Aging and Disease最新文献

Alzheimer's disease (AD) is marked by extracellular beta-amyloid (Aβ) plaques and intracellular Tau tangles, leading to progressive cognitive decline and neuronal dysfunction. Impaired autophagy, a process by which a cell breaks down and destroys damaged or abnormal proteins and other substances, contributes to AD progression. This study investigated Nuclear Receptor Subfamily 1 Group D Member 1 (NR1D1) as a potential therapeutic target for modulating autophagy. We show that NR1D1 depletion significantly enhances autophagic flux and mitophagy in human cell lines as well as wildtype and AD Caenorhabditis elegans (C. elegans) models. Our findings revealed that NR1D1 knockdown increased autophagy markers and activated the proteins Sirtuin 1 (SIRT1) and CTSB cathepsin B (Cathepsin B), both linked to autophagy function. In 5 familial AD mutations (5xFAD) mice, Nr1d1 knockdown restored the expression level of autophagy markers. C. elegans experiments revealed that depletion of the worm ortholog of NR1D1, nhr-85, improved neuronal mitophagy, enhanced associative memory in amyloid-β models, and extended lifespan. These findings suggest NR1D1 as a promising therapeutic target for improving cellular autophagy mechanisms in AD.

The current one-dimensional view of pathological brain changes in older persons leading to cognitive complaints, mild cognitive impairment, and ultimately dementia is incomplete. It neglects the earliest, non-cognitive, and multifaceted symptoms of gradually accumulating cerebral damage. Subtle personality changes, balance problems, muscle wasting, weight loss, changing sleep patterns and declining blood pressure and cholesterol, precede memory problems and cognitive impairment. Chronic cerebral deterioration offers a new comprehensive concept, capturing symptoms across late-life cerebral dysfunction domains, and revising alleged dementia 'risk factors' more realistically into prodromal signs of cerebral deterioration. This may reduce research waste on dementia prevention unsuccessfully targeting prodromes and help identify people at the highest risk of developing care needs. It will improve counselling of older people with signs and symptoms when memory or other cognitive impairments are not yet present. Emphasizing total cerebral function over cognition alone focuses on what is clinically most relevant: the patient's need of care.

There is increasing pressure for researchers to reduce their reliance on animals, particularly in early-stage research. The main reason for that change arises from the different biological behavior of humans that leads to frequent failure of translating data from bench to bed. The advent of organoid technology ten years ago, along with the feasibility of obtaining brain organoids in most laboratories, has created considerable expectations not exempting frustration. In this review, we make a critical appraisal of the advantages and limitations of studying Alzheimer's disease in brain cortical organoids derived from inducible pluripotent stem cells (iPSCs). While dealing with human neurons and glia in 3D poses a tremendous advantage versus murine brain cells, organoids typically lack microglia, blood vessels, immune interactions as well as proper CNS neuropil. In turn, they have relatively few oligodendrocytes and low myelination. In addition, lengthy procedures to get proper mature organoids constitute an additional limitation that may also affect the native biological properties of neurons and glia. We conclude that human brain organoids, while popular and useful, remain a model that needs further refinement before bringing substantial value to study Alzheimer's disease.

