Aging and Disease最新文献

Decompressive craniotomy, a common intervention for traumatic brain injury (TBI), can fail to effectively alleviate patient symptoms. Cisternostomy, reported for cistern drainage in patients with severe brain injury (SBI), has shown efficacy in reducing intracranial pressure and clearing detritus resulting from brain hemorrhage. However, the mechanisms underlying their effectiveness remain largely unknown. Here, we utilized non-targeted metabolomics to analyze cerebrospinal fluid (CSF) from cisterns alongside peripheral blood samples from SBI patients undergoing cisternostomy. Through a systematic comparison of the cisternal cerebrospinal fluid and blood plasma metabolomes, we identified multiple blood-enriched metabolites, including betaine, triethanolamine, and proline, that were efficiently cleared during the early stage of SBI. Notably, two metabolites linked to arginine metabolism and the urea cycle, N8-acetylspermidine and N-acetylputrescine, showed significant reductions that correlated with improvements in the Glasgow Coma Scale (GCS). Our findings indicate that cisternostomy effectively removes blood-derived substances and aids the recovery of patients with early-stage brain injury.

Late-onset rheumatoid arthritis (LORA) refers to rheumatoid arthritis (RA) with initial symptoms and signs appearing after the age of 60 or 65. A higher frequency of HLA-DRB1*01:01, *04:03, and *14:02 alleles and a lower frequency of HLA-DRB1*04 are observed in patients with LORA compared to young-onset RA (YORA). Due to immunosenescence, the immune response in LORA differs from that in YORA. Specifically, in LORA, there is an increase in M1 macrophages and CD56^dim NK cells, whereas the numbers of M2 macrophages, Mer proto-oncogene tyrosine kinase, and CD56^bright NK cells are reduced. Elevated levels of age-related B cells in older individuals may contribute to more swollen and tender joints, as well as higher disease severity scores in LORA than in YORA. Additionally, impaired DNA repair mechanisms, an increased ratio of CD4⁺/CD8⁺ T cells, and elevated CD28^- T cells may contribute to a higher risk of both articular and extra-articular complications in LORA. Conventional disease-modifying antirheumatic drugs (DMARDs) used in LORA are similar to those used in YORA. Methotrexate is often the first choice for LORA; however, the dosage should be adjusted according to renal function. Biologic DMARDs is used less frequently in LORA than in YORA, as patients with LORA may be at a higher risk for serious infections. Furthermore, patients with LORA are at an increased risk of cardiovascular disease, fragility fractures, and malignancy compared to those with YORA; they also exhibit a higher prevalence of geriatric syndrome features. Furthermore, the use of antirheumatoid drugs can influence geriatric syndromes.

Obesity is a recognized risk factor for age-related cognitive decline, with central (abdominal) obesity posing a particular strong threat to brain health. In a cross-sectional study of 89 cognitively healthy adults (52-79 years, mean 65.7 ± 6.4; 58 women), we compared the effects of central versus overall obesity on brain connectivity measured with resting-state fMRI. We focused on network segregation, an index of functional specialization that captures the balance between connections within and across large-scale brain networks. Central obesity, but not overall obesity, was associated with reduced segregation in associative and sensorimotor networks, even after adjusting for overall obesity, highlighting the role of abdominal fat accumulation. To explore underlying mechanisms, we combined a widely used clinical index of peripheral insulin resistance (HOMA-IR) with multimodal neuroimaging, including structural MRI for cortical thickness, T1w/T2w MRI for intracortical myelin, FDG-PET for glucose metabolism, and FBB-PET for Aβ load. Mediation analyses showed that central obesity was associated with insulin resistance, which was related to alterations in intracortical myelin, cortical glucose metabolism, and cortical Aβ accumulation. These changes were collectively linked to reduced network segregation. Modeling cortical Aβ load as preceding cortical glucose metabolism further revealed stronger and more widespread network disruption, which may reflect bidirectional interactions between amyloid pathology and metabolic dysfunction. These findings describe a pattern of metabolic and structural brain changes linked to central obesity that may compromise brain functional integrity. Although causality cannot be inferred from this cross-sectional design, targeting abdominal fat and related metabolic factors could help preserve brain health and reduce cognitive vulnerability with aging.

Neuronal excitation/inhibition (E/I) imbalance, epileptiform activity, and synaptic dysfunction are present in individuals diagnosed with dementia, including sporadic Alzheimer's disease (sAD), even at early stages. These abnormalities are associated with altered neuronal oscillatory activity, as seen in EEG recordings of sAD patients and transgenic rodents. Hippocampal theta oscillations are crucial for sensorimotor integration, memory consolidation, and network coordination, and depend on synaptic and ionic mechanisms, including the Ih current, mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Lamotrigine (LTG), an HCN channel modulator, influences neuronal excitability and oscillations. Amyloid beta (Aβ) peptide, specifically Aβ1-42 form plays a key role in AD pathology, promoting hyperexcitability, synaptic dysfunction, and neurodegeneration, particularly in the hippocampus (HPC) and associative cortices. However, only a few electrophysiological studies have examined HPC theta in relation to early cognitive deficits in sAD animal models. Our first goal was to study the temporal progression of theta oscillations impairment following repeated unilateral intracerebroventricular (ICV) Aβ1-42 infusions in rats at 7, 14, and 21 days, in vivo and in vitro. Second, we assessed whether local LTG administration could restore theta oscillations and long-term potentiation (LTP) in this model. We found that: i) Aβ1-42 ICV infusions led to significant reductions in theta amplitude and power on days 7 and 14, with a complete loss by day 21; ii) LTG restored LTP and theta rhythms in terms of power and amplitude in HPC obtained from Aβ1-42-treated animals 14 days post-ICV infusion; iii) histological analysis confirmed neurodegeneration, Tau hyperphosphorylation, astrogliosis, increased number of parvalbimun positive (PV+) interneurons, and GluN2B receptor upregulation in HPC of Aβ1-42-treated animals 14 days post-ICV infusion. These findings suggest that hippocampal theta disruption may serve as an early biomarker of network dysfunction in sAD, and that LTG-mediated partial restoration of theta and LTP offers a potential early therapeutic strategy.

