated the microglial inflammatory response through mitochondrial dynamic changes. After interferon-γ-induced activation of human microglial cells, we observed increased mitochondrial fission and superoxide production that was inhibited by Angiotensin 1-7 treatment. Angiotensin 1-7 also inhibited mitochondrial metabolic changes induced by pro-inflammatory microglial activation. The role of RAS in mitochondrial dynamic changes was confirmed in vivo using the LPS-induced inflammation model in wild-type, AT1-KO, and AT2-KO mice. The effect of Angiotensin 1-7 is mediated by IL-10, specifically by decreasing the post-transcriptional phosphorylated Drp1 form, and translocation of STAT3 to mitochondria. Angiotensin 1-7, acting on mitochondrial Angiotensin 1-7 receptors (Mas/Mas related receptors), increased the phosphorylated form of STAT3 at Ser727, which is mediated by mitochondrial PKA activation. In conclusion, the present findings show the role of RAS components in modulation of mitochondrial dynamics and mitochondrial function, revealing the associated signaling pathways. The results lead to better understanding of the effects of RAS dysfunction in aging-related diseases, and particularly dopaminergic degeneration and neuroinflammation in Parkinson's disease.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581237","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":"Time and Tissue Windows in Futile Reperfusion after Ischemic Stroke.","authors":"Zhe Cheng, Hongrui Wang, Xiaokun Geng, Gary B Rajah, Omar Elmadhoun, Guangge Peng, Yuchuan Ding","doi":"10.14336/AD.2024.1024","DOIUrl":"https://doi.org/10.14336/AD.2024.1024","url":null,"abstract":"<p><p>Reperfusion strategies such as vascular thrombolysis and thrombectomy are the first-line treatments recommended for acute ischemic stroke. However, only half of these patients achieve functional independence after endovascular reperfusion of large vessel occlusions. Timely restoration of blood flow is crucial, but not all reperfusion results in benefit, a phenomenon termed futile reperfusion. Futile reperfusion occurs when brain tissue has already suffered irreversible damage before reperfusion or when other factors undermine the benefits of restored blood flow. These factors include reperfusion-not rescued injury, reperfusion-induced injury, and the no-reflow phenomenon. The success of reperfusion therapies also hinges on timing and tissue condition after stroke. Defining these time and tissue windows more precisely could refine stroke interventions, potentially expanding effective reperfusion opportunities tailored to individual patients, thereby reducing the incidence of futile reperfusion. This perspective article delves into the complexities of futile reperfusion and the critical roles of time and tissue windows in determining stroke outcomes.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581368","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}