Prehabilitation has become a field of increasing interest over recent decades. However, few studies specifically investigated prehabilitation for older patients with cancer. The objective of this umbrella review was to summarize evidence on prehabilitation programs to identify the physical interventions that may be applied with benefit to older cancer patients who will undergo complex medical-surgical procedures. The protocol was registered in Prospero. Major databases, namely PubMed, Embase, CINAHL, Cochrane, Web of Science and Prospero, were searched until summer 2020 and a second search was performed until November 2023. All systematic reviews and meta-analyses were included, dealing with the major topic of prehabilitation for older patients with cancer diagnosis. Among 1425 records (633 until 2020, 792 until November 2023), 14 reviews were selected for inclusion. According to the AMSTAR-2 checklist, the median quality score was 11 (range: 5-12). Total duration of prehabilitation ranged from 1 to 5 weeks, session duration from 20 to 50 minutes, session frequency from 3 to 6 per week. Reported program modes were aerobic and resistance exercises. Concerning the outcome measures, the functional as well as the respiratory status was significantly affected. Quality of life did not benefit significantly, but showed a positive trend. The length of hospital stay was not significantly improved in the majority of the studies. In contrast, most systematic reviews reported significantly lower numbers of total postoperative complications. Functional recovery was enhanced in half of the found reviews. Prehabilitation is a growing field, notably also in reviews focussing on oncological care for elderly patients included in this umbrella review. Aerobic and resistance exercises are the core of the majority of the programs evaluated but their characteristics (total duration, frequency) are partly heterogeneous. Prehabilitation for older patients may also include other modalities of geriatric interventions like nutritional or psychological optimization.

Autophagy in microglia is essential for the clearance of amyloid-beta (Aβ) and amyloid plaques in Alzheimer's disease. However, reports regarding the levels of autophagy in microglia have been inconsistent; some studies indicate an early enhancement followed by a subsequent reduction, while others describe a persistently weakened state. Notably, there is a lack of systematic studies documenting the temporal changes in microglial autophagy. TBC1D15, a Rab GTPase, plays a crucial role in lysosomal membrane repair, yet its function in regulating microglial autophagy in Alzheimer's disease remains unexplored. Current research suggests that microglial autophagy is activated in 3-month-old AD mice but gradually decreases by 12 months of age. Furthermore, TBC1D15 levels are significantly elevated in the lysosomes of microglia in Alzheimer's disease. Silencing TBC1D15 markedly inhibits swelling and Aβ phagocytosis in BV2 cells following Aβ treatment while simultaneously promoting autophagy and lysophagy. LIMP II/ATG8-TBC1D15-Dynamin2/RAB7 might participate in lysosome swelling of microglia in AD. These findings indicate that TBC1D15 in microglia is critical for the decline of autophagy in Alzheimer's disease. It is suggested that targeting microglial TBC1D15 may be an important strategy for enhancing autophagy, which facilitates the clearance of amyloid plaques as a therapeutic approach for Alzheimer's disease.

Alzheimer's disease (AD), a leading cause of dementia, is associated with significant respiratory dysfunctions. Our study explores the role of astrogliosis in the brainstem retrotrapezoid nucleus (RTN), a key breathing regulatory center, and its impact on breathing control and AD pathology in mice. Using Tg-2576 AD and wild-type mice, we investigated the effect of silencing the transforming growth factor-beta receptor II (TGFβR II) in the RTN. We performed behavioral tests, including the Barnes maze and novel object recognition test, along with whole-body plethysmography to assess breathing disorders. Our results showed that AD mice exhibited increased apneas and cognitive impairment, which were significantly mitigated following TGFβR II gene silencing. Immunohistochemistry revealed elevated levels of GFAP and TGFβR II in the RTN of AD mice, which were reduced post-gene silencing, alongside a decrease in amyloid-beta expression in the cortex and hippocampus. These findings suggest that targeting astrogliosis and improving respiratory control may offer a novel therapeutic avenue for managing Alzheimer's disease. Our study provides the first mechanistic insights into how TGFβ signaling influences both respiratory control and AD pathogenesis, highlighting the potential benefits of stabilizing breathing patterns in AD treatment.

