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.

Increased entropy is a common cause of disease and aging. Lifespan entropy is the overall increase in disorder caused by a person over their lifetime. Aging leads to the excessive production of reactive oxygen species (ROS), which damage the antioxidant system and disrupt redox balance. Organ aging causes chronic inflammation, disrupting the balance of proinflammatory and anti-inflammatory factors. Inflammaging, which is a chronic low-grade inflammatory state, is activated by oxidative stress and can lead to immune system senescence. During this process, entropy increases significantly as the body transitions from a state of low order to high disorder. However, the connection among inflammation, aging, and immune system activity is still not fully understood. This review introduces the idea of the ROS-inflammation-immune balance for the first time and suggests that this balance may be connected to aging and the development of age-related diseases. We also explored how the balance of these three factors controls and affects age-related diseases. Moreover, imbalance in the relationship described above disrupts the regular structures of cells and alters their functions, leading to cellular damage and the emergence of a disorganized state marked by increased entropy. Maintaining a low entropy state is crucial for preventing and reversing aging processes. Consequently, we examined the current preclinical evidence for antiaging medications that target this balance. Ultimately, comprehending the intricate relationships between these three factors and the risk of age-related diseases in organisms will aid in the development of clinical interventions that promote long-term health.

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.

Circadian rhythm is the internal homeostatic physiological clock that regulates the 24-hour sleep/wake cycle. This biological clock helps to adapt to environmental changes such as light, dark, temperature, and behaviors. Aging, on the other hand, is a process of physiological changes that results in a progressive decline in cells, tissues, and other vital systems of the body. Both aging and the circadian clock are highly interlinked phenomena with a bidirectional relationship. The process of aging leads to circadian disruptions while dysfunctional circadian rhythms promote age-related complications. Both processes involve diverse physiological, molecular, and cellular changes such as modifications in the DNA repair mechanisms, mechanisms, ROS generation, apoptosis, and cell proliferation. This review aims to examine the role of aging and circadian rhythms in the context of lung cancer. This will also review the existing literature on the role of circadian disruptions in the process of aging and vice versa. Various molecular pathways and genes such as BMAL1, SIRT1, HLF, and PER1 and their implications in aging, circadian rhythms, and lung cancer will also be discussed.

The gut-brain axis is a bidirectional communication pathway that modulates cognitive function. A dysfunctional gut-brain axis has been associated with cognitive impairments during aging. Therefore, we propose evaluating whether modulation of the gut microbiota through fecal microbiota transplantation (FMT) from young-trained donors (YT) to middle-aged or aged mice could enhance brain function and cognition in old age. Twelve-month-old male mice received an initial FMT from YT (YT-Tr) or age-matched donors (Auto-Tr) following antibiotic treatment. Three months later, the mice received a second FMT as reinforcement. Additionally, 18-month-old mice received Auto-Tr, YT-Tr, or FMT from young sedentary donors (YS-Tr). Cognitive function was assessed using novel object recognition and object location memory tests. Long-term potentiation (LTP) in hippocampal brain slices was studied, while neuroinflammation and synaptic plasticity were analyzed in hippocampal samples via qPCR and immunoblot. Gut permeability was evaluated in ileum and colon sections, serum samples were analyzed for cytokine levels, and fecal samples were used to measure short-chain fatty acid (SCFA) levels and perform 16S rRNA gene sequencing. We observed that YT-Tr, whether performed in middle age or old age, improved cognitive function in aged mice. Recognition and spatial memory were significantly enhanced in YT-Tr mice compared to Auto-Tr and YS-Tr groups. Intact LTP was observed in YT-Tr mice at 18 months of age, whereas LTP was impaired in the Auto-Tr group. Neuroinflammation was reduced, and synaptic plasticity modulators such as PSD-95 and FNDC5/Irisin were upregulated in the hippocampus of YT-Tr mice compared to both YS-Tr and Auto-Tr groups. A significant reduction in ileal and colon permeability was detected in YT-Tr animals, along with elevated cecal levels of butyrate and valerate compared to Auto-Tr. Moreover, YT-Tr decreased pro-inflammatory factors and increased anti-inflammatory factors in the serum of aged mice. Beta diversity analysis revealed significant differences in microbial community composition between YT-Tr and Auto-Tr animals, with higher abundances of Akkermansia, Prevotellaceae_UCG-001, and Odoribacter in YT-Tr mice. In conclusion, our study demonstrates that FMT from young-trained donors improves cognitive function and synaptic plasticity by modulating gut permeability, inflammation, SCFA levels, and gut microbiota composition in aged mice.

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.

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.

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.

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 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.

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.

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.