The intricate crosstalk between epigenetic modification and regulated cell death (RCD) constitutes a pivotal yet underexplored axis in aging and its associated diseases. This Perspective conceptualizes age-related epigenetic reprogramming as a master switch that recalibrates the execution thresholds of diverse RCD pathways-including pyroptosis, ferroptosis, cuproptosis, necroptosis, and autophagy-dependent cell death-across multiple organ systems. We systematically decode how this epigenetic-RCD axis drives the pathophysiology of major aging-related conditions, such as diabetes, neurodegenerative disorders, cardiovascular diseases, and cancer, by synthesizing evidence of how DNA methylation, histone modifications, chromatin remodeling, non-coding RNAs, and RNA methylation intricately govern RCD networks. Building upon this mechanistic framework, the therapeutic potential of targeting this axis is critically examined, highlighting both emerging opportunities and translational challenges for future intervention strategies. Our analysis provides a novel paradigm for understanding aging mechanisms and proposes a roadmap for developing next-generation therapeutics.

Due to baseline differences in cognitive test performance and their variable capacity to predict progression from Mild Cognitive Impairment (MCI) to Alzheimer's disease (AD), this systematic review and meta-analysis aimed to identify the most frequently used neuropsychological tests and their predictive value. Given the high prevalence of MCI, identifying accurate diagnostic tools is crucial. This study examined cognitive test differences between MCI patients and healthy individuals in clinical studies. A random-effects meta-analysis was conducted to account for variability. To this end, a comprehensive search was conducted across PubMed, Scopus, ScienceDirect, and Cochrane databases. Of the 103 studies that met the inclusion criteria and were reviewed, 34 were excluded from the meta-analysis due to the absence of control groups, and 7 articles were excluded because there were not enough comparable studies to perform a meaningful analysis. The meta-analysis revealed significant cognitive impairment in global cognition, language, and emotional well-being. Some studies reported hippocampal atrophy and amyloid-β/tau deposition in MCI patients progressing to AD, while others found benefits from physical and cognitive training. These findings highlight the need for standardized cognitive assessments to identify MCI patients at risk of AD conversion and implement effective treatments. Nevertheless, this meta-analysis faced limitations due to missing patient data, including the MCI subtype and disease duration.

The goal of this study was to determine if measures of healthspan, which have been shown to decline with age, are associated with and predict mortality. We measured voluntary running activity, spontaneous activity, and cognition in male and female C57BL/6 mice at 26- to 28-months of age followed by analysis of the survival of each mouse. Voluntary running activity was positively associated with age at death in both male and female mice; however, only 14 to 21% of the variance in lifespan was explained by running wheel performance. In contrast, cognitive parameters assessed during a working memory paradigm were not predictive of lifespan, despite a negative correlation with day-time activity, suggesting an important relationship between quality of sleep and cognition. Finally, using a multiple regression model to identify the best predictors of longevity we found that a combination of various independent variables of activity and cognition predicted 55% and 21% of the lifespan of female and male mice, respectively. These data highlight the importance of movement parameters and day-time activity in mice that influence healthspan and lifespan.

Cardiovascular disease (CVD) remains the leading cause of global mortality and disability. As an inevitable risk factor, cardiac aging significantly exacerbates the incidence and progression of age-related cardiovascular pathologies, including coronary artery disease, cardiomyopathies, and heart failure in the elderly population. Mitochondria function as central organelles in cardiac energy metabolism. Dysregulation of functional homeostasis, characterized by impaired quality control mechanisms, such as diminished energy production efficiency and exacerbated oxidative stress, is a primary driver of the cardiac aging process. Accumulating evidence in recent years indicates that sirtuin 1 (SIRT1) plays a crucial role in regulating cardiac aging. A range of therapeutic agents, including natural compounds and synthetic molecules, ameliorate cardiac aging and related pathologies by activating SIRT1 to modulate mitochondrial function. This review systematically summarizes the emerging roles of SIRT1 in cardiac aging, with a focus on the molecular mechanisms through which SIRT1 governs mitochondrial homeostasis. We also highlight recent advances in SIRT1-targeted therapeutic strategies, thereby providing a theoretical basis and translational perspectives for preventing and treating cardiac aging-related diseases.

Microglial replacement is emerging as a promising concept for treating age-related disorders, but effects on epigenetic age remain unclear. Here, we examined DNA methylation dynamics in microglia from young and old mice and evaluated how ischemic stroke and microglial depletion/repopulation (D/R) influence their epigenetic landscape. Using epigenetic clocks, we confirmed that old microglia display an aged DNA methylation profile, consistent with functional decline. Both stroke and microglial D/R induced an acceleration of epigenetic age, likely reflecting proliferative stress associated with these conditions. However, genome-wide methylation profiling using DNA methylation arrays revealed that microglial repopulation also reversed a large fraction of age-associated DNA methylation changes, particularly within pathways related to immune activation and inflammatory responses. These findings suggest that microglial D/R, though linked to epigenetic age acceleration, leads to the widespread reversal of aging-associated DNA methylation changes, which may help explain the beneficial outcomes observed after microglial replacement. Overall, our results highlight the complexity of interpreting epigenetic age measures and underscore the potential of microglial replacement strategies for brain rejuvenation.