Aging and Disease最新文献

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.

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.

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.

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.

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.

Alzheimer's disease is an irreversible neurodegenerative disease that manifests clinically as memory loss and so on. Neuroinflammation plays an important role in Alzheimer's disease. Meanwhile, widely distributed throughout the central nervous system, substance P exhibits important pro-inflammatory properties. The level of substance P is found to correlate with the course of Alzheimer's disease. Substance P can modulate the protein hydrolysis of amyloid precursor protein, the voltage-gated potassium channel, and the protein hydrolysis of this channel, exerting neuroprotective effects. At the same time, substance P can also exert damaging effects by mediating neuroinflammation, inhibiting cellular autophagy, activating mast cells, acting on leukocytes and altering blood-brain barrier permeability. Based on the complex manifestations of substance P in Alzheimer's disease, this review discusses both protective and damaging mechanisms, and plausible explanations for the double-edged effect of substance P, providing an outlook for future research focusing on substance P and Alzheimer's disease.

Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. Aging is an important risk factor for eye diseases. The gradual deterioration of ocular tissue structure and function with age leads to the onset and progression of ocular diseases. During aging, ocular tissues such as the lens, vitreous and retina are affected by age-related changes, such as oxidative stress and protein accumulation in the lens leading to cataract formation, and a decline in retinal pigment epithelial cell function associated with macular degeneration. This article reviews the relationships between aging and ocular diseases, takes age-related macular degeneration, age-related cataracts, glaucoma, diabetic retinal degeneration, and dry eye disease as focal points, analyses the complex interactions between aging and ocular diseases, and describes the therapeutic options and potential targets for age-related ocular diseases.

Characterization of cognitive profiles across genetic FTD gene mutations is crucial for the identification of sensitive endpoints for clinical trials targeting specific pathologies. However, no systematic overview of the literature describing cognitive profiles in different FTD gene mutations has been made thus far. We performed a meta-analysis and systematic review to characterize cognitive profiles across the different FTD gene mutations and clinical disease stages of familial frontotemporal dementia (FTD). We included 27 studies comparing presymptomatic (n=1027), and/or symptomatic (n=574) mutation carriers (GRN, MAPT, C9orf72) with controls (n=1296). We extracted cognitive data and grouped them into six cognitive domains (language, attention and mental processing speed, executive function (EF), memory, social cognition, and visuospatial abilities). These domains were further subdivided into specific cognitive sub-processes. We calculated Hedges' g and performed multilevel meta-analyses per cognitive domain and FTD gene mutation comparing presymptomatic and symptomatic mutation carriers to controls. Moderator analyses were performed to the effect of age, education, sex, and cognitive subprocess. Eleven studies into rarer FTD mutations were included in the systematic review. Presymptomatic GRN mutation carriers showed deficits in EF, and presymptomatic C9orf72 mutation carriers in language, EF, and attention. Presymptomatic MAPT mutation carriers did not differ from controls on any of the cognitive domains. All symptomatic mutation carriers had deficits in language, EF, attention, and memory. Both in the presymptomatic and symptomatic stage cognitive sub-processes for language, attention and mental processing speed, EF, and memory were differentially affected in GRN, MAPT, and C9orf72. Cognitive decline was present in the presymptomatic stage of GRN and C9orf72 mutation carriers, but not MAPT mutation carriers. Unique cognitive sub-processes were affected in GRN, MAPT, and C9orf72. This study increased our knowledge of the cognitive deficits in familial FTD, which can aid in differential diagnosis and selection of endpoints for clinical trials.

With the continuous improvement of people's understanding of healthy aging, how to age decently and healthily has become a new topic of human exploration. Various factors make sarcopenia and dysphagia very common in the elderly, and the concept of "sarcopenic dysphagia" was born. This review synthesizes and extends the current understanding of sarcopenic dysphagia, emphasizing novel diagnostic and therapeutic strategies, particularly emerging technologies and multidisciplinary approaches. We begin by discussing pathophysiology and overlap with malnutrition and oral frailty. Next, we explore cutting-edge diagnostic tools and treatment modalities, focusing on how recent technological advancements have reshaped clinical practices. This review highlights the significance of integrating care across specialties, including nutrition, physical therapy, and speech-language pathology, to offer holistic care. It is hoped that our review will contribute to further understanding of sarcopenic dysphagia and thus provide new insights into promoting healthy aging in the elderly.