Osteoarthritis (OA) is a multifaceted degenerative joint disorder affected by various risk factors such as age, mechanical stress, inflammation, and metabolic influences. These elements contribute to its diverse phenotypes and endotypes, underscoring the disease's inherent complexity. The involvement of multiple tissues and their interplay further complicates OA's investigation. The current limitations in spatial phenotyping technologies, coupled with the intricate web of multifactorial interactions, have hindered the discovery of reliable early diagnostic markers and the development of tailored therapeutic strategies. However, recent advances in spatiotemporal analysis have revolutionised researchers' capacity to explore OA's spatiotemporal dynamics. These advancements provide unprecedented insights into the disease's progression, revealing patient-specific clinical presentations, tissue and joint structure alterations, and microscopic to molecular changes in tissue cell populations and extracellular matrices. This paper summarises the latest developments in utilising state-of-the-art technologies for the deep phenotyping of OA's spatiotemporal variations, emphasising their critical role in elucidating OA's pathophysiology and how this can change clinical practice and advancing personalised treatment approaches, and finally lead to better clinical outcomes.

Angina pectoris (AP), a clinical syndrome characterized by paroxysmal chest pain, is caused by insufficient blood supply to the coronary arteries and sudden temporary myocardial ischemia and hypoxia. Long-term AP typically induces other cardiovascular events, including myocardial infarction and heart failure, posing a serious threat to patient safety. However, AP's complex pathological mechanisms and developmental processes introduce significant challenges in the rapid diagnosis and accurate treatment of its different subtypes, including stable angina pectoris (SAP), unstable angina pectoris (UAP), and variant angina pectoris (VAP). Omics research has contributed significantly to revealing the pathological mechanisms of various diseases with the rapid development of high-throughput sequencing approaches. The application of multi-omics approaches effectively interprets systematic information on diseases from the perspective of genes, RNAs, proteins, and metabolites. Integrating multi-omics research introduces novel avenues for identifying biomarkers to distinguish different AP subtypes. This study reviewed articles related to multi-omics and AP to elaborate on the research progress in multi-omics approaches (including genomics, transcriptomics, proteomics, and metabolomics), summarized their applications in screening biomarkers employed to discriminate multiple AP subtypes, and delineated integration methods for multi-omics approaches. Finally, we discussed the advantages and disadvantages of applying a single-omics approach in distinguishing diverse AP subtypes. Our review demonstrated that the integration of multi-omics technologies is preferable for quick and precise diagnosis of the three AP types, namely SAP, UAP, and VAP.

Predicting health trajectories and accurately measuring aging processes across the human lifespan remain profound scientific challenges. Assessing the effectiveness and impact of interventions targeting aging is even more elusive, largely due to the intricate, multidimensional nature of aging-a process that defies simple quantification. Traditional biomarkers offer only partial perspectives, capturing limited aspects of the aging landscape. Yet, over the past decade, groundbreaking advancements have emerged. Epigenetic clocks, derived from DNA methylation patterns, have established themselves as powerful aging biomarkers, capable of estimating biological age and assessing aging rates across diverse tissues with remarkable precision. These clocks provide predictive insights into mortality and age-related disease risks, effectively distinguishing biological age from chronological age and illuminating enduring questions in gerontology. Despite significant progress in epigenetic clock development, substantial challenges remain, underscoring the need for continued investigation to fully unlock their potential in the science of aging.

With complex pathogenesis, Alzheimer's disease (AD) is a neurological illness that has worsened over time. Inter-organ crosstalk, which is essential for coordinating organ function and maintaining homeostasis, is involved in multiple physiological and pathological events. Increasing evidence suggests that AD is closely associated with multiple diseases of peripheral organs, including the gut, adipose tissue, liver, and bone. Despite numerous studies on AD, the ambiguous role of pathological peripheral organ-brain crosstalk in the development of AD remains incompletely understood, and the potential mechanisms remain obscure. This review summarizes the current knowledge of the relationship between AD and disorders of various organs from clinical and preclinical evidence. Additionally, we elucidate the mechanisms underlying AD development from the perspective of "organ-organ crosstalk", including the gut-brain, adipose tissue-brain, liver-brain and bone-brain axes. On the basis of the peripheral organ-brain crosstalk, we emphasize promising therapeutic targets with the hope of providing novel perspectives for AD management.