Alzheimer's disease [AD] disproportionately affects our seniors, diminishing their health and life expectancy. As the world population grows older, the collective burden of AD has become unsustainable. Globally, there were 43.8 million patients in 2016, with a projection of affecting 152 million by 2050. Recent discoveries have shown that molecular changes characteristic to AD manifested 20 years before discernable neurological phenotypes emerge. It is feasible to halt or reverse this pathological process before reaching an irremediable stage. To take advantage of this treatment window, we need to make rapid progress in early detection and monitoring, targeted implementation of preventative measures, invention of novel therapeutics, and pragmatic ramping-up of relevant supporting policies. PET is a powerful tool for prognosis. The utilization of AI technology, on the other hand, has favorable features of low cost per capita, easy dissemination and broad scale data collection to uncover previously unknown hotspots or risk factors. FDA approved drugs, lecanemab and donanemab, have started to show efficacy to put a pause on AD progression. Additional clinical data will enable comprehensive evaluation of the impacts of these drugs. Gene therapy holds the potential of eliciting long term protection, while several candidate loci have been identified. The urgency of a tsunami of rising AD epidemiology demands rapid actions on all fronts of advanced diagnostics, monitoring, preventative and interventive strategies.

Obesity causes an imbalance in the expression and secretion of several organokines, which in turn contributes to the development of metabolic disorders such as type 2 diabetes mellitus. Organokines are produced by corresponding organs and affect systemic metabolic homeostasis. Diverse organokines play a crucial role in the communication between adipose tissue, skeletal muscle and other organs. In this review, we discuss the biological properties of specific organokines such as adipokines, hepatokines, and myokines. We also highlight the cumulative roles and crosstalk of organokines in obesity-related T2DM. Moreover, we attempt to identify the diagnostic and therapeutic potential of obesity-related T2DM from the perspective of organokines.

Inflammaging refers to chronic, low-grade inflammation that becomes more common with age and plays a central role in the pathophysiology of various vascular diseases. Key inflammatory mediators involved in inflammaging contribute to endothelial dysfunction and accelerate the progression of atherosclerosis. In addition, specific pathological mechanisms and the role of inflammasomes have emerged as critical drivers of immune responses within the vasculature. A comprehensive understanding of these processes may lead to innovative treatment strategies that could significantly improve the management of age-related vascular diseases. Emerging therapeutic approaches, including cytokine inhibitors, senolytics, and specialized pro-resolving mediators, aim to counteract inflammaging and restore vascular health. This review seeks to provide an in-depth exploration of the molecular pathways underlying vascular inflammaging and highlight potential therapeutic interventions.

The role of endogenous cannabinoids (endocannabinoids; eCBs) in cognitive-related processes has been demonstrated in preclinical studies. However, observational studies are lacking. We examined the associations of multiple circulating eCBs and eCB-like molecules with cognitive function in a sample of dementia-free older adults. In this exploratory, cross-sectional study, serum levels of 44 eCBs were analyzed in 237 older participants of the Framingham Heart Study Offspring cohort who attended examination cycle 9 (2011-2014). Linear regression models were used to examine the associations of eCB levels with cognitive function while adjusting for potential confounders and correcting for multiple testing. Effect modification by sex and apolipoprotein ε4 (ApoEε4) was additionally examined. Participants' mean age was 73.3±6.2y and 40% were men. After correction for multiple comparisons, increased levels of linoleic acid, linolenic acid, oleic acid, oleoyl alanine and palmitoyl alanine were associated with poorer executive function (B±SE=-0.0002±0.0001, p=0.002; B±SE=-0.0005±0.0001, p<0.001; B±SE=-0.0002±0.0001, p=0.003; B±SE=-0.74±0.25, p=0.003 and B±SE=-1.75±0.62, p=0.005, respectively). In addition, elevated levels of linolenoyl amide and linoleoyl amide were associated with poorer verbal memory (B±SE=-1.45±0.44, p=0.001 and B±SE=-0.16±0.05, p<0.001, respectively) and attention (B±SE=-0.12±0.04, p<0.001 and B±SE=-0.013±0.004, p<0.001, respectively). A significant interaction with sex was observed such that most of the above associations were present only among women. Furthermore, associations between several eCBs and perceptual organization were observed only among participants with ApoEε4 genotype. We identified novel eCB compounds that may be related to cognitive function. Validation of these findings is warranted and should consider sex and ApoEε4 interactions.