The negative effects of particulate matter up to 2.5 μm in diameter (PM) and their mediating mechanisms have been studied in various tissues. However, little is known about the mechanism and long-term tracking underlying the sex-dependent effects of PM on skeletal muscle system modulation. During youth, skeletal muscle grows rapidly and develops at its highest rate. Here we explore how exposure to atmospherically relevant levels of artificial PM affects the skeletal muscle system in 4-week-old C57BL6 mice according to sex and track the effects for 15 months post-exposure. We found that PM retarded muscle fiber growth and caused mitochondrial damage by modulating factors related to mitochondrial kinetics. However, the effects of PM on the modulation of the skeletal muscle system differed by sex and post-exposure time. The negative impacts of PM on skeletal muscle continued until they were overwhelmed by aging-related oxidative stress and inflammation, which were more severe in older PM-exposed female mice compared with male mice. Older PM-exposed female mice, but not older PM-exposed male mice, exhibited obesity-related phenotypes in the form of increased weight and fat mass. Overall, initial exposure to PM affected the skeletal muscle system with long-lasting impacts that differed according to sex.

The complex set of interactions between the immune system and metabolism, known as immunometabolism, has emerged as a critical regulator of disease outcomes in the central nervous system. Numerous studies have linked metabolic disturbances to impaired immune responses in brain aging, neurodegenerative disorders, and brain injury. In this review, we will discuss how disruptions in brain immunometabolism balance contribute to the pathophysiology of brain dysfunction. The first part of the review summarizes the contributions of critical immune cell populations such as microglia, astrocytes, and infiltrating immune cells in mediating inflammation and metabolism in CNS disorders. The remainder of the review addresses the impact of metabolic changes on immune cell activation and disease progression in brain aging, Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, spinal cord injury, and traumatic brain injury. Furthermore, we also address the therapeutic potential of targeting immunometabolic pathways to reduce neuroinflammation and slow disease progression. By focusing on the interactions among brain immune cells and the metabolic mechanisms they recruit in disease, we present a comprehensive overview of brain immunometabolism in human health and disease.

Vascular cognitive impairment and dementia (VCID), resulting from chronic cerebral hypoperfusion, represent the second most prevalent form of dementia globally. Aerobic exercise is widely acknowledged as an effective intervention for various cognitive disorders. This study utilized a bilateral common carotid artery stenosis (BCAS) model to investigate whether aerobic exercise promotes cognitive recovery through the Annexin-A1 (ANXA1)/mitogen-activated protein kinase (MAPK) axis in BCAS mice. Our findings demonstrate that aerobic exercise improved spatial memory in BCAS mice by enhancing white matter (WM) integrity and hippocampal function. WM integrity was confirmed through Luxol Fast Blue (LFB) staining and protein assays. Additionally, aerobic exercise mitigated BCAS-induced long-term potentiation (LTP) decay and upregulated hippocampal expression of key synaptic proteins, including N-methyl-D-aspartate receptor subunits NR2B and NR1, vesicular glutamate transporter 1 (vGluT1), and the synaptic scaffolding protein postsynaptic density protein 95 (PSD95). Furthermore, aerobic exercise enhanced the expression of the anti-inflammatory mediator ANXA1 through exosome secretion while simultaneously suppressing the MAPK signaling pathway. These molecular changes were associated with increased astrocyte proliferation and the polarization of astrocytes toward the A2 phenotype. These findings were further validated using an in vitro co-culture model of astrocytes (U251) and neurons (HT22). In summary, our study demonstrates that aerobic exercise improves WM integrity and hippocampal function by modulating the ANXA1/MAPK axis following astrocyte polarization. Thus, aerobic exercise emerges as a promising intervention for promoting functional recovery in VCID.

This review summarizes the mechanism and role of physical activity in maintaining the proper functioning of the musculoskeletal system. Bone adaptation to the mechanical environment occurs in skeletal regions subjected to the greatest stresses resulting from the nature of exercise, however, there is a varied response of bone tissue to mechanical loads depending on its material and structural properties (trabecular and cortical). The regulation of bone tissue metabolism during physical exercise is influenced by factors associated with mechanical stress (gravitational forces, impact loading, and muscular contractions) as well as by systemic mechanisms (hormones, myokines, cytokines). The presence of insulin receptors and glucose transporters in osteoblasts indicates that these cells consume large amounts of glucose. Therefore, when energy demand during physical activity increases, nutritional factors play an important role in bone response. On the other hand, the musculoskeletal system participates in the regulation of energy metabolism. To maintain bone homeostasis, an optimized form of physical activity should be used (e.g. intensity, duration, training session frequency). The complexity of factors modulating the sensitivity of bones to mechanical stimuli causes the results of physical training are age- and sex-dependent. Moreover, when selecting exercises to improve bone health, it is important to take into account metabolic and musculoskeletal system conditions. In addition, exercise should be safe and adapted to the health and fitness level so as not to increase the risk of fractures. Participation in regular physical activity should continue after the training program to maintain bone mass.